Addiction

<h2 id="signs-and-symptoms">Signs and symptoms</h2>
<a href="/facts/Signs_and_symptoms/BzP6MrTN">Signs and symptoms</a> of drug addiction can vary depending on the type of addiction. Symptoms may include:

<ul><li>Continuation of drug use despite the knowledge of consequences<a class="footnote-ref" id="fnref:14" href="#fn:14">14</a></li>
<li>Disregarding financial status when it comes to drug purchases</li>
<li>Ensuring a stable supply of the drug</li>
<li>Needing more of the drug over time to achieve similar effects<a class="footnote-ref" id="fnref:15" href="#fn:15">15</a></li>
<li>Social and work life impacted due to drug use<a class="footnote-ref" id="fnref:16" href="#fn:16">16</a></li>
<li>Unsuccessful attempts to stop drug use<a class="footnote-ref" id="fnref:17" href="#fn:17">17</a></li>
<li>Urge to use drug regularly</li></ul>
Other signs and symptoms can be categorized across relevant dimensions:

<table><tbody><tr><th>Behavioral Changes</th><th>Physical Changes</th><th>Social Changes</th></tr><tr><td><ul><li>Angry and irritable</li><li>Changes to eating or sleeping habits</li><li>Changes to personality and attitude</li><li>Decreased attendance and performance in workplace or school setting<a class="footnote-ref" id="fnref:18" href="#fn:18">18</a></li><li>Fearful, paranoid and anxious without probable cause<a class="footnote-ref" id="fnref:19" href="#fn:19">19</a></li><li>Frequently engaging in conflicts (fights, illegal activity)</li><li>Frequent or sudden changes in mood and temperament</li><li>Hiding or in denial of certain behaviors</li><li>Lack of motivation</li><li>Periodic hyperactivity</li><li>Using substances in inappropriate settings</li></ul></td><td><ul><li>Abnormal pupil size</li><li>Bloodshot eyes</li><li>Body odor</li><li>Impaired motor coordination<a class="footnote-ref" id="fnref:20" href="#fn:20">20</a></li><li>Periodic tremors</li><li>Poor physical appearance</li><li>Slurred speech</li><li>Sudden changes in weight</li></ul></td><td><ul><li>Changes in hobbies</li><li>Changes to financial status (unexplained need for money)</li><li>Legal problems related to substance abuse</li><li>Sudden changes in friends and associates</li><li>Use of substance despite consequences to personal relationships<a class="footnote-ref" id="fnref:21" href="#fn:21">21</a></li></ul></td></tr></tbody></table>
<h2 id="substance-addiction">Substance addiction</h2>
Main article: <a href="/facts/Substance_use_disorder/pSbdzb6a">Substance use disorder</a>
Further information: <a href="/facts/Substance_abuse/e3jLXFsF">Substance abuse</a> and <a href="/facts/Substance-related_disorder/YTcrDILK">Substance-related disorder</a>

<h3>Drug addiction</h3>
<a href="/facts/Substance_use_disorder/pSbdzb6a">Drug addiction</a>, which belongs to the class of <a href="/facts/Substance-related_disorder/YTcrDILK">substance-related disorders</a>, is a chronic and relapsing brain disorder that features drug seeking and drug abuse, despite their harmful effects.<a class="footnote-ref" id="fnref:22" href="#fn:22">22</a> This form of addiction changes brain circuitry such that the brain's reward system is compromised,<a class="footnote-ref" id="fnref:23" href="#fn:23">23</a> causing functional consequences for stress management and self-control.<a class="footnote-ref" id="fnref:24" href="#fn:24">24</a> Damage to the functions of the organs involved can persist throughout a lifetime and cause death if untreated.<a class="footnote-ref" id="fnref:25" href="#fn:25">25</a> Substances involved with drug addiction include alcohol, nicotine, marijuana, opioids, cocaine, amphetamines, and even foods with high fat and sugar content.<a class="footnote-ref" id="fnref:26" href="#fn:26">26</a> Addictions can begin experimentally in social contexts<a class="footnote-ref" id="fnref:27" href="#fn:27">27</a> and can arise from the use of prescribed medications or a variety of other measures.<a class="footnote-ref" id="fnref:28" href="#fn:28">28</a>
Drug addiction has been shown to work in <a href="/facts/Phenomenology_(psychology)/Rse4u0LN">phenomenological</a>, conditioning (<a href="/facts/Operant_conditioning/8TqfQQGq">operant</a> and <a href="/facts/Classical_conditioning/ddtohoz3">classical</a>), cognitive models, and the <a href="/facts/Cue_reactivity/8bb173ad">cue reactivity</a> model. However, no one model completely illustrates substance abuse.<a class="footnote-ref" id="fnref:29" href="#fn:29">29</a>
Risk factors for addiction include:

<ul><li>Aggressive behavior (particularly in childhood)</li>
<li>Availability of substance<a class="footnote-ref" id="fnref:30" href="#fn:30">30</a></li>
<li>Community economic status</li>
<li>Experimentation<a class="footnote-ref" id="fnref:31" href="#fn:31">31</a></li>
<li><a href="/facts/Epigenetics/UfAAERcn">Epigenetics</a></li>
<li><a href="/facts/Impulsivity/WrjoEyg5">Impulsivity</a> (attentional, motor, or non-planning)<a class="footnote-ref" id="fnref:32" href="#fn:32">32</a></li>
<li>Lack of parental supervision<a class="footnote-ref" id="fnref:33" href="#fn:33">33</a></li>
<li>Lack of peer refusal skills<a class="footnote-ref" id="fnref:34" href="#fn:34">34</a></li>
<li>Mental disorders<a class="footnote-ref" id="fnref:35" href="#fn:35">35</a></li>
<li>Method substance is taken<a class="footnote-ref" id="fnref:36" href="#fn:36">36</a></li>
<li>Usage of substance in youth<a class="footnote-ref" id="fnref:37" href="#fn:37">37</a></li></ul>
<h3>Food addiction</h3>
Main article: <a href="/facts/Food_addiction/e4ogL5xj">Food addiction</a>
The diagnostic criteria for food or eating addiction has not been categorized or defined in references such as the <a href="/facts/Diagnostic_and_Statistical_Manual_of_Mental_Disorders/pJ29wFmm">Diagnostic and Statistical Manual of Mental Disorders</a> (DSM or DSM-5) and is based on subjective experiences similar to substance use disorders.<a class="footnote-ref" id="fnref:38" href="#fn:38">38</a><a class="footnote-ref" id="fnref:39" href="#fn:39">39</a> Food addiction may be found in those with eating disorders, though not all people with eating disorders have food addiction and not all of those with food addiction have a diagnosed eating disorder.<a class="footnote-ref" id="fnref:40" href="#fn:40">40</a> Long-term frequent and excessive consumption of foods high in fat, salt, or sugar, such as chocolate, can produce an addiction<a class="footnote-ref" id="fnref:41" href="#fn:41">41</a><a class="footnote-ref" id="fnref:42" href="#fn:42">42</a> similar to drugs since they trigger the brain's reward system, such that the individual may desire the same foods to an increasing degree over time.<a class="footnote-ref" id="fnref:43" href="#fn:43">43</a><a class="footnote-ref" id="fnref:44" href="#fn:44">44</a><a class="footnote-ref" id="fnref:45" href="#fn:45">45</a> The signals sent when consuming highly palatable foods have the ability to counteract the body's signals for fullness and persistent cravings will result.<a class="footnote-ref" id="fnref:46" href="#fn:46">46</a> Those who show signs of food addiction may develop food tolerances, in which they eat more, despite the food becoming less satisfactory.<a class="footnote-ref" id="fnref:47" href="#fn:47">47</a>
Chocolate's sweet flavor and pharmacological ingredients are known to create a strong craving or feel 'addictive' by the consumer.<a class="footnote-ref" id="fnref:48" href="#fn:48">48</a> A person who has a strong liking for chocolate may refer to themselves as a <a href="/facts/Chocoholic/Vb08rhXz">chocoholic</a>.
Risk factors for developing food addiction include excessive <a href="/facts/Overeating/gmlaYUv2">overeating</a> and impulsivity.<a class="footnote-ref" id="fnref:49" href="#fn:49">49</a>
The <a href="/facts/Yale_Food_Addiction_Scale/tdqnFddB">Yale Food Addiction Scale</a> (YFAS), version 2.0, is the current standard measure for assessing whether an individual exhibits signs and symptoms of food addiction.<a class="footnote-ref" id="fnref:50" href="#fn:50">50</a><a class="footnote-ref" id="fnref:51" href="#fn:51">51</a><a class="footnote-ref" id="fnref:52" href="#fn:52">52</a> It was developed in 2009 at <a href="/facts/Yale_University/KUdS6jt1">Yale University</a> on the hypothesis that foods high in fat, sugar, and salt have addictive-like effects which contribute to problematic eating habits.<a class="footnote-ref" id="fnref:53" href="#fn:53">53</a><a class="footnote-ref" id="fnref:54" href="#fn:54">54</a> The YFAS is designed to address 11 substance-related and addictive disorders (SRADs) using a 25-item self-report questionnaire, based on the diagnostic criteria for SRADs as per DSM-5.<a class="footnote-ref" id="fnref:55" href="#fn:55">55</a><a class="footnote-ref" id="fnref:56" href="#fn:56">56</a> A potential food addiction diagnosis is predicted by the presence of at least two out of 11 SRADs and a significant impairment to daily activities.<a class="footnote-ref" id="fnref:57" href="#fn:57">57</a>
The <a href="/facts/Barratt_Impulsiveness_Scale/S7tW2XlN">Barratt Impulsiveness Scale</a>, specifically the BIS-11 scale, and the <a href="/facts/Impulsivity/WrjoEyg5">UPPS-P Impulsive Behavior</a> subscales of Negative Urgency and Lack of Perseverance have been shown to have relation to food addiction.<a class="footnote-ref" id="fnref:58" href="#fn:58">58</a>

<h2 id="behavioral-addiction">Behavioral addiction</h2>
Main article: <a href="/facts/Behavioral_addiction/yQbYGfQj">Behavioral addiction</a>
The term behavioral addiction refers to a <a href="/facts/Compulsive_behavior/89bgqdzs">compulsion</a> to engage in a <a href="/facts/Natural_reward/yQbYGfQj">natural reward</a> – which is a behavior that is inherently rewarding (i.e., desirable or appealing) – despite adverse consequences.<a class="footnote-ref" id="fnref:59" href="#fn:59">59</a><a class="footnote-ref" id="fnref:60" href="#fn:60">60</a><a class="footnote-ref" id="fnref:61" href="#fn:61">61</a> Preclinical evidence has demonstrated that marked increases in the expression of <a href="/facts/%25CE%2594FosB/KHElvauK">ΔFosB</a> through repetitive and excessive exposure to a natural reward induces the same behavioral effects and <a href="/facts/Neuroplasticity/c0o0fvVm">neuroplasticity</a> as occurs in a drug addiction.<a class="footnote-ref" id="fnref:62" href="#fn:62">62</a><a class="footnote-ref" id="fnref:63" href="#fn:63">63</a><a class="footnote-ref" id="fnref:64" href="#fn:64">64</a><a class="footnote-ref" id="fnref:65" href="#fn:65">65</a>
Addiction can exist without psychotropic drugs, an idea that was popularized by psychologist <a href="/facts/Stanton_Peele/ko5VRBEV">Stanton Peele</a>.<a class="footnote-ref" id="fnref:66" href="#fn:66">66</a> These are termed behavioral addictions. Such addictions may be passive or active, but they commonly contain reinforcing features, which are found in most addictions.<a class="footnote-ref" id="fnref:67" href="#fn:67">67</a> Sexual behavior, eating, gambling, playing video games, and shopping are all associated with compulsive behaviors in humans and have been shown to activate the mesolimbic pathway and other parts of the reward system.<a class="footnote-ref" id="fnref:68" href="#fn:68">68</a> Based on this evidence, <a href="/facts/Sexual_addiction/WmK1GnHJ">sexual addiction</a>, <a href="/facts/Gambling_addiction/1d3Uygzb">gambling addiction</a>, <a href="/facts/Video_game_addiction/BlElxadE">video game addiction</a>, and <a href="/facts/Shopping_addiction/nskafozI">shopping addiction</a> are classified accordingly.<a class="footnote-ref" id="fnref:69" href="#fn:69">69</a>

<h2 id="causes">Causes</h2>
<h3>Personality theories</h3>
Main article: <a href="/facts/Personality_theories_of_addiction/FBzcgz1B">Personality theories of addiction</a>
<a href="/facts/Personality_theories_of_addiction/FBzcgz1B">Personality theories of addiction</a> are <a href="/facts/Psychology/duoqW7Sz">psychological models</a> that associate <a href="/facts/Personality_traits/Iun5UFdX">personality traits</a> or modes of thinking (i.e., <a href="/facts/Affective_science/uYCq1RlW">affective states</a>) with an individual's proclivity for developing an addiction. <a href="/facts/Data_analysis/CNtARxLW">Data analysis</a> demonstrates that psychological profiles of drug users and non-users have significant differences and the psychological predisposition to using different drugs may be different.<a class="footnote-ref" id="fnref:70" href="#fn:70">70</a> Models of addiction risk that have been proposed in psychology literature include: an <a href="/facts/Affect_dysregulation/lyXjLExE">affect dysregulation</a> model of positive and negative <a href="/facts/Psychological_affect/jEQ6IWSm">psychological affects</a>, the <a href="/facts/Reinforcement_sensitivity_theory/fHVkxCr4">reinforcement sensitivity theory</a> of <a href="/facts/Impulsiveness/WrjoEyg5">impulsiveness</a> and behavioral inhibition, and an impulsivity model of reward sensitization and impulsiveness.<a class="footnote-ref" id="fnref:71" href="#fn:71">71</a><a class="footnote-ref" id="fnref:72" href="#fn:72">72</a><a class="footnote-ref" id="fnref:73" href="#fn:73">73</a><a class="footnote-ref" id="fnref:74" href="#fn:74">74</a><a class="footnote-ref" id="fnref:75" href="#fn:75">75</a>

<h3>Neuropsychology</h3>
The <a href="/facts/Transtheoretical_model/xCDs6Il0">transtheoretical model</a> of change (TTM) can point to how someone may be conceptualizing their addiction and the thoughts around it, including not being aware of their addiction.<a class="footnote-ref" id="fnref:76" href="#fn:76">76</a>
<a href="/facts/Cognitive_control/QtflLj55">Cognitive control</a> and <a href="/facts/Stimulus_control/SrFGBFMw">stimulus control</a>, which is associated with <a href="/facts/Operant_conditioning/8TqfQQGq">operant</a> and <a href="/facts/Classical_conditioning/ddtohoz3">classical conditioning</a>, represent opposite processes (i.e., internal vs external or environmental, respectively) that compete over the control of an individual's elicited behaviors.<a class="footnote-ref" id="fnref:77" href="#fn:77">77</a> Cognitive control, and particularly <a href="/facts/Inhibitory_control/XD74uhFc">inhibitory control over behavior</a>, is impaired in both addiction and <a href="/facts/Attention_deficit_hyperactivity_disorder/uSqjIyhd">attention deficit hyperactivity disorder</a>.<a class="footnote-ref" id="fnref:78" href="#fn:78">78</a><a class="footnote-ref" id="fnref:79" href="#fn:79">79</a> Stimulus-driven behavioral responses (i.e., stimulus control) that are associated with a particular <a href="/facts/Rewarding_stimulus/fotI0rcM">rewarding stimulus</a> tend to dominate one's behavior in an addiction.<a class="footnote-ref" id="fnref:80" href="#fn:80">80</a>

<table><tbody><tr><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="6" rowspan="2"><a href="/facts/Operant_conditioning/8TqfQQGq">Operant conditioning</a></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="6" rowspan="2"><a href="/facts/Extinction_(psychology)/sKmrjKa8">Extinction</a></td></tr><tr></tr><tr><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td></td><td></td><td colspan="2"></td><td colspan="2"></td><td colspan="2"></td><td></td><td></td><td colspan="2"></td><td colspan="2"></td><td></td><td rowspan="2"></td></tr><tr><td></td><td></td><td colspan="2"></td><td colspan="2"></td><td colspan="2"></td><td colspan="2"></td><td colspan="2"></td><td colspan="2"></td><td></td></tr><tr><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="6" rowspan="2"><a href="/facts/Reinforcement/bn271VLa">Reinforcement</a>Increase behavior</td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="6" rowspan="2"><a href="/facts/Punishment_(psychology)/kIBdlS9Y">Punishment</a>Decrease behavior</td></tr><tr></tr><tr><td colspan="2" rowspan="2"></td><td></td><td></td><td colspan="2"></td><td></td><td></td><td colspan="2"></td><td></td><td rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td></td><td></td><td colspan="2"></td><td></td><td></td><td colspan="2"></td><td></td><td rowspan="2"></td></tr><tr><td></td><td></td><td colspan="2"></td><td colspan="2"></td><td colspan="2"></td><td></td><td></td><td></td><td colspan="2"></td><td colspan="2"></td><td colspan="2"></td><td></td></tr><tr><td colspan="6" rowspan="2"><a href="/facts/Positive_reinforcement/bn271VLa">Positive reinforcement</a>Add appetitive stimulusfollowing correct behavior</td><td colspan="2" rowspan="2"></td><td colspan="6" rowspan="2"><a href="/facts/Negative_reinforcement/bn271VLa">Negative reinforcement</a></td><td colspan="2" rowspan="2"></td><td colspan="6" rowspan="2"><a href="/facts/Positive_punishment/kIBdlS9Y">Positive punishment</a>Add noxious stimulusfollowing behavior</td><td colspan="2" rowspan="2"></td><td colspan="6" rowspan="2"><a href="/facts/Negative_punishment/kIBdlS9Y">Negative punishment</a>Remove appetitive stimulusfollowing behavior</td></tr><tr></tr><tr><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td></td><td></td><td colspan="2"></td><td></td><td></td><td colspan="2"></td><td></td><td rowspan="2"></td></tr><tr><td></td><td></td><td colspan="2"></td><td colspan="2"></td><td colspan="2"></td><td></td></tr><tr><td colspan="2" rowspan="2"></td><td colspan="2" rowspan="2"></td><td colspan="6" rowspan="2"><a href="/facts/Escape_response/AlgghCqD">Escape</a>Remove noxious stimulusfollowing correct behavior</td><td colspan="2" rowspan="2"></td><td colspan="6" rowspan="2"><a href="/facts/Avoidance_response/8sANL4Ho">Active avoidance</a>Behavior avoids noxious stimulus</td></tr><tr></tr></tbody></table>

<h4>Stimulus control of behavior</h4>
See also: <a href="/facts/Stimulus_control/SrFGBFMw">Stimulus control</a>
In operant conditioning, behavior is influenced by outside stimulus, such as a drug. The operant conditioning theory of learning is useful in understanding why the mood-altering or stimulating consequences of drug use can reinforce continued use (an example of <a href="/facts/Positive_reinforcement/bn271VLa">positive reinforcement</a>) and why the addicted person seeks to avoid withdrawal through continued use (an example of <a href="/facts/Negative_reinforcement/bn271VLa">negative reinforcement</a>). Stimulus control is using the absence of the stimulus or presence of a reward to influence the resulting behavior.<a class="footnote-ref" id="fnref:81" href="#fn:81">81</a>

<h4>Cognitive control of behavior</h4>
See also: <a href="/facts/Cognitive_control/QtflLj55">Cognitive control</a>
Cognitive control is the intentional selection of thoughts, behaviors, and emotions, based on our environment. It has been shown that drugs alter the way our brains function, and its structure.<a class="footnote-ref" id="fnref:82" href="#fn:82">82</a><a class="footnote-ref" id="fnref:83" href="#fn:83">83</a> Cognitive functions such as learning, memory, and impulse control, are affected by drugs.<a class="footnote-ref" id="fnref:84" href="#fn:84">84</a> These effects promote drug use, as well as hinder the ability to abstain from it.<a class="footnote-ref" id="fnref:85" href="#fn:85">85</a> The increase in dopamine release is prominent in drug use, specifically in the <a href="/facts/Ventral_striatum/MjNnTjSd">ventral striatum</a> and the <a href="/facts/Nucleus_accumbens/2M43u5X4">nucleus accumbens</a>.<a class="footnote-ref" id="fnref:86" href="#fn:86">86</a> Dopamine is responsible for producing pleasurable feelings, as well driving us to perform important life activities. Addictive drugs cause a significant increase in this reward system, causing a large increase in dopamine signaling as well as increase in reward-seeking behavior, in turn motivating drug use.<a class="footnote-ref" id="fnref:87" href="#fn:87">87</a><a class="footnote-ref" id="fnref:88" href="#fn:88">88</a> This promotes the development of a maladaptive drug to stimulus relationship.<a class="footnote-ref" id="fnref:89" href="#fn:89">89</a> Early drug use leads to these maladaptive associations, later affecting cognitive processes used for coping, which are needed to successfully abstain from them.<a class="footnote-ref" id="fnref:90" href="#fn:90">90</a><a class="footnote-ref" id="fnref:91" href="#fn:91">91</a>

<h2 id="risk-factors">Risk factors</h2>
Further information: <a href="/facts/Addiction_vulnerability/BB5XvP0q">Addiction vulnerability</a>
A number of genetic and environmental risk factors exist for developing an addiction.<a class="footnote-ref" id="fnref:92" href="#fn:92">92</a><a class="footnote-ref" id="fnref:93" href="#fn:93">93</a> Genetic and environmental risk factors each account for roughly half of an individual's risk for developing an addiction;<a class="footnote-ref" id="fnref:94" href="#fn:94">94</a> the contribution from epigenetic risk factors to the total risk is unknown.<a class="footnote-ref" id="fnref:95" href="#fn:95">95</a> Even in individuals with a relatively low genetic risk, exposure to sufficiently high doses of an addictive drug for a long period of time (e.g., weeks–months) can result in an addiction.<a class="footnote-ref" id="fnref:96" href="#fn:96">96</a> Adverse childhood events are associated with negative health outcomes, such as substance use disorder. Childhood abuse or exposure to violent crime is related to developing a mood or anxiety disorder, as well as a substance dependence risk.<a class="footnote-ref" id="fnref:97" href="#fn:97">97</a>

<h3>Genetic factors</h3>
Main articles: <a href="/facts/Epigenetics_of_cocaine_addiction/WRkHL6JS">Epigenetics of cocaine addiction</a> and <a href="/facts/Molecular_and_epigenetic_mechanisms_of_alcoholism/aReKpNgl">Molecular and epigenetic mechanisms of alcoholism</a>
Further information: <a href="/facts/Alcoholism/KGPzpChp">Alcoholism § Genetic variation</a>, <a href="/facts/History_of_drinking/znlyymAq">History of drinking</a>, <a href="/facts/History_of_smoking/g5U4J6nN">History of smoking</a>, and <a href="/facts/Prevalence_of_tobacco_use/BFL4kJ77">Prevalence of tobacco use</a>
Genetic factors, along with <a href="/facts/Social/twVnad19">socio</a>-environmental (e.g., <a href="/facts/Biopsychosocial_model/bCKxyD5s">psychosocial</a>) factors, have been established as significant contributors to addiction vulnerability.<a class="footnote-ref" id="fnref:98" href="#fn:98">98</a><a class="footnote-ref" id="fnref:99" href="#fn:99">99</a><a class="footnote-ref" id="fnref:100" href="#fn:100">100</a><a class="footnote-ref" id="fnref:101" href="#fn:101">101</a> Studies done on 350 hospitalized drug-dependent patients showed that over half met the criteria for alcohol abuse, with a role of familial factors being prevalent.<a class="footnote-ref" id="fnref:102" href="#fn:102">102</a> Genetic factors account for 40–60% of the risk factors for alcoholism.<a class="footnote-ref" id="fnref:103" href="#fn:103">103</a> Similar rates of heritability for other types of drug addiction have been indicated, specifically in genes that encode the <a href="/facts/Alpha5_Nicotinic_Acetylcholine_Receptor/0cICJ5PR">Alpha5 Nicotinic Acetylcholine Receptor</a>.<a class="footnote-ref" id="fnref:104" href="#fn:104">104</a> Knestler hypothesized in 1964 that a gene or group of genes might contribute to predisposition to addiction in several ways. For example, altered levels of a normal protein due to environmental factors may change the structure or functioning of specific brain neurons during development. These altered brain neurons could affect the susceptibility of an individual to an initial drug use experience. In support of this hypothesis, animal studies have shown that environmental factors such as stress can affect an animal's genetic expression.<a class="footnote-ref" id="fnref:105" href="#fn:105">105</a>
In humans, twin studies into addiction have provided some of the highest-quality evidence of this link, with results finding that if one twin is affected by addiction, the other twin is likely to be as well, and to the same substance.<a class="footnote-ref" id="fnref:106" href="#fn:106">106</a> Further evidence of a genetic component is research findings from family studies which suggest that if one family member has a history of addiction, the chances of a relative or close family developing those same habits are much higher than one who has not been introduced to addiction at a young age.<a class="footnote-ref" id="fnref:107" href="#fn:107">107</a>
The data implicating specific genes in the development of drug addiction is mixed for most genes. Many addiction studies that aim to identify specific genes focus on common variants with an allele frequency of greater than 5% in the general population. When associated with disease, these only confer a small amount of additional risk with an <a href="/facts/Odds_ratio/7WcmubfN">odds ratio</a> of 1.1–1.3 percent; this has led to the development the rare variant hypothesis, which states that genes with low frequencies in the population (<1%) confer much greater additional risk in the development of the disease.<a class="footnote-ref" id="fnref:108" href="#fn:108">108</a>
<a href="/facts/Genome-wide_association_study/qemSYa3a">Genome-wide association studies</a> (GWAS) are used to examine genetic associations with dependence, addiction, and drug use.<a class="footnote-ref" id="fnref:109" href="#fn:109">109</a> These studies rarely identify genes from proteins previously described via animal knockout models and candidate gene analysis. Instead, large percentages of genes involved in processes such as cell adhesion are commonly identified. The important effects of <a href="/facts/Endophenotype/FlCVJevn">endophenotypes</a> are typically not capable of being captured by these methods. Genes identified in GWAS for drug addiction may be involved either in adjusting brain behavior before drug experiences, subsequent to them, or both.<a class="footnote-ref" id="fnref:110" href="#fn:110">110</a>

<h3>Environmental factors</h3>
Environmental risk factors for addiction are the experiences of an individual during their lifetime that interact with the individual's genetic composition to increase or decrease his or her vulnerability to addiction.<a class="footnote-ref" id="fnref:111" href="#fn:111">111</a> For example, after the nationwide[where?] outbreak of COVID-19, more people quit (vs. started) smoking; and smokers, on average, reduced the quantity of cigarettes they consumed.<a class="footnote-ref" id="fnref:112" href="#fn:112">112</a> More generally, a number of different environmental factors have been implicated as risk factors for addiction, including various psycho<a href="/facts/Social_stress/HFAqvF8J">social stressors</a>. The <a href="/facts/National_Institute_on_Drug_Abuse/SjgLWamH">National Institute on Drug Abuse</a> (NIDA) and studies cite lack of parental supervision, the prevalence of peer substance use, substance availability, and poverty as risk factors for substance use among children and adolescents.<a class="footnote-ref" id="fnref:113" href="#fn:113">113</a><a class="footnote-ref" id="fnref:114" href="#fn:114">114</a> The brain disease model of addiction posits that an individual's exposure to an addictive drug is the most significant environmental risk factor for addiction.<a class="footnote-ref" id="fnref:115" href="#fn:115">115</a> Many researchers, including neuroscientists, indicate that the brain disease model presents a misleading, incomplete, and potentially detrimental explanation of addiction.<a class="footnote-ref" id="fnref:116" href="#fn:116">116</a>
The psychoanalytic theory model defines addiction as a form of defense against feelings of hopelessness and helplessness as well as a symptom of failure to regulate powerful emotions related to adverse childhood experiences (ACEs), various forms of maltreatment and dysfunction experienced in childhood. In this case, the addictive substance provides brief but total relief and positive feelings of control.<a class="footnote-ref" id="fnref:117" href="#fn:117">117</a> The <a href="/facts/Adverse_Childhood_Experiences_Study/v7eRhPCV">Adverse Childhood Experiences Study</a> by the <a href="/facts/Centers_for_Disease_Control_and_Prevention/NmoJNDV5">Centers for Disease Control and Prevention</a> has shown a strong <a href="/facts/Dose%25E2%2580%2593response_relationship/DLcuLdHc">dose–response relationship</a> between ACEs and numerous health, social, and behavioral problems throughout a person's lifespan, including substance use disorder.<a class="footnote-ref" id="fnref:118" href="#fn:118">118</a> Children's neurological development can be permanently disrupted when they are chronically exposed to stressful events such as physical, emotional, or sexual abuse, physical or emotional neglect, witnessing violence in the household, or a parent being incarcerated or having a mental illness. As a result, the child's cognitive functioning or ability to cope with negative or disruptive emotions may be impaired. Over time, the child may adopt substance use as a coping mechanism or as a result of reduced impulse control, particularly during adolescence.<a class="footnote-ref" id="fnref:119" href="#fn:119">119</a><a class="footnote-ref" id="fnref:120" href="#fn:120">120</a><a class="footnote-ref" id="fnref:121" href="#fn:121">121</a> Vast amounts of children who experienced abuse have gone on to have some form of addiction in their adolescence or adult life.<a class="footnote-ref" id="fnref:122" href="#fn:122">122</a> This pathway towards addiction that is opened through stressful experiences during childhood can be avoided by a change in environmental factors throughout an individual's life and opportunities of professional help.<a class="footnote-ref" id="fnref:123" href="#fn:123">123</a> If one has friends or peers who engage in drug use favorably, the chances of them developing an addiction increases. Family conflict and home management is a cause for one to become engaged in drug use.<a class="footnote-ref" id="fnref:124" href="#fn:124">124</a>

<h4>Social control theory</h4>
Main article: <a href="/facts/Social_control_theory/f5hdSX9J">Social control theory</a>
According to Travis Hirschi's social control theory, adolescents with stronger attachments to family, religious, academic, and other social institutions are less likely to engage in delinquent and maladaptive behavior such as drug use leading to addiction.<a class="footnote-ref" id="fnref:125" href="#fn:125">125</a>

<h3>Age</h3>
Adolescence represents a period of increased vulnerability for developing an addiction.<a class="footnote-ref" id="fnref:126" href="#fn:126">126</a> In adolescence, the incentive-rewards systems in the brain mature well before the cognitive control center. This consequentially grants the incentive-rewards systems a disproportionate amount of power in the behavioral decision-making process. Therefore, adolescents are increasingly likely to act on their impulses and engage in risky, potentially addicting behavior before considering the consequences.<a class="footnote-ref" id="fnref:127" href="#fn:127">127</a> Not only are adolescents more likely to initiate and maintain drug use, but once addicted they are more resistant to treatment and more liable to relapse.<a class="footnote-ref" id="fnref:128" href="#fn:128">128</a><a class="footnote-ref" id="fnref:129" href="#fn:129">129</a>
Most individuals are exposed to and use addictive drugs for the first time during their teenage years.<a class="footnote-ref" id="fnref:130" href="#fn:130">130</a> In the United States, there were just over 2.8 million new users of illicit drugs in 2013 (7,800 new users per day);<a class="footnote-ref" id="fnref:131" href="#fn:131">131</a> among them, 54.1% were under 18 years of age.<a class="footnote-ref" id="fnref:132" href="#fn:132">132</a> In 2011, there were approximately 20.6 million people in the United States over the age of 12 with an addiction.<a class="footnote-ref" id="fnref:133" href="#fn:133">133</a> Over 90% of those with an addiction began drinking, smoking or using illicit drugs before the age of 18.<a class="footnote-ref" id="fnref:134" href="#fn:134">134</a>

<h3>Comorbid disorders</h3>
Individuals with <a href="/facts/Comorbid/tX5TvuKJ">comorbid</a> (i.e., co-occurring) <a href="/facts/Mental_health/QIszfk6D">mental health</a> disorders such as depression, anxiety, attention-deficit/hyperactivity disorder (ADHD) or post-traumatic stress disorder are more likely to develop substance use disorders.<a class="footnote-ref" id="fnref:135" href="#fn:135">135</a><a class="footnote-ref" id="fnref:136" href="#fn:136">136</a><a class="footnote-ref" id="fnref:137" href="#fn:137">137</a><a class="footnote-ref" id="fnref:138" href="#fn:138">138</a> The NIDA cites early aggressive behavior as a risk factor for substance use.<a class="footnote-ref" id="fnref:139" href="#fn:139">139</a> The <a href="/facts/National_Bureau_of_Economic_Research/oQREczIe">National Bureau of Economic Research</a> found that there is a "definite connection between mental illness and the use of addictive substances" and a majority of mental health patients participate in the use of these substances: 38% alcohol, 44% cocaine, and 40% cigarettes.<a class="footnote-ref" id="fnref:140" href="#fn:140">140</a>

<h3>Epigenetic</h3>
<a href="/facts/Epigenetics/UfAAERcn">Epigenetics</a> is the study of stable <a href="/facts/Phenotype/vxWXKGLj">phenotypic</a> changes that do not involve alterations in the DNA sequence.<a class="footnote-ref" id="fnref:141" href="#fn:141">141</a> Illicit drug use has been found to cause epigenetic changes in <a href="/facts/DNA_methylation/npoRhsnX">DNA methylation</a>, as well as <a href="/facts/Chromatin_remodeling/ukC9TjoG">chromatin remodeling</a>.<a class="footnote-ref" id="fnref:142" href="#fn:142">142</a> The epigenetic state of chromatin may pose as a risk for the development of substance addictions.<a class="footnote-ref" id="fnref:143" href="#fn:143">143</a> It has been found that emotional stressors, as well as social adversities may lead to an initial epigenetic response, which causes an alteration to the reward-signalling pathways.<a class="footnote-ref" id="fnref:144" href="#fn:144">144</a> This change may predispose one to experience a positive response to drug use.<a class="footnote-ref" id="fnref:145" href="#fn:145">145</a>

<h4>Transgenerational epigenetic inheritance</h4>
Main article: <a href="/facts/Transgenerational_epigenetic_inheritance/N3xnHIEd">Transgenerational epigenetic inheritance</a>
<a href="/facts/Epigenetic/UfAAERcn">Epigenetic</a> genes and their products (e.g., proteins) are the key components through which environmental influences can affect the genes of an individual:<a class="footnote-ref" id="fnref:146" href="#fn:146">146</a> they serve as the mechanism responsible for <a href="/facts/Transgenerational_epigenetic_inheritance/N3xnHIEd">transgenerational epigenetic inheritance</a>, a phenomenon in which environmental influences on the genes of a parent can affect the associated traits and <a href="/facts/Behavioral_phenotype/vxWXKGLj">behavioral phenotypes</a> of their offspring (e.g., behavioral responses to environmental stimuli).<a class="footnote-ref" id="fnref:147" href="#fn:147">147</a> In addiction, epigenetic mechanisms play a central role in the <a href="/facts/Pathophysiology/Tp3Dny0c">pathophysiology</a> of the disease;<a class="footnote-ref" id="fnref:148" href="#fn:148">148</a> it has been noted that some of the alterations to the <a href="/facts/Epigenome/hjW9Dwgb">epigenome</a> which arise through chronic exposure to addictive stimuli during an addiction can be transmitted across generations, in turn affecting the behavior of one's children (e.g., the child's behavioral responses to addictive drugs and natural rewards).<a class="footnote-ref" id="fnref:149" href="#fn:149">149</a><a class="footnote-ref" id="fnref:150" href="#fn:150">150</a>
The general classes of epigenetic alterations that have been implicated in transgenerational epigenetic inheritance include DNA methylation, <a href="/facts/Histone_modification/krb5VJfp">histone modifications</a>, and <a href="/facts/Downregulation_and_upregulation/6nRoa28r">downregulation or upregulation</a> of <a href="/facts/MicroRNA/UjqbYYpe">microRNAs</a>.<a class="footnote-ref" id="fnref:151" href="#fn:151">151</a> With respect to addiction, more research is needed to determine the specific <a href="/facts/Heredity/t0aMmRWx">heritable</a> epigenetic alterations that arise from various forms of addiction in humans and the corresponding behavioral phenotypes from these epigenetic alterations that occur in human offspring.<a class="footnote-ref" id="fnref:152" href="#fn:152">152</a><a class="footnote-ref" id="fnref:153" href="#fn:153">153</a> Based on preclinical evidence from <a href="/facts/Animal_research/mHMf98y8">animal research</a>, certain addiction-induced epigenetic alterations in rats can be transmitted from parent to offspring and produce behavioral phenotypes that decrease the offspring's risk of developing an addiction.<a class="footnote-ref" id="fnref:154" href="#fn:154">154</a><a class="footnote-ref" id="fnref:155" href="#fn:155">155</a> More generally, the heritable behavioral phenotypes that are derived from addiction-induced epigenetic alterations and transmitted from parent to offspring may serve to either increase or decrease the offspring's risk of developing an addiction.<a class="footnote-ref" id="fnref:156" href="#fn:156">156</a><a class="footnote-ref" id="fnref:157" href="#fn:157">157</a>

<h2 id="mechanisms">Mechanisms</h2>
Addiction is a disorder of the brain's reward system developing through <a href="/facts/Transcriptional/bDgp9HDN">transcriptional</a> and epigenetic mechanisms as a result of chronically high levels of exposure to an addictive stimulus (e.g., eating food, the use of cocaine, engagement in sexual activity, participation in high-thrill cultural activities such as gambling, etc.) over extended time.<a class="footnote-ref" id="fnref:158" href="#fn:158">158</a><a class="footnote-ref" id="fnref:159" href="#fn:159">159</a><a class="footnote-ref" id="fnref:160" href="#fn:160">160</a> <a href="/facts/FOSB/KHElvauK">DeltaFosB</a> (ΔFosB), a gene <a href="/facts/Transcription_factor/wro0DPHe">transcription factor</a>, is a critical component and common factor in the development of virtually all forms of behavioral and drug addictions.<a class="footnote-ref" id="fnref:161" href="#fn:161">161</a><a class="footnote-ref" id="fnref:162" href="#fn:162">162</a><a class="footnote-ref" id="fnref:163" href="#fn:163">163</a><a class="footnote-ref" id="fnref:164" href="#fn:164">164</a> Two decades of research into ΔFosB's role in addiction have demonstrated that addiction arises, and the associated compulsive behavior intensifies or attenuates, along with the <a href="/facts/Overexpression/N9yVF3lR">overexpression</a> of ΔFosB in the <a href="/facts/D1-type/yu13N9ky">D1-type</a> <a href="/facts/Medium_spiny_neuron/pgzI2WKw">medium spiny neurons</a> of the nucleus accumbens.<a class="footnote-ref" id="fnref:165" href="#fn:165">165</a><a class="footnote-ref" id="fnref:166" href="#fn:166">166</a><a class="footnote-ref" id="fnref:167" href="#fn:167">167</a><a class="footnote-ref" id="fnref:168" href="#fn:168">168</a> Due to the causal relationship between ΔFosB expression and addictions, it is used <a href="/facts/Preclinical_research/WSI14rnq">preclinically</a> as an addiction <a href="/facts/Biomarker_(medicine)/uVSh5z78">biomarker</a>.<a class="footnote-ref" id="fnref:169" href="#fn:169">169</a><a class="footnote-ref" id="fnref:170" href="#fn:170">170</a><a class="footnote-ref" id="fnref:171" href="#fn:171">171</a> ΔFosB expression in these neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement, while decreasing sensitivity to aversion.<a class="footnote-ref" id="fnref:172" href="#fn:172">172</a><a class="footnote-ref" id="fnref:173" href="#fn:173">173</a><a class="footnote-ref" id="fnref:174" href="#fn:174">174</a>

<table><tbody><tr><td></td></tr></tbody></table>
Chronic addictive drug use causes alterations in gene expression in the <a href="/facts/Mesocorticolimbic_projection/EFooas5U">mesocorticolimbic projection</a>.<a class="footnote-ref" id="fnref:175" href="#fn:175">175</a><a class="footnote-ref" id="fnref:176" href="#fn:176">176</a><a class="footnote-ref" id="fnref:177" href="#fn:177">177</a> The most important transcription factors that produce these alterations are ΔFosB, <a href="/facts/Cyclic_adenosine_monophosphate/flK2vwUe">cAMP</a> response element binding protein (<a href="/facts/CAMP_response_element_binding_protein/ug1kE9j0">CREB</a>), and nuclear factor kappa B (<a href="/facts/Nuclear_factor_kappa_B/qcpt5vuQ">NF-κB</a>).<a class="footnote-ref" id="fnref:178" href="#fn:178">178</a> ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is <a href="/facts/Necessary_and_sufficient/G45aDCY9">necessary and sufficient</a> for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction.<a class="footnote-ref" id="fnref:179" href="#fn:179">179</a> ΔFosB expression in nucleus accumbens D1-type medium spiny neurons directly and positively regulates drug <a href="/facts/Self-administration/QpVQv4xS">self-administration</a> and reward sensitization through positive reinforcement while decreasing sensitivity to aversion.<a class="footnote-ref" id="fnref:180" href="#fn:180">180</a><a class="footnote-ref" id="fnref:181" href="#fn:181">181</a><a class="footnote-ref" id="fnref:182" href="#fn:182">182</a> ΔFosB has been implicated in mediating addictions to many different drugs and drug classes, including alcohol, amphetamine and other <a href="/facts/Substituted_amphetamines/KlmrodPb">substituted amphetamines</a>, <a href="/facts/Cannabinoid/MHcltwTn">cannabinoids</a>, <a href="/facts/Cocaine/rdQP4zwF">cocaine</a>, <a href="/facts/Methylphenidate/PHmG2R5p">methylphenidate</a>, <a href="/facts/Nicotine/VQ6HcIrY">nicotine</a>, <a href="/facts/Opiates/IHfQkMkU">opiates</a>, <a href="/facts/Phenylcyclidine/4LaNo5Cl">phenylcyclidine</a>, and <a href="/facts/Propofol/t34FW3fL">propofol</a>, among others.<a class="footnote-ref" id="fnref:183" href="#fn:183">183</a><a class="footnote-ref" id="fnref:184" href="#fn:184">184</a><a class="footnote-ref" id="fnref:185" href="#fn:185">185</a><a class="footnote-ref" id="fnref:186" href="#fn:186">186</a><a class="footnote-ref" id="fnref:187" href="#fn:187">187</a> <a href="/facts/%25CE%2594JunD/7o63oyDk">ΔJunD</a>, a transcription factor, and <a href="/facts/EHMT2/UtjShjts">G9a</a>, a <a href="/facts/Histone_methyltransferase/bbCDPmlz">histone methyltransferase</a>, both oppose the function of ΔFosB and inhibit increases in its expression.<a class="footnote-ref" id="fnref:188" href="#fn:188">188</a><a class="footnote-ref" id="fnref:189" href="#fn:189">189</a><a class="footnote-ref" id="fnref:190" href="#fn:190">190</a> Increases in nucleus accumbens ΔJunD expression (via <a href="/facts/Viral_vector/sqkIdcqo">viral vector</a>-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations that result from chronic high-dose use of addictive drugs (i.e., the alterations mediated by ΔFosB).<a class="footnote-ref" id="fnref:191" href="#fn:191">191</a><a class="footnote-ref" id="fnref:192" href="#fn:192">192</a>
ΔFosB plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.<a class="footnote-ref" id="fnref:193" href="#fn:193">193</a><a class="footnote-ref" id="fnref:194" href="#fn:194">194</a> Natural rewards, like drugs of abuse, <a href="/facts/Inducible_gene/alCPohLR">induce gene expression</a> of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.<a class="footnote-ref" id="fnref:195" href="#fn:195">195</a><a class="footnote-ref" id="fnref:196" href="#fn:196">196</a><a class="footnote-ref" id="fnref:197" href="#fn:197">197</a> Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well;<a class="footnote-ref" id="fnref:198" href="#fn:198">198</a><a class="footnote-ref" id="fnref:199" href="#fn:199">199</a><a class="footnote-ref" id="fnref:200" href="#fn:200">200</a> in particular, ΔFosB in the nucleus accumbens is critical for the <a href="/facts/Reinforcing/bn271VLa">reinforcing</a> effects of sexual reward.<a class="footnote-ref" id="fnref:201" href="#fn:201">201</a> Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional cross-<a href="/facts/Sensitization/TSD1MtAl">sensitization</a> effects that are mediated through ΔFosB.<a class="footnote-ref" id="fnref:202" href="#fn:202">202</a><a class="footnote-ref" id="fnref:203" href="#fn:203">203</a><a class="footnote-ref" id="fnref:204" href="#fn:204">204</a> This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has been observed in some individuals taking <a href="/facts/Dopaminergic/y2PcAHB2">dopaminergic</a> medications.<a class="footnote-ref" id="fnref:205" href="#fn:205">205</a>
ΔFosB inhibitors (drugs or treatments that oppose its action) may be an effective treatment for addiction and addictive disorders.<a class="footnote-ref" id="fnref:206" href="#fn:206">206</a>
The release of dopamine in the nucleus accumbens plays a role in the reinforcing qualities of many forms of stimuli, including naturally reinforcing stimuli like palatable food and sex.<a class="footnote-ref" id="fnref:207" href="#fn:207">207</a><a class="footnote-ref" id="fnref:208" href="#fn:208">208</a><a class="footnote-ref" id="fnref:209" href="#fn:209">209</a> Altered dopamine <a href="/facts/Neurotransmission/9H38LExu">neurotransmission</a> is frequently observed following the development of an addictive state.<a class="footnote-ref" id="fnref:210" href="#fn:210">210</a><a class="footnote-ref" id="fnref:211" href="#fn:211">211</a> In humans and lab animals that have developed an addiction, alterations in dopamine or <a href="/facts/Opioid/EGnE2x99">opioid</a> neurotransmission in the nucleus accumbens and other parts of the striatum are evident.<a class="footnote-ref" id="fnref:212" href="#fn:212">212</a> Use of certain drugs (e.g., cocaine) affect <a href="/facts/Cholinergic_neuron/2aW79po4">cholinergic neurons</a> that innervate the reward system, in turn affecting dopamine signaling in this region.<a class="footnote-ref" id="fnref:213" href="#fn:213">213</a>
A recent study in <a href="/facts/Addiction_(journal)/pTr5A4E1">Addiction</a> reports that <a href="/facts/GLP-1_receptor_agonist/ruP4tEJC">GLP-1 agonist</a> medications, such as <a href="/facts/Semaglutide/g565XV32">semaglutide</a>, which are commonly used for <a href="/facts/Diabetes/2xeHXbsI">diabetes</a> and weight management, may also reduce the risk of overdose and alcohol intoxication in people with substance use disorders.<a class="footnote-ref" id="fnref:214" href="#fn:214">214</a> The study analyzed nearly nine years of health records from 1.3 million individuals across 136 U.S. hospitals, including 500,000 with opioid use disorder and over 800,000 with alcohol use disorder.<a class="footnote-ref" id="fnref:215" href="#fn:215">215</a> Researchers found that those who used Ozempic or similar medications had a 40% lower risk of opioid overdose and a 50% lower risk of alcohol intoxication compared to those not using these drugs.

<h3>Reward system</h3>
Main article: <a href="/facts/Reward_system/fotI0rcM">Reward system</a>
<h4>Mesocorticolimbic pathway</h4>
<table><tbody><tr><td></td></tr></tbody></table>
Understanding the pathways in which drugs act and how drugs can alter those pathways is key when examining the biological basis of drug addiction. The reward pathway, known as the <a href="/facts/Mesolimbic_system/pkEaYUNf">mesolimbic pathway</a>,<a class="footnote-ref" id="fnref:216" href="#fn:216">216</a> or its extension, the <a href="/facts/Mesocorticolimbic_pathway/EFooas5U">mesocorticolimbic pathway</a>, is characterized by the interaction of several areas of the brain.

<ul><li>The projections from the <a href="/facts/Ventral_tegmentum/f1rcxshF">ventral tegmental area</a> (VTA) are a network of <a href="/facts/Dopaminergic/y2PcAHB2">dopaminergic</a> <a href="/facts/Neurons/G7CyTVdH">neurons</a> with co-localized postsynaptic <a href="/facts/Glutamate/7oXbNcvu">glutamate</a> receptors (<a href="/facts/AMPAR/FJHDlvkg">AMPAR</a> and <a href="/facts/NMDAR/BqMhXEbU">NMDAR</a>). These cells respond when stimuli indicative of a reward are present.<a class="footnote-ref" id="fnref:217" href="#fn:217">217</a> The VTA supports learning and sensitization development and releases dopamine (DA) into the <a href="/facts/Forebrain/X3H1IqLq">forebrain</a>.<a class="footnote-ref" id="fnref:218" href="#fn:218">218</a> These neurons project and release DA into the nucleus accumbens,<a class="footnote-ref" id="fnref:219" href="#fn:219">219</a> through the <a href="/facts/Mesolimbic_pathway/pkEaYUNf">mesolimbic pathway</a>. Virtually all drugs causing drug addiction increase the DA release in the mesolimbic pathway.<a class="footnote-ref" id="fnref:220" href="#fn:220">220</a><a class="footnote-ref" id="fnref:221" href="#fn:221">221</a></li>
<li>The <a href="/facts/Nucleus_accumbens/2M43u5X4">nucleus accumbens</a> (NAcc) is one output of the VTA projections. The nucleus accumbens itself consists mainly of <a href="/facts/GABA/IbYbIxzr">GABAergic</a> <a href="/facts/Medium_spiny_neuron/pgzI2WKw">medium spiny neurons</a> (MSNs).<a class="footnote-ref" id="fnref:222" href="#fn:222">222</a> The NAcc is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses.<a class="footnote-ref" id="fnref:223" href="#fn:223">223</a><a class="footnote-ref" id="fnref:224" href="#fn:224">224</a> Overexpression of <a href="/facts/%25CE%2594FosB/KHElvauK">ΔFosB</a> in the nucleus accumbens is a necessary common factor in essentially all known forms of addiction;<a class="footnote-ref" id="fnref:225" href="#fn:225">225</a> ΔFosB is a strong positive modulator of <a href="/facts/Positively_reinforced/bn271VLa">positively reinforced</a> behaviors.<a class="footnote-ref" id="fnref:226" href="#fn:226">226</a></li>
<li>The <a href="/facts/Prefrontal_cortex/dypYIrwx">prefrontal cortex</a>, including the <a href="/facts/Anterior_cingulate/gMBsA5EJ">anterior cingulate</a> and <a href="/facts/Orbitofrontal_cortex/r61gtngW">orbitofrontal</a> cortices,<a class="footnote-ref" id="fnref:227" href="#fn:227">227</a><a class="footnote-ref" id="fnref:228" href="#fn:228">228</a> is another VTA output in the mesocorticolimbic pathway; it is important for the integration of information which helps determine whether a behavior will be elicited.<a class="footnote-ref" id="fnref:229" href="#fn:229">229</a> It is critical for forming associations between the rewarding experience of drug use and cues in the environment. Importantly, these cues are strong mediators of drug-seeking behavior and can trigger relapse even after months or years of abstinence.<a class="footnote-ref" id="fnref:230" href="#fn:230">230</a><a class="footnote-ref" id="fnref:231" href="#fn:231">231</a></li></ul>
Other brain structures that are involved in addiction include:

<ul><li>The <a href="/facts/Basolateral_amygdala/U8XImwsF">basolateral amygdala</a> projects into the NAcc and is thought to be important for motivation.<a class="footnote-ref" id="fnref:232" href="#fn:232">232</a></li>
<li>The <a href="/facts/Hippocampus/X7CqbP8X">hippocampus</a> is involved in drug addiction, because of its role in learning and memory. Much of this evidence stems from investigations showing that manipulating cells in the hippocampus alters DA levels in NAcc and firing rates of VTA dopaminergic cells.<a class="footnote-ref" id="fnref:233" href="#fn:233">233</a></li></ul>
<h4>Role of dopamine and glutamate</h4>
Dopamine is the primary neurotransmitter of the reward system in the brain. It plays a role in regulating movement, emotion, cognition, motivation, and feelings of pleasure.<a class="footnote-ref" id="fnref:234" href="#fn:234">234</a> Natural rewards, like eating, as well as recreational drug use cause a release of dopamine, and are associated with the reinforcing nature of these stimuli.<a class="footnote-ref" id="fnref:235" href="#fn:235">235</a><a class="footnote-ref" id="fnref:236" href="#fn:236">236</a><a class="footnote-ref" id="fnref:237" href="#fn:237">237</a> Nearly all addictive drugs, directly or indirectly, act on the brain's reward system by heightening dopaminergic activity.<a class="footnote-ref" id="fnref:238" href="#fn:238">238</a><a class="footnote-ref" id="fnref:239" href="#fn:239">239</a>
Excessive intake of many types of addictive drugs results in repeated release of high amounts of dopamine, which in turn affects the reward pathway directly through heightened dopamine receptor activation. Prolonged and abnormally high levels of dopamine in the <a href="/facts/Synaptic_cleft/M1x5rhz7">synaptic cleft</a> can induce receptor downregulation in the neural pathway. Downregulation of <a href="/facts/Mesolimbic/pkEaYUNf">mesolimbic</a> dopamine receptors can result in a decrease in the sensitivity to natural reinforcers.<a class="footnote-ref" id="fnref:240" href="#fn:240">240</a>
Drug seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the nucleus accumbens. This idea is supported with data from experiments showing that drug seeking behavior can be prevented following the inhibition of <a href="/facts/AMPA/jeQWeMVw">AMPA</a> glutamate receptors and glutamate release in the nucleus accumbens.<a class="footnote-ref" id="fnref:241" href="#fn:241">241</a>

<h3>Reward sensitization</h3>
Neural and behavioral effects of validated ΔFosB transcriptional targets in the <a href="/facts/Striatum/MjNnTjSd">striatum</a><a class="footnote-ref" id="fnref:242" href="#fn:242">242</a><a class="footnote-ref" id="fnref:243" href="#fn:243">243</a><table><tbody><tr><th scope="col">Targetgene</th><th scope="col">Target<a href="/facts/Gene_expression/alCPohLR">expression</a></th><th scope="col">Neural effects</th><th scope="col">Behavioral effects</th></tr><tr><td scope="row"><a href="/facts/C-Fos/SHKzGqYX">c-Fos</a></td><td>↓</td><td>Molecular switch enabling the chronicinduction of ΔFosB<a class="footnote-ref" id="fnref:244" href="#fn:244">244</a></td><td>–</td></tr><tr><td scope="row"><a href="/facts/Dynorphin/ent2QkXk">dynorphin</a></td><td>↓<a class="footnote-ref" id="fnref:245" href="#fn:245">245</a></td><td> • Downregulation of <a href="/facts/%25CE%259A-opioid_receptor/zJRo3NoF">κ-opioid</a> feedback loop</td><td> • Increased drug reward</td></tr><tr><td scope="row"><a href="/facts/NF-%25CE%25BAB/qcpt5vuQ">NF-κB</a></td><td>↑</td><td> • Expansion of <a href="/facts/Nucleus_accumbens/2M43u5X4">NAcc</a> dendritic processes • NF-κB inflammatory response in the NAcc • NF-κB inflammatory response in the <a href="/facts/Caudate_putamen/MjNnTjSd">CP</a>Tooltip caudate putamen</td><td> • Increased drug reward • <a href="/facts/Stereotypy/mFySByoE">Locomotor sensitization</a></td></tr><tr><td scope="row"><a href="/facts/GluR2/zr84KVnv">GluR2</a></td><td>↑</td><td> • Decreased <a href="/facts/Sensitization/TSD1MtAl">sensitivity</a> to <a href="/facts/Glutamate/7oXbNcvu">glutamate</a></td><td> • Increased drug reward</td></tr><tr><td scope="row"><a href="/facts/Cdk5/qAxbEHaT">Cdk5</a></td><td>↑</td><td> • <a href="/facts/GluR1/dhRPruvI">GluR1</a> synaptic protein phosphorylation • Expansion of NAcc dendritic processes</td><td>Decreased drug reward(net effect)</td></tr></tbody></table>
Reward sensitization is a process that causes an increase in the amount of reward (specifically, <a href="/facts/Incentive_salience/zCVbavjh">incentive salience</a><a class="footnote-ref" id="fnref:246" href="#fn:246">246</a>) that is assigned by the brain to a rewarding stimulus (e.g., a drug). In simple terms, when reward sensitization to a specific stimulus (e.g., a drug) occurs, an individual's "wanting" or desire for the stimulus itself and its associated <a href="/facts/Cue_reactivity/8bb173ad">cues</a> increases.<a class="footnote-ref" id="fnref:247" href="#fn:247">247</a><a class="footnote-ref" id="fnref:248" href="#fn:248">248</a><a class="footnote-ref" id="fnref:249" href="#fn:249">249</a> Reward sensitization normally occurs following chronically high levels of exposure to the stimulus.<a class="footnote-ref" id="fnref:250" href="#fn:250">250</a> ΔFosB expression in D1-type medium spiny neurons in the nucleus accumbens has been shown to directly and positively regulate reward sensitization involving drugs and natural rewards.<a class="footnote-ref" id="fnref:251" href="#fn:251">251</a><a class="footnote-ref" id="fnref:252" href="#fn:252">252</a><a class="footnote-ref" id="fnref:253" href="#fn:253">253</a>
"Cue-induced wanting" or "cue-triggered wanting", a form of craving that occurs in addiction, is responsible for most of the compulsive behavior that people with addictions exhibit.<a class="footnote-ref" id="fnref:254" href="#fn:254">254</a><a class="footnote-ref" id="fnref:255" href="#fn:255">255</a> During the development of an addiction, the repeated association of otherwise neutral and even non-rewarding <a href="/facts/Stimulation/qTbolu55">stimuli</a> with drug consumption triggers an <a href="/facts/Associative_learning/lehEKRjC">associative learning</a> process that causes these previously neutral stimuli to act as <a href="/facts/Reinforcement/bn271VLa">conditioned positive reinforcers</a> of addictive drug use (i.e., these stimuli start to function as <a href="/facts/Drug_cues/8bb173ad">drug cues</a>).<a class="footnote-ref" id="fnref:256" href="#fn:256">256</a><a class="footnote-ref" id="fnref:257" href="#fn:257">257</a><a class="footnote-ref" id="fnref:258" href="#fn:258">258</a> As conditioned positive reinforcers of drug use, these previously neutral stimuli are assigned incentive salience (which manifests as a craving) – sometimes at pathologically high levels due to reward sensitization – which can <a href="/facts/Pavlovian-instrumental_transfer/etBvA1MQ">transfer to the primary reinforcer</a> (e.g., the use of an addictive drug) with which it was originally paired.<a class="footnote-ref" id="fnref:259" href="#fn:259">259</a><a class="footnote-ref" id="fnref:260" href="#fn:260">260</a><a class="footnote-ref" id="fnref:261" href="#fn:261">261</a>
Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess a bidirectional reward cross-sensitization effect<a class="footnote-ref" id="fnref:262" href="#fn:262">262</a> that is mediated through ΔFosB.<a class="footnote-ref" id="fnref:263" href="#fn:263">263</a><a class="footnote-ref" id="fnref:264" href="#fn:264">264</a><a class="footnote-ref" id="fnref:265" href="#fn:265">265</a> In contrast to ΔFosB's reward-sensitizing effect, <a href="/facts/CREB/ug1kE9j0">CREB</a> transcriptional activity decreases user's sensitivity to the rewarding effects of the substance. CREB transcription in the nucleus accumbens is implicated in <a href="/facts/Psychological_dependence/9M3oLRP5">psychological dependence</a> and symptoms involving a <a href="/facts/Anhedonia/SMPHrCon">lack of pleasure or motivation</a> during <a href="/facts/Drug_withdrawal/lGr6VEBU">drug withdrawal</a>.<a class="footnote-ref" id="fnref:266" href="#fn:266">266</a><a class="footnote-ref" id="fnref:267" href="#fn:267">267</a><a class="footnote-ref" id="fnref:268" href="#fn:268">268</a>

Summary of addiction-related plasticity<table><tbody><tr><th scope="col" rowspan="2">Form of <a href="/facts/Neuroplasticity/c0o0fvVm">neuroplasticity</a> or <a href="/facts/Behavioral_plasticity/Bezn2xm1">behavioral plasticity</a></th><th scope="col" colspan="6">Type of <a href="/facts/Reinforcement/bn271VLa">reinforcer</a></th><th scope="col" rowspan="2">Sources</th></tr><tr><th scope="col">Opiates</th><th scope="col">Psychostimulants</th><th scope="col">High fat or sugar food</th><th scope="col"><a href="/facts/Sexual_intercourse/okjwpVnB">Sexual intercourse</a></th><th scope="col"><a href="/facts/Neurobiological_effects_of_physical_exercise/kVVntCLn">Physical exercise(aerobic)</a></th><th scope="col"><a href="/facts/Environmental_enrichment/UDueI4mS">Environmentalenrichment</a></th></tr><tr><td scope="row"><a href="/facts/%25CE%2594FosB/KHElvauK">ΔFosB</a> expression in<a href="/facts/Nucleus_accumbens/2M43u5X4">nucleus accumbens</a> <a href="/facts/D1-type/yu13N9ky">D1-type</a> <a href="/facts/Medium_spiny_neurons/pgzI2WKw">MSNs</a>Tooltip medium spiny neurons</td><td>↑</td><td>↑</td><td>↑</td><td>↑</td><td>↑</td><td>↑</td><td><a class="footnote-ref" id="fnref:269" href="#fn:269">269</a></td></tr><tr><th scope="col" colspan="8">Behavioral plasticity</th></tr><tr><td scope="row">Escalation of intake</td><td>Yes</td><td>Yes</td><td>Yes</td><td></td><td></td><td></td><td><a class="footnote-ref" id="fnref:270" href="#fn:270">270</a></td></tr><tr><td scope="row">Psychostimulantcross-sensitization</td><td>Yes</td><td>Not applicable</td><td>Yes</td><td>Yes</td><td>Attenuated</td><td>Attenuated</td><td><a class="footnote-ref" id="fnref:271" href="#fn:271">271</a></td></tr><tr><td scope="row">Psychostimulant<a href="/facts/Self-administration/QpVQv4xS">self-administration</a></td><td>↑</td><td>↑</td><td>↓</td><td></td><td>↓</td><td>↓</td><td><a class="footnote-ref" id="fnref:272" href="#fn:272">272</a></td></tr><tr><td scope="row">Psychostimulant<a href="/facts/Conditioned_place_preference/C69ShbqG">conditioned place preference</a></td><td>↑</td><td>↑</td><td>↓</td><td>↑</td><td>↓</td><td>↑</td><td><a class="footnote-ref" id="fnref:273" href="#fn:273">273</a></td></tr><tr><td scope="row"><a href="/facts/Reinstatement_of_drug-seeking_behavior/XskgIodS">Reinstatement of drug-seeking behavior</a></td><td>↑</td><td>↑</td><td></td><td></td><td>↓</td><td>↓</td><td><a class="footnote-ref" id="fnref:274" href="#fn:274">274</a></td></tr><tr><th scope="col" colspan="8">Neurochemical plasticity</th></tr><tr><td scope="row"><a href="/facts/CAMP_response_element-binding_protein/ug1kE9j0">CREB</a>Tooltip cAMP response element-binding protein <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a>in the nucleus accumbens</td><td>↓</td><td>↓</td><td>↓</td><td></td><td>↓</td><td>↓</td><td><a class="footnote-ref" id="fnref:275" href="#fn:275">275</a></td></tr><tr><td scope="row">Sensitized <a href="/facts/Dopamine/5gNy8Xkd">dopamine</a> responsein the nucleus accumbens</td><td>No</td><td>Yes</td><td>No</td><td>Yes</td><td></td><td></td><td><a class="footnote-ref" id="fnref:276" href="#fn:276">276</a></td></tr><tr><td scope="row">Altered <a href="/facts/Striatum/MjNnTjSd">striatal</a> <a href="/facts/Dopamine_receptor/fgsjJwkL">dopamine signaling</a></td><td>↓<a href="/facts/DRD2/SmmP3QyU">DRD2</a>, ↑<a href="/facts/DRD3/e1L1KnJq">DRD3</a></td><td>↑<a href="/facts/DRD1/fkWRTblS">DRD1</a>, ↓<a href="/facts/DRD2/SmmP3QyU">DRD2</a>, ↑<a href="/facts/DRD3/e1L1KnJq">DRD3</a></td><td>↑<a href="/facts/DRD1/fkWRTblS">DRD1</a>, ↓<a href="/facts/DRD2/SmmP3QyU">DRD2</a>, ↑<a href="/facts/DRD3/e1L1KnJq">DRD3</a></td><td></td><td>↑<a href="/facts/DRD2/SmmP3QyU">DRD2</a></td><td>↑<a href="/facts/DRD2/SmmP3QyU">DRD2</a></td><td><a class="footnote-ref" id="fnref:277" href="#fn:277">277</a></td></tr><tr><td scope="row">Altered striatal <a href="/facts/Opioid_receptor/eDIAqgV3">opioid signaling</a></td><td>No change or↑<a href="/facts/%25CE%259C-opioid_receptor/8a3wdeTc">μ-opioid receptors</a></td><td>↑<a href="/facts/%25CE%259C-opioid_receptor/8a3wdeTc">μ-opioid receptors</a>↑<a href="/facts/%25CE%259A-opioid_receptor/zJRo3NoF">κ-opioid receptors</a></td><td>↑<a href="/facts/%25CE%259C-opioid_receptor/8a3wdeTc">μ-opioid receptors</a></td><td>↑<a href="/facts/%25CE%259C-opioid_receptor/8a3wdeTc">μ-opioid receptors</a></td><td>No change</td><td>No change</td><td><a class="footnote-ref" id="fnref:278" href="#fn:278">278</a></td></tr><tr><td scope="row">Changes in striatal <a href="/facts/Opioid_peptide/FhQc0ntm">opioid peptides</a></td><td>↑<a href="/facts/Dynorphin/ent2QkXk">dynorphin</a>No change: <a href="/facts/Enkephalin/lVvearbQ">enkephalin</a></td><td>↑<a href="/facts/Dynorphin/ent2QkXk">dynorphin</a></td><td>↓<a href="/facts/Enkephalin/lVvearbQ">enkephalin</a></td><td></td><td>↑<a href="/facts/Dynorphin/ent2QkXk">dynorphin</a></td><td>↑<a href="/facts/Dynorphin/ent2QkXk">dynorphin</a></td><td><a class="footnote-ref" id="fnref:279" href="#fn:279">279</a></td></tr><tr><th scope="col" colspan="8"><a href="/facts/Dopaminergic_pathways/EFooas5U">Mesocorticolimbic</a> <a href="/facts/Synaptic_plasticity/rdVFxItN">synaptic plasticity</a></th></tr><tr><td scope="row">Number of <a href="/facts/Dendrite/bwv8MABY">dendrites</a> in the nucleus accumbens</td><td>↓</td><td>↑</td><td></td><td>↑</td><td></td><td></td><td><a class="footnote-ref" id="fnref:280" href="#fn:280">280</a></td></tr><tr><td scope="row"><a href="/facts/Dendritic_spine/wg54o3YT">Dendritic spine</a> density inthe nucleus accumbens</td><td>↓</td><td>↑</td><td></td><td>↑</td><td></td><td></td><td><a class="footnote-ref" id="fnref:281" href="#fn:281">281</a></td></tr></tbody></table>

<h3>Neuroepigenetic mechanisms</h3>
Further information: <a href="/facts/Neuroepigenetics/7tlYw9xr">Neuroepigenetics</a> and <a href="/facts/Chromatin_remodeling/ukC9TjoG">Chromatin remodeling</a>
Altered epigenetic regulation of gene expression within the brain's reward system plays a significant and complex role in the development of drug addiction.<a class="footnote-ref" id="fnref:282" href="#fn:282">282</a><a class="footnote-ref" id="fnref:283" href="#fn:283">283</a> Addictive drugs are associated with three types of epigenetic modifications within neurons.<a class="footnote-ref" id="fnref:284" href="#fn:284">284</a> These are (1) histone modifications, (2) <a href="/facts/Epigenetic_methylation/EvDMWVW5">epigenetic methylation</a> of DNA at <a href="/facts/CpG_site/PbPHokwh">CpG sites</a> at (or adjacent to) particular genes, and (3) epigenetic downregulation or upregulation of microRNAs which have particular target genes.<a class="footnote-ref" id="fnref:285" href="#fn:285">285</a><a class="footnote-ref" id="fnref:286" href="#fn:286">286</a><a class="footnote-ref" id="fnref:287" href="#fn:287">287</a> As an example, while hundreds of genes in the cells of the nucleus accumbens (NAc) exhibit histone modifications following drug exposure – particularly, altered acetylation and methylation states of <a href="/facts/Histone/krb5VJfp">histone</a> <a href="/facts/Residue_(chemistry)/xE6sUTDa">residues</a><a class="footnote-ref" id="fnref:288" href="#fn:288">288</a> – most other genes in the NAc cells do not show such changes.<a class="footnote-ref" id="fnref:289" href="#fn:289">289</a>

<h2 id="diagnosis">Diagnosis</h2>
Further information: <a href="/facts/Substance_use_disorder/pSbdzb6a">Substance use disorder § Diagnosis</a>, and <a href="/facts/Problem_gambling/1d3Uygzb">Problem gambling § Diagnosis</a>
<h3>Classification</h3>
<h4>DSM-5</h4>
The fifth edition of the DSM uses the term substance use disorder to refer to a spectrum of drug use-related disorders. The DSM-5 eliminates the terms <a href="/facts/Drug_abuse/e3jLXFsF">abuse</a> and dependence from diagnostic categories, instead using the specifiers of mild, moderate and severe to indicate the extent of disordered use. These specifiers are determined by the number of diagnostic criteria present in a given case. In the DSM-5, the term drug addiction is synonymous with severe substance use disorder.<a class="footnote-ref" id="fnref:290" href="#fn:290">290</a><a class="footnote-ref" id="fnref:291" href="#fn:291">291</a>
The DSM-5 introduced a new diagnostic category for behavioral addictions. Problem gambling is the only condition included in this category in the fifth edition.<a class="footnote-ref" id="fnref:292" href="#fn:292">292</a> <a href="/facts/Internet_gaming_disorder/BlElxadE">Internet gaming disorder</a> is listed as a "condition requiring further study" in the DSM-5.<a class="footnote-ref" id="fnref:293" href="#fn:293">293</a>
Past editions have used <a href="/facts/Physical_dependence/y2rzJnfB">physical dependence</a> and the associated withdrawal syndrome to identify an addictive state. Physical dependence occurs when the body has adjusted by incorporating the substance into its "normal" functioning – i.e., attains <a href="/facts/Homeostasis/rloTGAHa">homeostasis</a> – and therefore physical withdrawal symptoms occur on cessation of use.<a class="footnote-ref" id="fnref:294" href="#fn:294">294</a> Tolerance is the process by which the body continually adapts to the substance and requires increasingly larger amounts to achieve the original effects. Withdrawal refers to physical and psychological symptoms experienced when reducing or discontinuing a substance that the body has become dependent on. Symptoms of withdrawal generally include but are not limited to body aches, <a href="/facts/Anxiety/Geekl883">anxiety</a>, <a href="/facts/Irritability/yK49u3EP">irritability</a>, intense <a href="/facts/Craving_(withdrawal)/PbQR0n9w">cravings</a> for the substance, <a href="/facts/Dysphoria/ltFryLsg">dysphoria</a>, <a href="/facts/Nausea/dyhkcbeD">nausea</a>, <a href="/facts/Hallucinations/5eUvLcnp">hallucinations</a>, <a href="/facts/Headaches/mdmmC9DP">headaches</a>, cold sweats, <a href="/facts/Tremor/rD6ogM7X">tremors</a>, and seizures. During acute physical opioid withdrawal, symptoms of <a href="/facts/Restless_legs_syndrome/XNn8sPDN">restless legs syndrome</a> are common and may be profound. This phenomenon originated the idiom "kicking the habit".
Medical researchers who actively study addiction have criticized the DSM classification of addiction for being flawed and involving arbitrary diagnostic criteria.<a class="footnote-ref" id="fnref:295" href="#fn:295">295</a>

<h4>ICD-11</h4>
The eleventh revision of the <a href="/facts/International_Classification_of_Diseases/mxID6rJp">International Classification of Diseases</a>, commonly referred to as <a href="/facts/ICD-11/AAItcoCH">ICD-11</a>, conceptualizes diagnosis somewhat differently. ICD-11 first distinguishes between problems with psychoactive substance use ("Disorders due to substance use") and behavioral addictions ("Disorders due to addictive behaviours").<a class="footnote-ref" id="fnref:296" href="#fn:296">296</a> With regard to psychoactive substances, ICD-11 explains that the included substances initially produce "pleasant or appealing psychoactive effects that are rewarding and reinforcing with repeated use, [but] with continued use, many of the included substances have the capacity to produce dependence. They have the potential to cause numerous forms of harm, both to mental and physical health."<a class="footnote-ref" id="fnref:297" href="#fn:297">297</a> Instead of the DSM-5 approach of one diagnosis ("Substance Use Disorder") covering all types of problematic substance use, ICD-11 offers three diagnostic possibilities: 1) Episode of Harmful Psychoactive Substance Use, 2) Harmful Pattern of Psychoactive Substance Use, and 3) Substance Dependence.<a class="footnote-ref" id="fnref:298" href="#fn:298">298</a>

<h3>Screening and assessment</h3>
<h4>Addictions Neuroclinical Assessment</h4>
The Addictions Neuroclinical Assessment is used to diagnose addiction disorders. This tool measures three different domains: <a href="/facts/Executive_functions/QtflLj55">executive function</a>, <a href="/facts/Motivational_salience/zCVbavjh">incentive salience</a>, and <a href="/facts/Emotionality/PVD2lkwg">negative emotionality</a>.<a class="footnote-ref" id="fnref:299" href="#fn:299">299</a><a class="footnote-ref" id="fnref:300" href="#fn:300">300</a> Executive functioning consists of processes that would be disrupted in addiction.<a class="footnote-ref" id="fnref:301" href="#fn:301">301</a> In the context of addiction, incentive salience determines how one perceives the addictive substance.<a class="footnote-ref" id="fnref:302" href="#fn:302">302</a> Increased negative emotional responses have been found with individuals with addictions.<a class="footnote-ref" id="fnref:303" href="#fn:303">303</a>

<h4>Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS)</h4>
This is a screening and assessment tool in one, assessing commonly used substances. This tool allows for a simple diagnosis, eliminating the need for several screening and assessment tools, as it includes both TAPS-1 and TAPS-2, screening and assessment tools respectively. The screening component asks about the frequency of use of the specific substance (tobacco, alcohol, prescription medication, and other).<a class="footnote-ref" id="fnref:304" href="#fn:304">304</a> If an individual screens positive, the second component will begin. This dictates the risk level of the substance.<a class="footnote-ref" id="fnref:305" href="#fn:305">305</a>

<h4>CRAFFT</h4>
The CRAFFT (Car-Relax-Alone-Forget-Family and Friends-Trouble) is a screening tool that is used in medical centers. The CRAFFT is in version 2.1 and has a version for nicotine and tobacco use called the CRAFFT 2.1+N.<a class="footnote-ref" id="fnref:306" href="#fn:306">306</a> This tool is used to identify substance use, substance related driving risk, and addictions among adolescents. This tool uses a set of questions for different scenarios.<a class="footnote-ref" id="fnref:307" href="#fn:307">307</a> In the case of a specific combination of answers, different question sets can be used to yield a more accurate answer. After the questions, the DSM-5 criteria are used to identify the likelihood of the person having substance use disorder.<a class="footnote-ref" id="fnref:308" href="#fn:308">308</a> After these tests are done, the clinician is to give the "5 RS" of brief counseling.
The five Rs of brief counseling includes:<a class="footnote-ref" id="fnref:309" href="#fn:309">309</a>

<ol><li>REVIEW screening results</li>
<li>RECOMMEND to not use</li>
<li>RIDING/DRIVING risk counseling</li>
<li>RESPONSE: elicit self-motivational statements</li>
<li>REINFORCE self-efficacy</li></ol>
<h4>Drug Abuse Screening Test (DAST-10)</h4>
The Drug Abuse Screening Test (DAST) is a self-reporting tool that measures problematic substance use.<a class="footnote-ref" id="fnref:310" href="#fn:310">310</a> Responses to this test are recorded as yes or no answers, and scored as a number between zero and 28. Drug abuse or dependence, are indicated by a cut off score of 6.<a class="footnote-ref" id="fnref:311" href="#fn:311">311</a> Three versions of this screening tool are in use: DAST-28, DAST-20, and DAST-10. Each of these instruments are copyrighted by Dr. Harvey A. Skinner.<a class="footnote-ref" id="fnref:312" href="#fn:312">312</a>

<h4>Alcohol, Smoking, and Substance Involvement Test (ASSIST)</h4>
The Alcohol, Smoking, and Substance Involvement Test (ASSIST) is an interview-based questionnaire consisting of eight questions developed by the WHO.<a class="footnote-ref" id="fnref:313" href="#fn:313">313</a> The questions ask about lifetime use; frequency of use; urge to use; frequency of health, financial, social, or legal problems related to use; failure to perform duties; if anyone has raised concerns over use; attempts to limit or moderate use; and use by injection.<a class="footnote-ref" id="fnref:314" href="#fn:314">314</a>

<h2 id="prevention">Prevention</h2>
Main articles: <a href="/facts/Harm_reduction/2cAHgTu7">Harm reduction</a> and <a href="/facts/Preventive_healthcare/pWGlacXu">Preventive healthcare</a>
<h3>Abuse liability</h3>
Abuse or addiction liability is the tendency to use drugs in a non-medical situation. This is typically for euphoria, mood changing, or sedation.<a class="footnote-ref" id="fnref:315" href="#fn:315">315</a> Abuse liability is used when the person using the drugs wants something that they otherwise can not obtain. The only way to obtain this is through the use of drugs. When looking at abuse liability there are a number of determining factors in whether the drug is abused. These factors are: the chemical makeup of the drug, the effects on the brain, and the age, vulnerability, and the health (mental and physical) of the population being studied.<a class="footnote-ref" id="fnref:316" href="#fn:316">316</a> There are a few drugs with a specific chemical makeup that leads to a high abuse liability. These are: cocaine, heroin, inhalants, marijuana, MDMA (ecstasy), methamphetamine, PCP, synthetic cannabinoids, synthetic cathinones (bath salts), nicotine (e.g. tobacco), and alcohol.<a class="footnote-ref" id="fnref:317" href="#fn:317">317</a>

<h3>Potential vaccines for addiction to substances</h3>
<a href="/facts/Vaccine/QcXzLug2">Vaccines</a> for addiction have been investigated as a possibility since the early 2000s.<a class="footnote-ref" id="fnref:318" href="#fn:318">318</a> The general theory of a vaccine intended to "immunize" against drug addiction or other <a href="/facts/Substance_abuse/e3jLXFsF">substance abuse</a> is that it would condition the <a href="/facts/Immune_system/HRCTf1pb">immune system</a> to attack and consume or otherwise disable the molecules of such substances that cause a reaction in the brain, thus preventing the addict from being able to realize the effect of the drug. Addictions that have been floated as targets for such treatment include <a href="/facts/Nicotine/VQ6HcIrY">nicotine</a>, <a href="/facts/Opioid/EGnE2x99">opioids</a>, and <a href="/facts/Fentanyl/MMD9GdD3">fentanyl</a>.<a class="footnote-ref" id="fnref:319" href="#fn:319">319</a><a class="footnote-ref" id="fnref:320" href="#fn:320">320</a><a class="footnote-ref" id="fnref:321" href="#fn:321">321</a><a class="footnote-ref" id="fnref:322" href="#fn:322">322</a> Vaccines have been identified as potentially being more effective than other anti-addiction treatments, due to "the long duration of action, the certainty of administration and a potential reduction of <a href="/facts/Toxicity/qa96rs60">toxicity</a> to important organs".<a class="footnote-ref" id="fnref:323" href="#fn:323">323</a>
Specific addiction vaccines in development include:

<ul><li><a href="/facts/NicVAX/0T1TGPKh">NicVAX</a>, a <a href="/facts/Conjugate_vaccine/DwqFnI4L">conjugate vaccine</a> intended to reduce or eliminate physical dependence on nicotine.<a class="footnote-ref" id="fnref:324" href="#fn:324">324</a> This proprietary vaccine is being developed by Nabi Biopharmaceuticals<a class="footnote-ref" id="fnref:325" href="#fn:325">325</a> of Rockville, MD. with the support from the <a href="/facts/U.S._National_Institute_on_Drug_Abuse/SjgLWamH">U.S. National Institute on Drug Abuse</a>. NicVAX consists of the <a href="/facts/Hapten/UJVgQb86">hapten</a> 3'-aminomethylnicotine which has been conjugated (attached) to <a href="/facts/Pseudomonas_aeruginosa/HBhyIxAn">Pseudomonas aeruginosa</a> <a href="/facts/Exotoxin_A/cFruo68A">exotoxin A</a>.<a class="footnote-ref" id="fnref:326" href="#fn:326">326</a></li>
<li><a href="/facts/TA-CD/NLJ8v0sI">TA-CD</a>, an active <a href="/facts/Vaccine/QcXzLug2">vaccine</a><a class="footnote-ref" id="fnref:327" href="#fn:327">327</a> developed by the Xenova Group which is used to negate the effects of <a href="/facts/Cocaine/rdQP4zwF">cocaine</a>. It is created by combining <a href="/facts/Norcocaine/1JhpgRxR">norcocaine</a> with inactivated <a href="/facts/Cholera/rk8JfWEp">cholera</a> toxin. It works in much the same way as a regular vaccine. A large <a href="/facts/Protein/Jxmagu3E">protein</a> molecule attaches to cocaine, which stimulates response from <a href="/facts/Antibodies/MX8pdTdP">antibodies</a>, which destroy the molecule. This also prevents the cocaine from crossing the <a href="/facts/Blood%25E2%2580%2593brain_barrier/xYzvVwdu">blood–brain barrier</a>, negating the euphoric high and <a href="/facts/Reward_system/fotI0rcM">rewarding</a> effect of cocaine caused from stimulation of <a href="/facts/Dopamine/5gNy8Xkd">dopamine</a> release in the <a href="/facts/Mesolimbic_reward_pathway/pkEaYUNf">mesolimbic reward pathway</a>. The vaccine does not affect the user's "desire" for cocaine—only the physical effects of the drug.<a class="footnote-ref" id="fnref:328" href="#fn:328">328</a></li>
<li><a href="/facts/TA-NIC/IrYXuptq">TA-NIC</a>, used to create human antibodies to destroy <a href="/facts/Nicotine/VQ6HcIrY">nicotine</a> in the human body so that it is no longer effective.<a class="footnote-ref" id="fnref:329" href="#fn:329">329</a></li></ul>
As of September 2023, it was further reported that a vaccine "has been tested against <a href="/facts/Heroin/rYwrKHPk">heroin</a> and <a href="/facts/Fentanyl/MMD9GdD3">fentanyl</a> and is on its way to being tested against <a href="/facts/Oxycontin/mv95L2c7">OxyContin</a>".<a class="footnote-ref" id="fnref:330" href="#fn:330">330</a>

<h2 id="treatment">Treatment</h2>
Main article: <a href="/facts/Treatment_and_management_of_addiction/C80R2AAL">Treatment and management of addiction</a>
To be effective, treatment for addiction that is pharmacological or biologically based need to be accompanied by other interventions such as <a href="/facts/Cognitive_behavioral_therapy/LRALDkkU">cognitive behavioral therapy</a> (CBT) and <a href="/facts/Dialectical_behavioral_therapy/jRwS2zQR">dialectical behavioral therapy</a> (DBT); individual and group psychotherapy, <a href="/facts/Behavior_modification/dIlI7Wan">behavior modification</a> strategies, <a href="/facts/Twelve-step_program/ks7tR2sv">twelve-step programs</a>, and residential treatment facilities.<a class="footnote-ref" id="fnref:331" href="#fn:331">331</a><a class="footnote-ref" id="fnref:332" href="#fn:332">332</a> The <a href="/facts/Transtheoretical_model/xCDs6Il0">transtheoretical model</a> (TTM) can be used to determine when treatment can begin and which method will be most effective. If treatment begins too early, it can cause a person to become <a href="/facts/Defence_mechanism/DElFgLaE">defensive</a> and resistant to change.<a class="footnote-ref" id="fnref:333" href="#fn:333">333</a><a class="footnote-ref" id="fnref:334" href="#fn:334">334</a>

<h2 id="epidemiology">Epidemiology</h2>
Further information: <a href="/facts/Countries_by_alcohol_consumption/W8N0seoL">Countries by alcohol consumption</a>, <a href="/facts/Opioid_epidemic/YLvVEDTs">Opioid epidemic</a>, and <a href="/facts/Prevalence_of_tobacco_use/BFL4kJ77">Prevalence of tobacco use</a>
Due to cultural variations, the proportion of individuals who develop a drug or behavioral addiction within a specified time period (i.e., the <a href="/facts/Prevalence/6UTuTGTH">prevalence</a>) varies over time, by country, and across national <a href="/facts/Demographics/VktYwWUD">population demographics</a> (e.g., by age group, socioeconomic status, etc.).<a class="footnote-ref" id="fnref:335" href="#fn:335">335</a> Where addiction is viewed as unacceptable, there will be fewer people addicted.

<h3>Asia</h3>
The prevalence of alcohol dependence is not as high as is seen in other regions. In Asia, not only socioeconomic factors but biological factors influence drinking behavior.<a class="footnote-ref" id="fnref:336" href="#fn:336">336</a>
Internet addiction disorder is highest in the Philippines, according to both the IAT (Internet Addiction Test) – 5% and the CIAS-R (Revised Chen Internet Addiction Scale) – 21%.<a class="footnote-ref" id="fnref:337" href="#fn:337">337</a>

<h3>Australia</h3>
Further information: <a href="/facts/Alcoholism_in_rural_Australia/KMUAMMlI">Alcoholism in rural Australia</a>
The prevalence of substance use disorder among Australians was reported at 5.1% in 2009.<a class="footnote-ref" id="fnref:338" href="#fn:338">338</a> In 2019 the <a href="/facts/Australian_Institute_of_Health_and_Welfare/xM8jDnWw">Australian Institute of Health and Welfare</a> conducted a national drug survey that quantified drug use for various types of drugs and demographics.<a class="footnote-ref" id="fnref:339" href="#fn:339">339</a> The survey found that in 2019, 11% of people over 14 years old smoke daily; that 9.9% of those who drink alcohol, which equates to 7.5% of the total population age 14 or older, may qualify as alcohol dependent; that 17.5% of the 2.4 million people who used cannabis in the last year may have hazardous use or a dependence problem; and that 63.5% of about 300000 recent users of meth and amphetamines were at risk for developing problem use.<a class="footnote-ref" id="fnref:340" href="#fn:340">340</a>

<h3>Europe</h3>
Further information: <a href="/facts/Alcoholism_in_Ireland/bx6hXBEb">Alcoholism in Ireland</a> and <a href="/facts/Alcoholism_in_Russia/2ELkxpWh">Alcoholism in Russia</a>
In 2015, the estimated prevalence among the adult population was 18.4% for heavy episodic alcohol use (in the past 30 days); 15.2% for daily tobacco smoking; and 3.8% for cannabis use, 0.77% for amphetamine use, 0.37% for opioid use, and 0.35% for cocaine use in 2017. The mortality rates for alcohol and illicit drugs were highest in Eastern Europe.<a class="footnote-ref" id="fnref:341" href="#fn:341">341</a> Data shows a downward trend of alcohol use among children 15 years old in most European countries between 2002 and 2014. First-time alcohol use before the age of 13 was recorded for 28% of European children in 2014.<a class="footnote-ref" id="fnref:342" href="#fn:342">342</a>

<h3>United States</h3>
Further information: <a href="/facts/Cocaine_in_the_United_States/yuzdkJVN">Cocaine in the United States</a>, <a href="/facts/Crack_epidemic_in_the_United_States/bAwccERY">Crack epidemic in the United States</a>, and <a href="/facts/Opioid_epidemic_in_the_United_States/c4MfeJvg">Opioid epidemic in the United States</a>
Based on <a href="/facts/Representative_sample/kIb01xdL">representative samples</a> of the US youth population in 2011, the <a href="/facts/Lifetime_prevalence/6UTuTGTH">lifetime prevalence</a><a class="footnote-ref" id="fnref:343" href="#fn:343">343</a> of addictions to alcohol and illicit drugs has been estimated to be approximately 8% and 2–3% respectively.<a class="footnote-ref" id="fnref:344" href="#fn:344">344</a> Based on representative samples of the US adult population in 2011, the <a href="/facts/Period_prevalence/6UTuTGTH">12-month prevalence</a> of alcohol and illicit drug addictions were estimated at 12% and 2–3% respectively.<a class="footnote-ref" id="fnref:345" href="#fn:345">345</a> The lifetime prevalence of <a href="/facts/Prescription_drug/a2zNYPMq">prescription drug</a> addictions is around 4.7%.<a class="footnote-ref" id="fnref:346" href="#fn:346">346</a>
As of 2021, 43.7 million people aged 12 or older surveyed by the National Survey on Drug Use and Health in the United States needed treatment for an addiction to alcohol, nicotine, or other drugs. The groups with the highest number of people were 18–25 years (25.1%) and "American Indian or Alaska Native" (28.7%).<a class="footnote-ref" id="fnref:347" href="#fn:347">347</a> Only about 10%, or a little over 2 million, receive any form of treatments, and those that do generally do not receive <a href="/facts/Evidence-based_medicine/InK1lB9l">evidence-based care</a>.<a class="footnote-ref" id="fnref:348" href="#fn:348">348</a><a class="footnote-ref" id="fnref:349" href="#fn:349">349</a> One-third of <a href="/facts/Inpatient_care/SWI6UE6E">inpatient</a> hospital costs and 20% of all deaths in the US every year are the result of untreated addictions and risky substance use.<a class="footnote-ref" id="fnref:350" href="#fn:350">350</a><a class="footnote-ref" id="fnref:351" href="#fn:351">351</a> In spite of the massive overall economic cost to society, which is greater than the cost of <a href="/facts/Diabetes/2xeHXbsI">diabetes</a> and all forms of cancer combined, most doctors in the US lack the training to effectively address a drug addiction.<a class="footnote-ref" id="fnref:352" href="#fn:352">352</a><a class="footnote-ref" id="fnref:353" href="#fn:353">353</a>
Estimates of lifetime prevalence rates in the US are 1–2% for compulsive gambling, 5% for sexual addiction, 2.8% for food addiction, and 5–6% for compulsive shopping.<a class="footnote-ref" id="fnref:354" href="#fn:354">354</a> The time-invariant prevalence rate for sexual addiction and related compulsive sexual behavior (e.g., compulsive masturbation with or without pornography, compulsive cybersex, etc.) within the US ranges from 3–6% of the population.<a class="footnote-ref" id="fnref:355" href="#fn:355">355</a>
According to a 2017 poll conducted by the <a href="/facts/Pew_Research_Center/082PuVBq">Pew Research Center</a>, almost half of US adults know a family member or close friend who has struggled with a drug addiction at some point in their life.<a class="footnote-ref" id="fnref:356" href="#fn:356">356</a>
In 2019, opioid addiction was acknowledged as a national crisis in the United States.<a class="footnote-ref" id="fnref:357" href="#fn:357">357</a> An article in <a href="/facts/The_Washington_Post/dRvzvqJc">The Washington Post</a> stated that "America's largest drug companies flooded the country with pain pills from 2006 through 2012, even when it became apparent that they were fueling addiction and overdoses."
The National Epidemiologic Survey on Alcohol and Related Conditions found that from 2012 to 2013 the prevalence of <a href="/facts/Cannabis_use_disorder/69T984ya">Cannabis use disorder</a> in U.S. adults was 2.9%.<a class="footnote-ref" id="fnref:358" href="#fn:358">358</a>

<h3>Canada</h3>
A <a href="/facts/Statistics_Canada/CxVJhh6I">Statistics Canada</a> Survey in 2012 found the lifetime prevalence and 12-month prevalence of substance use disorders were 21.6%, and 4.4% in those 15 and older.<a class="footnote-ref" id="fnref:359" href="#fn:359">359</a> Alcohol abuse or dependence reported a lifetime prevalence of 18.1% and a 12-month prevalence of 3.2%.<a class="footnote-ref" id="fnref:360" href="#fn:360">360</a> Cannabis abuse or dependence reported a lifetime prevalence of 6.8% and a 12-month prevalence of 3.2%.<a class="footnote-ref" id="fnref:361" href="#fn:361">361</a> Other drug abuse or dependence has a lifetime prevalence of 4.0% and a 12-month prevalence of 0.7%.<a class="footnote-ref" id="fnref:362" href="#fn:362">362</a> Substance use disorder is a term used interchangeably with a drug addiction.<a class="footnote-ref" id="fnref:363" href="#fn:363">363</a>
In <a href="/facts/Ontario/HUkxk5Rf">Ontario, Canada</a> between 2009 and 2017, outpatient visits for mental health and addiction increased from 52.6 to 57.2 per 100 people, emergency department visits increased from 13.5 to 19.7 per 1000 people and the number of hospitalizations increased from 4.5 to 5.5 per 1000 people.<a class="footnote-ref" id="fnref:364" href="#fn:364">364</a> Prevalence of care needed increased the most among the 14–17 age group overall.<a class="footnote-ref" id="fnref:365" href="#fn:365">365</a>

<h3>South America</h3>
The realities of opioid use and <a href="/facts/Opioid_use_disorder/WVGM7I24">opioid use disorder</a> in Latin America may be deceptive if observations are limited to epidemiological findings. In the <a href="/facts/United_Nations_Office_on_Drugs_and_Crime/6DxttWVq">United Nations Office on Drugs and Crime</a> report,<a class="footnote-ref" id="fnref:366" href="#fn:366">366</a> although South America produced 3% of the world's morphine and heroin and 0.01% of its opium, prevalence of use is uneven. According to the Inter-American Commission on Drug Abuse Control, consumption of heroin is low in most Latin American countries, although Colombia is the area's largest opium producer. Mexico, because of its border with the United States, has the highest incidence of use.<a class="footnote-ref" id="fnref:367" href="#fn:367">367</a>

<h2 id="etymology">Etymology</h2>
The word addiction derives from the <a href="/facts/Latin/pM3Kge85">Latin</a> "addico", meaning "giving over" with both positive connotations (devotion, dedication) and negative ones (being <a href="/facts/Slavery/IXX2S92u">enslaved</a> to a <a href="/facts/Creditor/kfEGTSzr">creditor</a> in <a href="/facts/Roman_law/m7peoAbG">Roman law</a>). This dual meaning persisted in traditional English dictionaries, encompassing both legal surrender and personal devotion to habits. Later, 19th century <a href="/facts/Temperance_movement/qT39UsE9">temperance movements</a> narrowed the definition of addiction to just drug-related disease, ignoring behavioral addictions and the possibility of positive or neutral addictions. This restrictive view opposes the current understanding of addiction.<a class="footnote-ref" id="fnref:368" href="#fn:368">368</a>
Addiction and addictive behavior are <a href="/facts/Polyseme/en5BnYGW">polysemes</a> denoting a category of <a href="/facts/Mental_disorder/EPNjFtFf">mental disorders</a>, of neuropsychological <a href="/facts/Signs_and_symptoms/BzP6MrTN">symptoms</a>, or of merely <a href="/facts/Maladaptation/n8awwPnV">maladaptive</a>/harmful <a href="/facts/Habit/qISaGCqe">habits</a> and <a href="/facts/Lifestyle_(social_sciences)/XVb7A8lN">lifestyles</a>.<a class="footnote-ref" id="fnref:369" href="#fn:369">369</a> A common use of the term addiction in medicine is for neuropsychological symptoms denoting pervasive/excessive and intense urges to engage in a category of behavioral <a href="/facts/Compulsive_behavior/89bgqdzs">compulsions</a> or <a href="/facts/Impulsivity/WrjoEyg5">impulses</a> towards sensory <a href="/facts/Reward_system/fotI0rcM">rewards</a> (e.g., <a href="/facts/Alcohol_(drug)/IeK2fVd5">alcohol</a>, <a href="/facts/Betel_quid/uQeTwPEl">betel quid</a>, drugs, sex, gambling, video gaming).<a class="footnote-ref" id="fnref:370" href="#fn:370">370</a><a class="footnote-ref" id="fnref:371" href="#fn:371">371</a><a class="footnote-ref" id="fnref:372" href="#fn:372">372</a><a class="footnote-ref" id="fnref:373" href="#fn:373">373</a><a class="footnote-ref" id="fnref:374" href="#fn:374">374</a> Addictive disorders or addiction disorders are mental disorders involving high intensities of addictions (as neuropsychological symptoms) that induce <a href="/facts/Disability/vr9BPUxo">functional disabilities</a> (i.e., limit subjects' social/family and occupational activities); the two categories of such disorders are substance-use addictions and behavioral addictions.<a class="footnote-ref" id="fnref:375" href="#fn:375">375</a><a class="footnote-ref" id="fnref:376" href="#fn:376">376</a><a class="footnote-ref" id="fnref:377" href="#fn:377">377</a><a class="footnote-ref" id="fnref:378" href="#fn:378">378</a>
The <a href="/facts/Etymology/18QG6y67">etymology</a> of the term addiction throughout history has been misunderstood and has taken on various meanings associated with the word.<a class="footnote-ref" id="fnref:379" href="#fn:379">379</a> An example is the usage of the word in the religious landscape of <a href="/facts/Early_modern_Europe/aeYvfAqx">early modern Europe</a>.<a class="footnote-ref" id="fnref:380" href="#fn:380">380</a> "Addiction" at the time meant "to attach" to something, giving it both positive and negative connotations. The object of this attachment could be characterized as "good or bad".<a class="footnote-ref" id="fnref:381" href="#fn:381">381</a> The meaning of addiction during the <a href="/facts/Early_modern_period/hhpHM721">early modern period</a> was mostly associated with positivity and goodness;<a class="footnote-ref" id="fnref:382" href="#fn:382">382</a> during this early modern and highly religious era of <a href="/facts/Christian_revivalism/p0UbXkK9">Christian revivalism</a> and <a href="/facts/Pietism/KI9nYduD">Pietistic tendencies</a>,<a class="footnote-ref" id="fnref:383" href="#fn:383">383</a> it was seen as a way of "devoting oneself to another".<a class="footnote-ref" id="fnref:384" href="#fn:384">384</a>

<h3>The suffixes "-holic" and "-holism"</h3>
In contemporary modern English "-holic" is a <a href="/facts/Suffix/Nlnft3NK">suffix</a> that can be added to a subject to denote an addiction to it. It was extracted from the word alcoholism (one of the first addictions to be widely identified both medically and socially) (correctly the root "alcohol" plus the suffix "-ism") by misdividing or <a href="/facts/Rebracketing/xS5lVA8N">rebracketing</a> it into "alco" and "-holism". There are correct <a href="/facts/Medico-legal/hymH5b44">medico-legal</a> terms for such addictions: <a href="/facts/Dipsomania/vVroKkAn">dipsomania</a> is the medico-legal term for alcoholism;<a class="footnote-ref" id="fnref:385" href="#fn:385">385</a> other examples are in this table:

<table><tbody><tr><th>Colloquial term</th><th>Addiction to</th><th>Medico-legal term</th></tr><tr><td><a href="/facts/Chocoholic/Vb08rhXz">chocoholic</a></td><td>chocolate</td><td></td></tr><tr><td>danceaholic</td><td>dance</td><td><a href="/facts/Choreomania/EI6G0XgM">choreomania</a></td></tr><tr><td><a href="/facts/Rageaholic/Szbf5TPS">rageaholic</a></td><td><a href="/facts/Rage_(emotion)/ABX4XR86">rage</a></td><td></td></tr><tr><td>sexaholic</td><td>sex</td><td><a href="/facts/Erotomania/ym6AxPIe">hypersexuality</a>, satyriasis, nymphomania</td></tr><tr><td>sugarholic</td><td>sugar</td><td>saccharomania</td></tr><tr><td><a href="/facts/Workaholic/bBfVLYxc">workaholic</a></td><td>work</td><td>ergomania</td></tr></tbody></table>
<h2 id="history">History</h2>
<a href="/facts/Addiction_medicine/fSQ95xBv">Modern research on addiction</a> has led to a better understanding of the disease with research on the topic dating back to 1875, specifically on <a href="/facts/Morphine/8ngpXHDc">morphine addiction</a>.<a class="footnote-ref" id="fnref:386" href="#fn:386">386</a> This furthered the understanding of addiction being a medical condition. It was not until the 19th century that addiction was seen and acknowledged in the Western world as a disease, being both a physical condition and <a href="/facts/Mental_illness/EPNjFtFf">mental illness</a>.<a class="footnote-ref" id="fnref:387" href="#fn:387">387</a> Today, addiction is understood both as a biopsychosocial and <a href="/facts/Brain_disorder/EGlB2D4w">neurological disorder</a> that negatively impacts those who are affected by it, most commonly associated with the use of drugs and <a href="/facts/Alcohol_use_disorder/KGPzpChp">excessive use of alcohol</a>.<a class="footnote-ref" id="fnref:388" href="#fn:388">388</a> The understanding of addiction has changed throughout history, which has impacted and continues to impact the ways it is medically treated and diagnosed.

<h2 id="addiction-and-art">Addiction and art</h2>
The arts can be used in a variety of ways to address issues related to addiction. Art can be used as a form of therapy in the treatment of substance use disorders. Creative activities like painting, sculpting, music, and writing can help people express their feelings and experiences in safe and healthy ways. The arts can be used as an assessment tool to identify underlying issues that may be contributing to a person's substance use disorder. Through art, individuals can gain insights into their own motivations and behaviors that can be helpful in determining a course of treatment. Finally, the arts can be used to advocate for those suffering from a substance use disorder by raising awareness of the issue and promoting understanding and compassion. Through art, individuals can share their stories, increase awareness, and offer support and hope to those struggling with substance use disorders.

<h3>As therapy</h3>
Addiction treatment is complex and not always effective due to engagement and service availability concerns, so researchers prioritize efforts to improve treatment retention and decrease relapse rates.<a class="footnote-ref" id="fnref:389" href="#fn:389">389</a><a class="footnote-ref" id="fnref:390" href="#fn:390">390</a> Characteristics of substance abuse may include feelings of <a href="/facts/Social_isolation/dnt9BzA8">isolation</a>, a lack of confidence, communication difficulties, and a perceived lack of control.<a class="footnote-ref" id="fnref:391" href="#fn:391">391</a> In a similar vein, people suffering from substance use disorders tend to be highly sensitive, creative, and as such, are likely able to express themselves meaningfully in creative arts such as dancing, painting, writing, music, and acting.<a class="footnote-ref" id="fnref:392" href="#fn:392">392</a> Further evidenced by Waller and Mahony (2002)<a class="footnote-ref" id="fnref:393" href="#fn:393">393</a> and Kaufman (1981),<a class="footnote-ref" id="fnref:394" href="#fn:394">394</a> the creative arts therapies can be a suitable treatment option for this population especially when verbal communication is ineffective.
Primary advantages of art therapy in the treatment of addiction have been identified as:<a class="footnote-ref" id="fnref:395" href="#fn:395">395</a><a class="footnote-ref" id="fnref:396" href="#fn:396">396</a>

<ul><li>Assess and characterize a client's substance use issues</li>
<li>Bypassing a client's resistances, defenses, and denial</li>
<li>Containing shame or anger</li>
<li>Facilitating the expression of suppressed and/or complicated emotions</li>
<li>Highlighting a client's strengths</li>
<li>Providing an alternative to verbal communication (via use of symbols) and conventional forms of therapy</li>
<li>Providing clients with a sense of control</li>
<li>Tackling feelings of isolation</li></ul>
Art therapy is an effective method of dealing with substance abuse in comprehensive treatment models. When included in psychoeducational programs, art therapy in a group setting can help clients internalize taught concepts in a more personalized manner.<a class="footnote-ref" id="fnref:397" href="#fn:397">397</a> During the course of treatment, by examining and comparing artwork created at different times, art therapists can be helpful in identifying and diagnosing issues, as well as charting the extent or direction of improvement as a person detoxifies.<a class="footnote-ref" id="fnref:398" href="#fn:398">398</a> Where increasing adherence to treatment regimes and maintaining abstinence is the target; art therapists can aid by customizing treatment directives (encourage the client to create collages that compare pros and cons, pictures that compare past and present and future, and drawings that depict what happened when a client went off medication).<a class="footnote-ref" id="fnref:399" href="#fn:399">399</a>
Art therapy can function as a complementary therapy used in conjunction with more conventional therapies and can integrate with harm reduction protocols to minimize the negative effects of drug use.<a class="footnote-ref" id="fnref:400" href="#fn:400">400</a><a class="footnote-ref" id="fnref:401" href="#fn:401">401</a> An evaluation of art therapy incorporation within a pre-existing Addiction Treatment Programme based on the 12 step Minnesota Model endorsed by the Alcoholics Anonymous found that 66% of participants expressed the usefulness of art therapy as a part of treatment.<a class="footnote-ref" id="fnref:402" href="#fn:402">402</a><a class="footnote-ref" id="fnref:403" href="#fn:403">403</a> Within the weekly art therapy session, clients were able to reflect and process the intense emotions and cognitions evoked by the programme. In turn, the art therapy component of the programme fostered stronger self-awareness, exploration, and externalization of repressed and unconscious emotions of clients, promoting the development of a more integrated 'authentic self'.<a class="footnote-ref" id="fnref:404" href="#fn:404">404</a><a class="footnote-ref" id="fnref:405" href="#fn:405">405</a>
Despite the large number of randomized control trials, clinical control trials, and anecdotal evidence supporting the effectiveness of art therapies for use in addiction treatment, a systematic review conducted in 2018 could not find enough evidence on visual art, drama, dance and movement therapy, or 'arts in health' methodologies to confirm their effectiveness as interventions for reducing substance misuse.<a class="footnote-ref" id="fnref:406" href="#fn:406">406</a> Music therapy was identified to have potentially strong beneficial effects in aiding contemplation and preparing those diagnosed with substance use for treatment.<a class="footnote-ref" id="fnref:407" href="#fn:407">407</a>

<h3>As an assessment tool</h3>
The Formal Elements Art Therapy Scale (FEATS) is an assessment tool used to evaluate drawings created by people suffering from substance use disorders by comparing them to drawings of a control group (consisting of individuals without SUDs).<a class="footnote-ref" id="fnref:408" href="#fn:408">408</a><a class="footnote-ref" id="fnref:409" href="#fn:409">409</a> FEATS consists of twelve elements, three of which were found to be particularly effective at distinguishing the drawings of those with SUDs from those without: Person, Realism, and Developmental. The Person element assesses the degree to which a human features are depicted realistically, the Realism element assesses the overall complexity of the artwork, and the Developmental element assesses "developmental age" of the artwork in relation to standardized drawings from children and adolescents.<a class="footnote-ref" id="fnref:410" href="#fn:410">410</a> By using the FEATS assessment tool, clinicians can gain valuable insight into the drawings of individuals with SUDs, and can compare them to those of the control group. Formal assessments such as FEATS provide healthcare providers with a means to quantify, standardize, and communicate abstract and visceral characteristics of SUDs to provide more accurate diagnoses and informed treatment decisions.<a class="footnote-ref" id="fnref:411" href="#fn:411">411</a>
Other artistic assessment methods include the Bird's Nest Drawing: a useful tool for visualizing a client's attachment security.<a class="footnote-ref" id="fnref:412" href="#fn:412">412</a><a class="footnote-ref" id="fnref:413" href="#fn:413">413</a> This assessment method looks at the amount of color used in the drawing, with a lack of color indicating an 'insecure attachment', a factor that the client's therapist or recovery framework must take into account.<a class="footnote-ref" id="fnref:414" href="#fn:414">414</a>
Art therapists working with children of parents suffering from alcoholism can use the Kinetic Family Drawings assessment tool to shed light on family dynamics and help children express and understand their family experiences.<a class="footnote-ref" id="fnref:415" href="#fn:415">415</a><a class="footnote-ref" id="fnref:416" href="#fn:416">416</a> The KFD can be used in family sessions to allow children to share their experiences and needs with parents who may be in recovery from alcohol use disorder. Depiction of isolation of self and isolation of other family members may be an indicator of parental alcoholism.<a class="footnote-ref" id="fnref:417" href="#fn:417">417</a>

<h3>Advocacy</h3>
Stigma can lead to feelings of shame that can prevent people with substance use disorders from seeking help and interfere with provision of harm reduction services.<a class="footnote-ref" id="fnref:418" href="#fn:418">418</a><a class="footnote-ref" id="fnref:419" href="#fn:419">419</a><a class="footnote-ref" id="fnref:420" href="#fn:420">420</a> It can influence healthcare policy, making it difficult for these individuals to access treatment.<a class="footnote-ref" id="fnref:421" href="#fn:421">421</a>
Artists attempt to change the societal perception of addiction from a punishable moral offense to instead a chronic illness necessitating treatment. This form of advocacy can help to relocate the fight of addiction from a judicial perspective to the public health system.<a class="footnote-ref" id="fnref:422" href="#fn:422">422</a>
Artists who have personally lived with addiction or undergone recovery may use art to depict their experiences in a manner that uncovers the "human face of addiction". By bringing experiences of addiction and recovery to a personal level and breaking down the "us and them", the viewer may be more inclined to show compassion, forego stereotypes and stigma of addiction, and label addiction as a social rather than individual problem.<a class="footnote-ref" id="fnref:423" href="#fn:423">423</a>
According to Santora<a class="footnote-ref" id="fnref:424" href="#fn:424">424</a> the main purposes in using art as a form of advocacy in the education and prevention of substance use disorders include:

<ul><li>Addiction art exhibitions can come from a variety of sources, but the underlying message of these works is the same: to communicate through emotions without relying on intellectually demanding/gatekept facts and figures. These exhibitions can either stand alone, reinforce, or challenge facts.</li>
<li>A powerful educational tool for increasing awareness and understanding of addiction as a medical illness. Exhibitions featuring personal stories and images can help to create lasting impressions on diverse audiences (including addiction scientists/researchers, family/friends of those affected by addiction etc.), highlighting the humanity of the problem and in turn encouraging compassion and understanding.</li>
<li>A way to destigmatize substance use disorders and shift public perception from viewing them as a moral failing to understanding them as a chronic medical condition which requires treatment.</li>
<li>Provide those who are struggling with addiction assurance and encouragement of healing, and let them know that they are not alone in their struggle.</li>
<li>The use of visual arts can help bring attention to the lack of adequate substance use treatment, prevention, and education programs and services in a healthcare system. Messages can encourage policymakers to allocate more resources to addiction treatment and prevention from federal, state, and local levels.</li></ul>
The Temple University College of Public Health department conducted a project to promote awareness around opioid use and reduce associated stigma by asking students to create art pieces that were displayed on a website they created and promoted via social media.<a class="footnote-ref" id="fnref:425" href="#fn:425">425</a> Quantitative and qualitative data was recorded to measure engagement, and the student artists were interviewed, which revealed a change in perspective and understanding, as well as greater appreciation of diverse experiences. Ultimately, the project found that art was an effective medium for empowering both the artist creating the work and the person interacting with it.<a class="footnote-ref" id="fnref:426" href="#fn:426">426</a>
Another author critically examined works by contemporary Canadian artists that deal with addiction via the metaphor of a cultural landscape to "unmap" and "remap" ideologies related to Indigenous communities and addiction to demonstrate how colonial violence in Canada has drastically impacted the relationship between Indigenous peoples, their land, and substance abuse.<a class="footnote-ref" id="fnref:427" href="#fn:427">427</a>
A project known as "Voice" was a collection of art, poetry and narratives created by women living with a history of addiction to explore women's understanding of harm reduction, challenge the effects of stigma and give voice to those who have historically been silenced or devalued.<a class="footnote-ref" id="fnref:428" href="#fn:428">428</a> In the project, nurses with knowledge of mainstream systems, aesthetic knowing, feminism and substance use organized weekly gatherings, wherein women with histories of substance use and addiction worked alongside a nurse to create artistic expressions. Creations were presented at several venues, including an International Conference on Drug Related Harm, a Nursing Conference and a local gallery to positive community response.<a class="footnote-ref" id="fnref:429" href="#fn:429">429</a>

<h2 id="social-scientific-models">Social scientific models</h2>

<h3>Biopsychosocial–cultural–spiritual</h3>
While regarded <a href="/facts/Biomedicine/DWFT3MFG">biomedically</a> as a <a href="/facts/Neuropsychology/eWY83ago">neuropsychological</a> disorder, addiction is multi-layered, with <a href="/facts/Biology/1M1ee3pB">biological</a>, psychological, social, <a href="/facts/Culture/c5JgMqpX">cultural</a>, and <a href="/facts/Spirituality/o2neYDkN">spiritual</a> (biopsychosocial–cultural–spiritual) elements.<a class="footnote-ref" id="fnref:430" href="#fn:430">430</a><a class="footnote-ref" id="fnref:431" href="#fn:431">431</a> A biopsychosocial–cultural–spiritual approach fosters the crossing of <a href="/facts/Academic_discipline/pKoQHpYL">disciplinary</a> boundaries, and promotes <a href="/facts/Holism/QnIpnLr6">holistic</a> considerations of addiction.<a class="footnote-ref" id="fnref:432" href="#fn:432">432</a><a class="footnote-ref" id="fnref:433" href="#fn:433">433</a><a class="footnote-ref" id="fnref:434" href="#fn:434">434</a> A biopsychosocial–cultural–spiritual approach considers, for example, how physical environments influence experiences, habits, and patterns of addiction.
<a href="/facts/Ethnography/qxJRLSwJ">Ethnographic</a> engagements and developments in fields of knowledge have contributed to biopsychosocial–cultural–spiritual understandings of addiction, including the work of <a href="/facts/Philippe_Bourgois/6udDdHnn">Philippe Bourgois</a>, whose <a href="/facts/Field_research/HctlVRR8">fieldwork</a> with street-level drug dealers in <a href="/facts/East_Harlem/tqpUuWRp">East Harlem</a> highlights correlations between drug use and structural <a href="/facts/Oppression/7Mp3lUwq">oppression</a> in the United States.<a class="footnote-ref" id="fnref:435" href="#fn:435">435</a> Prior models that have informed the prevailing biopsychosocial–cultural–spiritual consideration of addiction include:

<h3>Cultural model</h3>
The cultural model, an <a href="/facts/Anthropology/W6WK1C3a">anthropological</a> understanding of the emergence of drug use and abuse, was developed by <a href="/facts/Dwight_B._Heath/SyIzn3rL">Dwight Heath</a>.<a class="footnote-ref" id="fnref:436" href="#fn:436">436</a> Heath undertook ethnographic research and <a href="/facts/Field_research/HctlVRR8">fieldwork</a> with the <a href="/facts/Camba/IN7eoGHJ">Camba</a> people of <a href="/facts/Bolivia/YNBoDKKR">Bolivia</a> from June 1956 to August 1957.<a class="footnote-ref" id="fnref:437" href="#fn:437">437</a> Heath observed that adult members of society drank 'large quantities of <a href="/facts/Rum/a146KQB5">rum</a> and became intoxicated for several contiguous days at least twice a month'.<a class="footnote-ref" id="fnref:438" href="#fn:438">438</a> This frequent, heavy drinking from which <a href="/facts/Alcohol_intoxication/Kk9hRcsK">intoxication</a> followed was typically undertaken socially, during festivals.<a class="footnote-ref" id="fnref:439" href="#fn:439">439</a> Having returned in 1989, Heath observed that while much had changed, 'drinking parties' remained, as per his initial observations, and 'there appear to be no harmful consequences to anyone'.<a class="footnote-ref" id="fnref:440" href="#fn:440">440</a> Heath's observations and <a href="/facts/Social_interaction/DU3HW2Ah">interactions</a> reflected that this form of <a href="/facts/Social_behavior/RJtLfpfE">social behavior</a>, the habitual heavy consumption of alcohol, was encouraged and valued, enforcing social bonds in the Camba community.<a class="footnote-ref" id="fnref:441" href="#fn:441">441</a> Despite frequent intoxication, "even to the point of unconsciousness", the Camba held no concept of alcoholism (a form of addiction), and no visible social problems associated with drunkenness, or addiction, were apparent.<a class="footnote-ref" id="fnref:442" href="#fn:442">442</a>
As noted by <a href="/facts/Merrill_Singer/UDVHTFnI">Merrill Singer</a>, Heath's findings, when considered alongside subsequent cross-cultural experiences, challenged the perception that <a href="/facts/Substance_intoxication/LRnMxrKd">intoxication</a> is socially 'inherently disruptive'.<a class="footnote-ref" id="fnref:443" href="#fn:443">443</a> Following this <a href="/facts/Fieldwork/w66x8LQq">fieldwork</a>, Heath proposed the 'cultural model', suggesting that 'problems' associated with heavy drinking, such as alcoholism – a recognised form addiction – were cultural: that is, that alcoholism is determined by cultural beliefs, and therefore varies among cultures. Heath's findings challenged the notion that 'continued use [of alcohol] is inexorably addictive and damaging to the consumer's health'.<a class="footnote-ref" id="fnref:444" href="#fn:444">444</a><a class="footnote-ref" id="fnref:445" href="#fn:445">445</a>
The cultural model did face criticism by <a href="/facts/Sociology/d2Fd0N87">Sociologist</a> <a href="/facts/Robin_Room/BehYnBT6">Robin Room</a> and others, who felt anthropologists could "downgrade the severity of the problem".<a class="footnote-ref" id="fnref:446" href="#fn:446">446</a> Merrill Singer found it notable that the ethnographers working within the prominence of the cultural model were part of the 'wet generation': while not blind to the 'disruptive, dysfunctional and debilitating effects of alcohol consumption', they were products 'socialized to view alcohol consumption as normal'.<a class="footnote-ref" id="fnref:447" href="#fn:447">447</a>

<h3>Subcultural model</h3>
Historically, addiction has been viewed from the <a href="/facts/Emic_and_etic/00lCf8PT">etic</a> perspective, defining users through the <a href="/facts/Pathology/U9b18LJG">pathology</a> of their condition.<a class="footnote-ref" id="fnref:448" href="#fn:448">448</a> As reports of drug use rapidly increased, the cultural model found application in anthropological research exploring western drug <a href="/facts/Subculture/xUYDM25I">subculture</a> practices.<a class="footnote-ref" id="fnref:449" href="#fn:449">449</a>
The approach evolved from the ethnographic exploration into the lived experiences and <a href="/facts/Subjectivity/XVvftgCU">subjectivities</a> of 1960s and 1970s drug subcultures.<a class="footnote-ref" id="fnref:450" href="#fn:450">450</a> The seminal publication "Taking care of business", by Edward Preble and John J. Casey, documented the daily lives of New York street-based intravenous heroin users in rich detail, providing unique insight into the dynamic social worlds and activities that surrounded their drug use.<a class="footnote-ref" id="fnref:451" href="#fn:451">451</a> These findings challenge popular narratives of <a href="/facts/Immorality/o2fMklhR">immorality</a> and <a href="/facts/Deviance_(sociology)/LY4d0Ied">deviance</a>, conceptualizing substance abuse as a social <a href="/facts/Phenomenon/4CBrlVeW">phenomenon</a>. The prevailing culture can have a greater influence on drug taking behaviors than the physical and psychological effects of the drug itself.<a class="footnote-ref" id="fnref:452" href="#fn:452">452</a>[better source needed] To <a href="/facts/Social_exclusion/8or1ar6F">marginalized</a> individuals, drug subcultures can provide social connection, <a href="/facts/Symbol/GS8mTn0h">symbolic</a> meaning, and socially constructed purpose that they may feel is unattainable through conventional means.<a class="footnote-ref" id="fnref:453" href="#fn:453">453</a> The subcultural model demonstrates the complexities of addiction, highlighting the need for an integrated approach. It contends that a <a href="/facts/Biosocial_theory/FXq4nv3I">biosocial</a> approach is required to achieve a holistic understanding of addiction.<a class="footnote-ref" id="fnref:454" href="#fn:454">454</a>

<h3>Critical medical anthropology model</h3>
Emerging in the early 1980s, the critical medical anthropology model was introduced, and as Merrill Singer offers 'was applied quickly to the analysis of drug use'.<a class="footnote-ref" id="fnref:455" href="#fn:455">455</a> Where the cultural model of the 1950s looked at the social body, the critical medical anthropology model revealed the <a href="/facts/Body_politic/6FVpuGgp">body politic</a>, considering drug use and addiction within the context of macro level structures including larger political systems, <a href="/facts/Economic_inequality/2Kb0kBH5">economic inequalities</a>, and the institutional power held over social processes.<a class="footnote-ref" id="fnref:456" href="#fn:456">456</a>
Highly relevant to addiction, the three issues emphasized in the model are:

<ul><li><a href="/facts/Self-medication/wkD9fMtg">Self-medication</a></li>
<li>The social production of suffering</li>
<li>The political economy (<a href="/facts/Licit_and_Illicit_Drugs/5qHm74YS">Licit and Illicit Drugs</a>)<a class="footnote-ref" id="fnref:457" href="#fn:457">457</a></li></ul>
These three key points highlight how drugs may come to be used to self-medicate the <a href="/facts/Psychological_trauma/7UMnzzBy">psychological trauma</a> of socio-political disparity and <a href="/facts/Injustice/96GJB79t">injustice</a>, intertwining with <a href="/facts/Licit_and_Illicit_Drugs/5qHm74YS">licit and illicit drug</a> market politics.<a class="footnote-ref" id="fnref:458" href="#fn:458">458</a> Social suffering, "the misery among those on the weaker end of power relations in terms of physical health, mental health and lived experience", is used by anthropologists to analyze how individuals may have personal problems caused by political and economic power.<a class="footnote-ref" id="fnref:459" href="#fn:459">459</a> From the perspective of critical medical anthropology heavy drug use and addiction is a consequence of such larger scale unequal distributions of power.<a class="footnote-ref" id="fnref:460" href="#fn:460">460</a>
The three models developed here – the cultural model, the subcultural model, and the Critical Medical Anthropology Model – display how addiction is not an experience to be considered only biomedically. Through consideration of addiction alongside the biological, psychological, social, cultural and spiritual (biopsychosocial–spiritual) elements which influence its experience, a holistic and comprehensive understanding can be built.

<h2 id="social-learning-models">Social learning models</h2>
<h3>Social learning theory</h3>
Main article: <a href="/facts/Social_learning_theory/IcbScxFv">Social learning theory</a>
Albert Bandura's 1977 social learning theory posits that individuals acquire addictive behaviors by observing and imitating models in their social environment.<a class="footnote-ref" id="fnref:461" href="#fn:461">461</a><a class="footnote-ref" id="fnref:462" href="#fn:462">462</a> The likelihood of engaging in and sustaining similar addictive behaviors is influenced by the reinforcement and punishment observed in others. The principle of reciprocal determinism suggests that the functional relationships between personal, environmental, and behavioral factors act as determinants of addictive behavior.<a class="footnote-ref" id="fnref:463" href="#fn:463">463</a> Thus, effective treatment targets each dynamic facet of the biopsychosocial disorder.

<h3>Transtheoretical model (stages of change model)</h3>
Main article: <a href="/facts/Transtheoretical_model/xCDs6Il0">Transtheoretical model</a>
The transtheoretical model of change suggests that overcoming an addiction is a stepwise process that occurs through several stages.<a class="footnote-ref" id="fnref:464" href="#fn:464">464</a>
Precontemplation: This initial stage precedes individuals considering a change in their behavior. They might be oblivious to or in denial of their addiction, failing to recognize the need for change.
Contemplation is the stage in which individuals become aware of the problems caused by their addiction and are considering change. Although they may not fully commit, they weigh the costs and benefits of making a shift.
Preparation: Individuals in this stage are getting ready to change. They might have taken preliminary steps, like gathering information or making small commitments, in preparation for behavioral change.
Action involves actively modifying behavior by making specific, observable changes to address the addictive behavior. The action stage requires significant effort and commitment.
Maintenance: After successfully implementing a change, individuals enter the maintenance stage, where they work to sustain the new behavior and prevent relapse. This stage is characterized by ongoing effort and consolidation of gains.
Termination/relapse prevention: Recognizing that relapse is a common part of the change process, this stage focuses on identifying and addressing factors that may lead to a return to old behaviors. Relapse is viewed as an opportunity for learning and strategy adjustment, with the ultimate goal of eliminating or terminating the targeted behavior.
The transtheoretical model can be helpful in guiding development of tailored behavioral interventions that can promote lasting change. Progression through these stages may not always follow a linear path, as individuals may move back and forth between stages. Resistance to change is recognized as an expected part of the process.
Addiction causes an "astoundingly high financial and human toll" on individuals and society as a whole.<a class="footnote-ref" id="fnref:465" href="#fn:465">465</a><a class="footnote-ref" id="fnref:466" href="#fn:466">466</a><a class="footnote-ref" id="fnref:467" href="#fn:467">467</a> In the United States, the total economic cost to society is greater than that of all types of diabetes and all cancers combined.<a class="footnote-ref" id="fnref:468" href="#fn:468">468</a> These costs arise from the direct adverse effects of drugs and associated healthcare costs (e.g., emergency medical services and outpatient and inpatient care), long-term complications (e.g., lung cancer from smoking tobacco products, <a href="/facts/Liver_cirrhosis/bkLuLvCD">liver cirrhosis</a> and <a href="/facts/Alcohol-related_dementia/TMnsS7YK">dementia</a> from chronic alcohol consumption, and <a href="/facts/Meth_mouth/m1Fudljg">meth mouth</a> from methamphetamine use), the loss of productivity and associated welfare costs, fatal and non-fatal accidents (e.g., traffic collisions), suicides, homicides, and incarceration, among others.<a class="footnote-ref" id="fnref:469" href="#fn:469">469</a><a class="footnote-ref" id="fnref:470" href="#fn:470">470</a><a class="footnote-ref" id="fnref:471" href="#fn:471">471</a><a class="footnote-ref" id="fnref:472" href="#fn:472">472</a> The US National Institute on Drug Abuse has found that overdose deaths in the US have almost tripled among males and females from 2002 to 2017, with 72,306 overdose deaths reported in 2017 in the US.<a class="footnote-ref" id="fnref:473" href="#fn:473">473</a> 2020 marked the year with the highest number of overdose deaths over a 12-month period, with 81,000 overdose deaths, exceeding the records set in 2017.<a class="footnote-ref" id="fnref:474" href="#fn:474">474</a>

<h2 id="see-also">See also</h2>

<ul><li><a href="/facts/Autonomic_nervous_system/hdmEY1Ay">Autonomic nervous system</a></li>
<li><a href="/facts/Binge_drinking/hU8kBLq4">Binge drinking</a></li>
<li><a href="/facts/Binge_eating_disorder/4KSgj3BV">Binge eating disorder</a></li>
<li><a href="/facts/Cognitive_liberty/aNN2xly7">Cognitive liberty</a></li>
<li><a href="/facts/Darwinian_hedonism/u0d36w3f">Darwinian hedonism</a></li>
<li><a href="/facts/Discrimination_against_drug_addicts/Gvn5E74H">Discrimination against drug addicts</a></li>
<li><a href="/facts/Dopaminergic_pathways/EFooas5U">Dopaminergic pathways</a></li>
<li><a href="/facts/Pavlovian-instrumental_transfer/etBvA1MQ">Pavlovian-instrumental transfer</a></li>
<li><a href="/facts/Philosophy_of_medicine/KrUeE0Fw">Philosophy of medicine</a></li>
<li><a href="/facts/Substance_dependence/x9qrReh4">Substance dependence</a></li></ul>
<h2 id="endnotes">Endnotes</h2>

<h2 id="notes">Notes</h2>

Image legend

<h2 id="further-reading">Further reading</h2>

<ul><li>Pelchat ML (March 2009). <a href="https://doi.org/10.3945%2Fjn.108.097816">"Food Addiction in Humans"</a>. The Journal of Nutrition. 139 (3): 620–622. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.3945%2Fjn.108.097816">10.3945/jn.108.097816</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/19176747">19176747</a>.</li>
<li>Gordon HW (April 2016). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811731">"Laterality of Brain Activation for Risk Factors of Addiction"</a>. Current Drug Abuse Reviews. 9 (1): 1–18. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.2174%2F1874473709666151217121309">10.2174/1874473709666151217121309</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811731">4811731</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/26674074">26674074</a>.</li>
<li>Szalavitz M (2016). <a href="https://archive.org/details/unbrokenbrainrev0000szal">Unbroken Brain</a>. <a href="/facts/St._Martin%2527s_Press/a8JmlhsC">St. Martin's Press</a>. <a href="/facts/ISBN_(identifier)/15AdSPa9">ISBN</a> 978-1-250-05582-8.</li>
<li>Courtwright DT (2019). The Age of Addiction: How Bad Habits Became Big Business. Cambridge, Massachusetts: <a href="/facts/Harvard_University_Press/YluAnq74">Harvard University Press</a>. <a href="/facts/ISBN_(identifier)/15AdSPa9">ISBN</a> 9780674248229.</li></ul>

<h2 id="external-links">External links</h2>

Look up -ism in Wiktionary, the free dictionary.

Look up -holic in Wiktionary, the free dictionary.

Wikimedia Commons has media related to Addictions.

<ul><li><a href="http://learn.genetics.utah.edu/content/addiction/">"The Science of Addiction: Genetics and the Brain"</a>. learn.genetics.utah.edu. Learn.Genetics – <a href="/facts/University_of_Utah/0lhlnv7c">University of Utah</a>.</li>
<li><a href="http://www.tedmed.com/talks/show?id=309096">Why do our brains get addicted?</a> – a <a href="/facts/TEDMED/mkaDn1y6">TEDMED</a> 2014 talk by <a href="/facts/Nora_Volkow/vxd2uAJo">Nora Volkow</a>, the director of the <a href="/facts/National_Institute_on_Drug_Abuse/SjgLWamH">National Institute on Drug Abuse</a> at <a href="/facts/National_Institutes_of_Health/G3Eytfcc">NIH</a>.</li></ul>
<a href="/facts/Kyoto_Encyclopedia_of_Genes_and_Genomes/pK5La8ad">Kyoto Encyclopedia of Genes and Genomes</a> (KEGG) signal transduction pathways:

<ul><li><a href="http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354">KEGG – human alcohol addiction</a></li>
<li><a href="http://www.genome.jp/kegg-bin/show_pathway?hsa05031+2354">KEGG – human amphetamine addiction</a></li>
<li><a href="http://www.genome.jp/kegg-bin/show_pathway?hsa05030+2354">KEGG – human cocaine addiction</a></li></ul>

<h2 id="references">References</h2>

<ol>
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<li id="fn:2">Heilig M, MacKillop J, Martinez D, Rehm J, Leggio L, Vanderschuren LJ (September 2021). "Addiction as a brain disease revised: why it still matters, and the need for consilience". Neuropsychopharmacology. 46 (10): 1715–1723. doi:10.1038/s41386-020-00950-y. ISSN 0893-133X. PMC 8357831. PMID 33619327. pre-existing vulnerabilities and persistent drug use lead to a vicious circle of substantive disruptions in the brain that impair and undermine choice capacities for adaptive behavior, but do not annihilate them. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357831" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357831</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></li>
<li id="fn:3">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></li>
<li id="fn:4">"Drugs, Brains, and Behavior: The Science of Addiction – Drug Misuse and Addiction". www.drugabuse.gov. North Bethesda, Maryland: National Institute on Drug Abuse. 13 July 2020. Retrieved 23 December 2021. <a href="https://www.drugabuse.gov/publications/drugs-brains-behavior-science-addiction/drug-misuse-addiction" target="_blank">https://www.drugabuse.gov/publications/drugs-brains-behavior-science-addiction/drug-misuse-addiction</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></li>
<li id="fn:5">Henden E (2017). "Addiction, Compulsion, and Weakness of the Will: A Dual-Process Perspective.". In Heather N, Gabriel S (eds.). Addiction and Choice: Rethinking the Relationship. Oxford, UK: Oxford University Press. pp. 116–132. <a href="#fnref:5" class="footnote-back-ref">↩</a></li>
<li id="fn:6">In other words, a person cannot control the neurobiological processes that occur in the body in response to using an addictive drug. A person can make a voluntary choice to, for example, start using a drug (or not), or to seek help after becoming addicted, although resisting the urge to use drug(s) becomes increasingly difficult as addiction worsens. See [2] for detailed discussion. <a href="#fnref:6" class="footnote-back-ref">↩</a></li>
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<li id="fn:32">Maxwell AL, Gardiner E, Loxton NJ (9 February 2020). "Investigating the relationship between reward sensitivity, impulsivity, and food addiction: A systematic review". European Eating Disorders Review. 28 (4): 368–384. doi:10.1002/erv.2732. ISSN 1099-0968. PMID 32142199. S2CID 212565361. Retrieved 9 March 2023. <a href="https://doi.org/10.1002/erv.2732" target="_blank">https://doi.org/10.1002/erv.2732</a> <a href="#fnref:32" class="footnote-back-ref">↩</a></li>
<li id="fn:33">Skylstad V, Babirye JN, Kiguli J, Solheim Skar AM, et al. (March 2022). "Are we overlooking alcohol use by younger children?". BMJ Paediatrics Open. 6 (1): e001242. doi:10.1136/bmjpo-2021-001242. PMC 8905875. PMID 36053657. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875</a> <a href="#fnref:33" class="footnote-back-ref">↩</a></li>
<li id="fn:34">Skylstad V, Babirye JN, Kiguli J, Solheim Skar AM, et al. (March 2022). "Are we overlooking alcohol use by younger children?". BMJ Paediatrics Open. 6 (1): e001242. doi:10.1136/bmjpo-2021-001242. PMC 8905875. PMID 36053657. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875</a> <a href="#fnref:34" class="footnote-back-ref">↩</a></li>
<li id="fn:35">Skylstad V, Babirye JN, Kiguli J, Solheim Skar AM, et al. (March 2022). "Are we overlooking alcohol use by younger children?". BMJ Paediatrics Open. 6 (1): e001242. doi:10.1136/bmjpo-2021-001242. PMC 8905875. PMID 36053657. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875</a> <a href="#fnref:35" class="footnote-back-ref">↩</a></li>
<li id="fn:36">NIDA (13 July 2020). "Drug Misuse and Addiction". National Institute of Drug Abuse. U.S. Department of Health and Human Services. Retrieved 15 November 2022. <a href="https://nida.nih.gov/publications/drugs-brains-behavior-science-addiction/drug-misuse-addiction" target="_blank">https://nida.nih.gov/publications/drugs-brains-behavior-science-addiction/drug-misuse-addiction</a> <a href="#fnref:36" class="footnote-back-ref">↩</a></li>
<li id="fn:37">Skylstad V, Babirye JN, Kiguli J, Solheim Skar AM, et al. (March 2022). "Are we overlooking alcohol use by younger children?". BMJ Paediatrics Open. 6 (1): e001242. doi:10.1136/bmjpo-2021-001242. PMC 8905875. PMID 36053657. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875</a> <a href="#fnref:37" class="footnote-back-ref">↩</a></li>
<li id="fn:38">di Giacomo E, Aliberti F, Pescatore F, Santorelli M, Pessina R, Placenti V, et al. (August 2022). "Disentangling binge eating disorder and food addiction: a systematic review and meta-analysis". Eating and Weight Disorders. 27 (6): 1963–1970. doi:10.1007/s40519-021-01354-7. PMC 9287203. PMID 35041154. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203</a> <a href="#fnref:38" class="footnote-back-ref">↩</a></li>
<li id="fn:39">Maxwell AL, Gardiner E, Loxton NJ (9 February 2020). "Investigating the relationship between reward sensitivity, impulsivity, and food addiction: A systematic review". European Eating Disorders Review. 28 (4): 368–384. doi:10.1002/erv.2732. ISSN 1099-0968. PMID 32142199. S2CID 212565361. Retrieved 9 March 2023. <a href="https://doi.org/10.1002/erv.2732" target="_blank">https://doi.org/10.1002/erv.2732</a> <a href="#fnref:39" class="footnote-back-ref">↩</a></li>
<li id="fn:40">di Giacomo E, Aliberti F, Pescatore F, Santorelli M, Pessina R, Placenti V, et al. (August 2022). "Disentangling binge eating disorder and food addiction: a systematic review and meta-analysis". Eating and Weight Disorders. 27 (6): 1963–1970. doi:10.1007/s40519-021-01354-7. PMC 9287203. PMID 35041154. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203</a> <a href="#fnref:40" class="footnote-back-ref">↩</a></li>
<li id="fn:41">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:41" class="footnote-back-ref">↩</a></li>
<li id="fn:42">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:42" class="footnote-back-ref">↩</a></li>
<li id="fn:43">Goodman B (3 September 2022). Casarella J (ed.). "Food Addiction Signs and Treatments". WebMD. Retrieved 9 March 2023. <a href="https://www.webmd.com/mental-health/eating-disorders/binge-eating-disorder/mental-health-food-addiction" target="_blank">https://www.webmd.com/mental-health/eating-disorders/binge-eating-disorder/mental-health-food-addiction</a> <a href="#fnref:43" class="footnote-back-ref">↩</a></li>
<li id="fn:44">di Giacomo E, Aliberti F, Pescatore F, Santorelli M, Pessina R, Placenti V, et al. (August 2022). "Disentangling binge eating disorder and food addiction: a systematic review and meta-analysis". Eating and Weight Disorders. 27 (6): 1963–1970. doi:10.1007/s40519-021-01354-7. PMC 9287203. PMID 35041154. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203</a> <a href="#fnref:44" class="footnote-back-ref">↩</a></li>
<li id="fn:45">Maxwell AL, Gardiner E, Loxton NJ (9 February 2020). "Investigating the relationship between reward sensitivity, impulsivity, and food addiction: A systematic review". European Eating Disorders Review. 28 (4): 368–384. doi:10.1002/erv.2732. ISSN 1099-0968. PMID 32142199. S2CID 212565361. Retrieved 9 March 2023. <a href="https://doi.org/10.1002/erv.2732" target="_blank">https://doi.org/10.1002/erv.2732</a> <a href="#fnref:45" class="footnote-back-ref">↩</a></li>
<li id="fn:46">Goodman B (3 September 2022). Casarella J (ed.). "Food Addiction Signs and Treatments". WebMD. Retrieved 9 March 2023. <a href="https://www.webmd.com/mental-health/eating-disorders/binge-eating-disorder/mental-health-food-addiction" target="_blank">https://www.webmd.com/mental-health/eating-disorders/binge-eating-disorder/mental-health-food-addiction</a> <a href="#fnref:46" class="footnote-back-ref">↩</a></li>
<li id="fn:47">Goodman B (3 September 2022). Casarella J (ed.). "Food Addiction Signs and Treatments". WebMD. Retrieved 9 March 2023. <a href="https://www.webmd.com/mental-health/eating-disorders/binge-eating-disorder/mental-health-food-addiction" target="_blank">https://www.webmd.com/mental-health/eating-disorders/binge-eating-disorder/mental-health-food-addiction</a> <a href="#fnref:47" class="footnote-back-ref">↩</a></li>
<li id="fn:48">Nehlig A (2004). Coffee, tea, chocolate, and the brain. Boca Raton: CRC Press. pp. 203–218. ISBN 978-0-429-21192-8. <a href="978-0-429-21192-8" target="_blank">978-0-429-21192-8</a> <a href="#fnref:48" class="footnote-back-ref">↩</a></li>
<li id="fn:49">Maxwell AL, Gardiner E, Loxton NJ (9 February 2020). "Investigating the relationship between reward sensitivity, impulsivity, and food addiction: A systematic review". European Eating Disorders Review. 28 (4): 368–384. doi:10.1002/erv.2732. ISSN 1099-0968. PMID 32142199. S2CID 212565361. Retrieved 9 March 2023. <a href="https://doi.org/10.1002/erv.2732" target="_blank">https://doi.org/10.1002/erv.2732</a> <a href="#fnref:49" class="footnote-back-ref">↩</a></li>
<li id="fn:50">"Yale Food Addiction Scale". Food and Addiction Science & Treatment Lab. Department of Psychology, University of Michigan. Retrieved 1 November 2022. <a href="https://sites.lsa.umich.edu/fastlab/yale-food-addiction-scale/" target="_blank">https://sites.lsa.umich.edu/fastlab/yale-food-addiction-scale/</a> <a href="#fnref:50" class="footnote-back-ref">↩</a></li>
<li id="fn:51">di Giacomo E, Aliberti F, Pescatore F, Santorelli M, Pessina R, Placenti V, et al. (August 2022). "Disentangling binge eating disorder and food addiction: a systematic review and meta-analysis". Eating and Weight Disorders. 27 (6): 1963–1970. doi:10.1007/s40519-021-01354-7. PMC 9287203. PMID 35041154. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203</a> <a href="#fnref:51" class="footnote-back-ref">↩</a></li>
<li id="fn:52">Maxwell AL, Gardiner E, Loxton NJ (9 February 2020). "Investigating the relationship between reward sensitivity, impulsivity, and food addiction: A systematic review". European Eating Disorders Review. 28 (4): 368–384. doi:10.1002/erv.2732. ISSN 1099-0968. PMID 32142199. S2CID 212565361. Retrieved 9 March 2023. <a href="https://doi.org/10.1002/erv.2732" target="_blank">https://doi.org/10.1002/erv.2732</a> <a href="#fnref:52" class="footnote-back-ref">↩</a></li>
<li id="fn:53">Gearhardt AN, Corbin WR, Brownell KD (February 2016). "Development of the Yale Food Addiction Scale Version 2.0". Psychology of Addictive Behaviors. 30 (1): 113–121. doi:10.1037/adb0000136. PMID 26866783. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:53" class="footnote-back-ref">↩</a></li>
<li id="fn:54">Goodman B (3 September 2022). Casarella J (ed.). "Food Addiction Signs and Treatments". WebMD. Retrieved 9 March 2023. <a href="https://www.webmd.com/mental-health/eating-disorders/binge-eating-disorder/mental-health-food-addiction" target="_blank">https://www.webmd.com/mental-health/eating-disorders/binge-eating-disorder/mental-health-food-addiction</a> <a href="#fnref:54" class="footnote-back-ref">↩</a></li>
<li id="fn:55">Brunault P, Berthoz S, Gearhardt AN, Gierski F, Kaladjian A, Bertin E, et al. (8 September 2020). "The Modified Yale Food Addiction Scale 2.0: Validation Among Non-Clinical and Clinical French-Speaking Samples and Comparison With the Full Yale Food Addiction Scale 2.0". Frontiers in Psychiatry. 11: 480671. doi:10.3389/fpsyt.2020.480671. PMC 7509420. PMID 33033480. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509420" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509420</a> <a href="#fnref:55" class="footnote-back-ref">↩</a></li>
<li id="fn:56">di Giacomo E, Aliberti F, Pescatore F, Santorelli M, Pessina R, Placenti V, et al. (August 2022). "Disentangling binge eating disorder and food addiction: a systematic review and meta-analysis". Eating and Weight Disorders. 27 (6): 1963–1970. doi:10.1007/s40519-021-01354-7. PMC 9287203. PMID 35041154. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203</a> <a href="#fnref:56" class="footnote-back-ref">↩</a></li>
<li id="fn:57">Hauck C, Cook B, Ellrott T (February 2020). "Food addiction, eating addiction and eating disorders". The Proceedings of the Nutrition Society. 79 (1): 103–112. doi:10.1017/S0029665119001162. PMID 31744566. S2CID 208186539. <a href="https://doi.org/10.1017%2FS0029665119001162" target="_blank">https://doi.org/10.1017%2FS0029665119001162</a> <a href="#fnref:57" class="footnote-back-ref">↩</a></li>
<li id="fn:58">Maxwell AL, Gardiner E, Loxton NJ (9 February 2020). "Investigating the relationship between reward sensitivity, impulsivity, and food addiction: A systematic review". European Eating Disorders Review. 28 (4): 368–384. doi:10.1002/erv.2732. ISSN 1099-0968. PMID 32142199. S2CID 212565361. Retrieved 9 March 2023. <a href="https://doi.org/10.1002/erv.2732" target="_blank">https://doi.org/10.1002/erv.2732</a> <a href="#fnref:58" class="footnote-back-ref">↩</a></li>
<li id="fn:59">Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (second ed.). New York: McGraw-Hill Medical. pp. 364–65, 375. ISBN 978-0-07-148127-4. The defining feature of addiction is compulsive, out-of-control drug use, despite negative consequences. ...compulsive eating, shopping, gambling, and sex – so-called "natural addictions" – Indeed, addiction to both drugs and behavioral rewards may arise from similar dysregulation of the mesolimbic dopamine system. <a href="978-0-07-148127-4" target="_blank">978-0-07-148127-4</a> <a href="#fnref:59" class="footnote-back-ref">↩</a></li>
<li id="fn:60">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:60" class="footnote-back-ref">↩</a></li>
<li id="fn:61">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:61" class="footnote-back-ref">↩</a></li>
<li id="fn:62">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:62" class="footnote-back-ref">↩</a></li>
<li id="fn:63">Karila L, Wéry A, Weinstein A, Cottencin O, Petit A, Reynaud M, et al. (2014). "Sexual addiction or hypersexual disorder: different terms for the same problem? A review of the literature". Curr. Pharm. Des. 20 (25): 4012–20. doi:10.2174/13816128113199990619. PMID 24001295. S2CID 19042860. Sexual addiction, which is also known as hypersexual disorder, has largely been ignored by psychiatrists, even though the condition causes serious psychosocial problems for many people. A lack of empirical evidence on sexual addiction is the result of the disease's complete absence from versions of the Diagnostic and Statistical Manual of Mental Disorders. ... Existing prevalence rates of sexual addiction-related disorders range from 3% to 6%. Sexual addiction/hypersexual disorder is used as an umbrella construct to encompass various types of problematic behaviors, including excessive masturbation, cybersex, pornography use, sexual behavior with consenting adults, telephone sex, strip club visitation, and other behaviors. The adverse consequences of sexual addiction are similar to the consequences of other addictive disorders. Addictive, somatic and psychiatric disorders coexist with sexual addiction. In recent years, research on sexual addiction has proliferated, and screening instruments have increasingly been developed to diagnose or quantify sexual addiction disorders. In our systematic review of the existing measures, 22 questionnaires were identified. As with other behavioral addictions, the appropriate treatment of sexual addiction should combine pharmacological and psychological approaches. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:63" class="footnote-back-ref">↩</a></li>
<li id="fn:64">Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508</a> <a href="#fnref:64" class="footnote-back-ref">↩</a></li>
<li id="fn:65">Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). "Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats". Neuropharmacology. 101: 154–64. doi:10.1016/j.neuropharm.2015.09.023. PMID 26391065. S2CID 25317397. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:65" class="footnote-back-ref">↩</a></li>
<li id="fn:66">Alavi SS, Ferdosi M, Jannatifard F, Eslami M, Alaghemandan H, Setare M (April 2012). "Behavioral Addiction versus Substance Addiction: Correspondence of Psychiatric and Psychological Views". International Journal of Preventive Medicine. 3 (4): 290–294. PMC 3354400. PMID 22624087. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354400" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354400</a> <a href="#fnref:66" class="footnote-back-ref">↩</a></li>
<li id="fn:67">Alavi SS, Ferdosi M, Jannatifard F, Eslami M, Alaghemandan H, Setare M (April 2012). "Behavioral Addiction versus Substance Addiction: Correspondence of Psychiatric and Psychological Views". International Journal of Preventive Medicine. 3 (4): 290–294. PMC 3354400. PMID 22624087. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354400" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354400</a> <a href="#fnref:67" class="footnote-back-ref">↩</a></li>
<li id="fn:68">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:68" class="footnote-back-ref">↩</a></li>
<li id="fn:69">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:69" class="footnote-back-ref">↩</a></li>
<li id="fn:70">Fehrman E, Egan V, Gorban AN, Levesley J, Mirkes EM, Muhammad AK (2019). Personality Traits and Drug Consumption. A Story Told by Data. Springer, Cham. arXiv:2001.06520. doi:10.1007/978-3-030-10442-9. ISBN 978-3-030-10441-2. S2CID 151160405. <a href="978-3-030-10441-2" target="_blank">978-3-030-10441-2</a> <a href="#fnref:70" class="footnote-back-ref">↩</a></li>
<li id="fn:71">Cheetham A, Allen NB, Yücel M, Lubman DI (August 2010). "The role of affective dysregulation in drug addiction". Clin Psychol Rev. 30 (6): 621–34. doi:10.1016/j.cpr.2010.04.005. PMID 20546986. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:71" class="footnote-back-ref">↩</a></li>
<li id="fn:72">Franken IH, Muris P (2006). "BIS/BAS personality characteristics and college students' substance use". Personality and Individual Differences. 40 (7): 1497–503. doi:10.1016/j.paid.2005.12.005. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:72" class="footnote-back-ref">↩</a></li>
<li id="fn:73">Genovese JE, Wallace D (December 2007). "Reward sensitivity and substance abuse in middle school and high school students". J Genet Psychol. 168 (4): 465–69. doi:10.3200/GNTP.168.4.465-469. PMID 18232522. S2CID 207640075. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:73" class="footnote-back-ref">↩</a></li>
<li id="fn:74">Kimbrel NA, Nelson-Gray RO, Mitchell JT (April 2007). "Reinforcement sensitivity and maternal style as predictors of psychopathology". Personality and Individual Differences. 42 (6): 1139–49. doi:10.1016/j.paid.2006.06.028. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:74" class="footnote-back-ref">↩</a></li>
<li id="fn:75">Dawe S, Loxton NJ (May 2004). "The role of impulsivity in the development of substance use and eating disorders". Neurosci Biobehav Rev. 28 (3): 343–51. doi:10.1016/j.neubiorev.2004.03.007. PMID 15225976. S2CID 24435589. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:75" class="footnote-back-ref">↩</a></li>
<li id="fn:76">Hill R, Harris J (2 November 2021). "Psychological Approaches to Addiction". In Day E (ed.). Seminars in addiction psychiatry (2nd ed.). Cambridge: Cambridge University Press. pp. 147–169. doi:10.1017/9781911623199.009. ISBN 978-1-911623-19-9. S2CID 242036830. <a href="978-1-911623-19-9" target="_blank">978-1-911623-19-9</a> <a href="#fnref:76" class="footnote-back-ref">↩</a></li>
<li id="fn:77">Washburn DA (2016). "The Stroop effect at 80: The competition between stimulus control and cognitive control". J Exp Anal Behav. 105 (1): 3–13. doi:10.1002/jeab.194. PMID 26781048. Today, arguably more than at any time in history, the constructs of attention, executive functioning, and cognitive control seem to be pervasive and preeminent in research and theory. Even within the cognitive framework, however, there has long been an understanding that behavior is multiply determined, and that many responses are relatively automatic, unattended, contention-scheduled, and habitual. Indeed, the cognitive flexibility, response inhibition, and self-regulation that appear to be hallmarks of cognitive control are noteworthy only in contrast to responses that are relatively rigid, associative, and involuntary. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:77" class="footnote-back-ref">↩</a></li>
<li id="fn:78">Diamond A (2013). "Executive functions". Annu Rev Psychol. 64: 135–68. doi:10.1146/annurev-psych-113011-143750. PMC 4084861. PMID 23020641. Core EFs are inhibition [response inhibition (self-control – resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking "outside the box," seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances). ... EFs and prefrontal cortex are the first to suffer, and suffer disproportionately, if something is not right in your life. They suffer first, and most, if you are stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005), sad (Hirt et al. 2008, von Hecker & Meiser 2005), lonely (Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al. 2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et al. 2007), or not physically fit (Best 2010, Chaddock et al. 2011, Hillman et al. 2008). Any of these can cause you to appear to have a disorder of EFs, such as ADHD, when you do not. You can see the deleterious effects of stress, sadness, loneliness, and lack of physical health or fitness at the physiological and neuroanatomical level in prefrontal cortex and at the behavioral level in worse EFs (poorer reasoning and problem solving, forgetting things, and impaired ability to exercise discipline and self-control). ...EFs can be improved (Diamond & Lee 2011, Klingberg 2010). ... At any age across the life cycle EFs can be improved, including in the elderly and in infants. There has been much work with excellent results on improving EFs in the elderly by improving physical fitness (Erickson & Kramer 2009, Voss et al. 2011) ... Inhibitory control (one of the core EFs) involves being able to control one's attention, behavior, thoughts, and/or emotions to override a strong internal predisposition or external lure, and instead do what's more appropriate or needed. Without inhibitory control we would be at the mercy of impulses, old habits of thought or action (conditioned responses), and/or stimuli in the environment that pull us this way or that. Thus, inhibitory control makes it possible for us to change and for us to choose how we react and how we behave rather than being unthinking creatures of habit. It doesn't make it easy. Indeed, we usually are creatures of habit and our behavior is under the control of environmental stimuli far more than we usually realize, but having the ability to exercise inhibitory control creates the possibility of change and choice. ... The subthalamic nucleus appears to play a critical role in preventing such impulsive or premature responding (Frank 2006). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084861" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084861</a> <a href="#fnref:78" class="footnote-back-ref">↩</a></li>
<li id="fn:79">Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 313–21. ISBN 978-0-07-148127-4.  • Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans. • Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior. ...These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is called "top-down" control or cognitive control of behavior. ... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15). ...In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 15), or in attention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result. ... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression). ... Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior. Subjects with ADHD exhibit less activation of the medial prefrontal cortex than healthy controls even when they succeed in such tasks and utilize different circuits. ... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention. <a href="978-0-07-148127-4" target="_blank">978-0-07-148127-4</a> <a href="#fnref:79" class="footnote-back-ref">↩</a></li>
<li id="fn:80">Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 313–21. ISBN 978-0-07-148127-4.  • Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans. • Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior. ...These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is called "top-down" control or cognitive control of behavior. ... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15). ...In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 15), or in attention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result. ... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression). ... Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior. Subjects with ADHD exhibit less activation of the medial prefrontal cortex than healthy controls even when they succeed in such tasks and utilize different circuits. ... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention. <a href="978-0-07-148127-4" target="_blank">978-0-07-148127-4</a> <a href="#fnref:80" class="footnote-back-ref">↩</a></li>
<li id="fn:81">Hill R, Harris J (2 November 2021). "Psychological Approaches to Addiction". In Day E (ed.). Seminars in addiction psychiatry (2nd ed.). Cambridge: Cambridge University Press. pp. 147–169. doi:10.1017/9781911623199.009. ISBN 978-1-911623-19-9. S2CID 242036830. <a href="978-1-911623-19-9" target="_blank">978-1-911623-19-9</a> <a href="#fnref:81" class="footnote-back-ref">↩</a></li>
<li id="fn:82">Gould TJ (December 2010). "Addiction and cognition". Addiction Science & Clinical Practice. 5 (2): 4–14. PMC 3120118. PMID 22002448. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118</a> <a href="#fnref:82" class="footnote-back-ref">↩</a></li>
<li id="fn:83">Levy N (2019). "Chapter 5 Addiction: The belief oscillation hypothesis". In Pickard H, Ahmed SH (eds.). The Routledge handbook of philosophy and science of addiction. Wellcome Trust–Funded Monographs and Book Chapters. Oxon (UK): Routledge. doi:10.4324/9781315689197-6. ISBN 978-1-138-90928-1. OCLC 1042341025. PMID 31017751. S2CID 242067468. <a href="978-1-138-90928-1" target="_blank">978-1-138-90928-1</a> <a href="#fnref:83" class="footnote-back-ref">↩</a></li>
<li id="fn:84">Gould TJ (December 2010). "Addiction and cognition". Addiction Science & Clinical Practice. 5 (2): 4–14. PMC 3120118. PMID 22002448. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118</a> <a href="#fnref:84" class="footnote-back-ref">↩</a></li>
<li id="fn:85">Gould TJ (December 2010). "Addiction and cognition". Addiction Science & Clinical Practice. 5 (2): 4–14. PMC 3120118. PMID 22002448. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118</a> <a href="#fnref:85" class="footnote-back-ref">↩</a></li>
<li id="fn:86">Gould TJ (December 2010). "Addiction and cognition". Addiction Science & Clinical Practice. 5 (2): 4–14. PMC 3120118. PMID 22002448. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118</a> <a href="#fnref:86" class="footnote-back-ref">↩</a></li>
<li id="fn:87">Gould TJ (December 2010). "Addiction and cognition". Addiction Science & Clinical Practice. 5 (2): 4–14. PMC 3120118. PMID 22002448. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118</a> <a href="#fnref:87" class="footnote-back-ref">↩</a></li>
<li id="fn:88">Levy N (2019). "Chapter 5 Addiction: The belief oscillation hypothesis". In Pickard H, Ahmed SH (eds.). The Routledge handbook of philosophy and science of addiction. Wellcome Trust–Funded Monographs and Book Chapters. Oxon (UK): Routledge. doi:10.4324/9781315689197-6. ISBN 978-1-138-90928-1. OCLC 1042341025. PMID 31017751. S2CID 242067468. <a href="978-1-138-90928-1" target="_blank">978-1-138-90928-1</a> <a href="#fnref:88" class="footnote-back-ref">↩</a></li>
<li id="fn:89">Feltenstein MW, See RE (May 2008). "The neurocircuitry of addiction: an overview". British Journal of Pharmacology. 154 (2): 261–274. doi:10.1038/bjp.2008.51. PMC 2442446. PMID 18311189. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2442446" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2442446</a> <a href="#fnref:89" class="footnote-back-ref">↩</a></li>
<li id="fn:90">Gould TJ (December 2010). "Addiction and cognition". Addiction Science & Clinical Practice. 5 (2): 4–14. PMC 3120118. PMID 22002448. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118</a> <a href="#fnref:90" class="footnote-back-ref">↩</a></li>
<li id="fn:91">Hill R, Harris J (2 November 2021). "Psychological Approaches to Addiction". In Day E (ed.). Seminars in addiction psychiatry (2nd ed.). Cambridge: Cambridge University Press. pp. 147–169. doi:10.1017/9781911623199.009. ISBN 978-1-911623-19-9. S2CID 242036830. <a href="978-1-911623-19-9" target="_blank">978-1-911623-19-9</a> <a href="#fnref:91" class="footnote-back-ref">↩</a></li>
<li id="fn:92">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:92" class="footnote-back-ref">↩</a></li>
<li id="fn:93">Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494</a> <a href="#fnref:93" class="footnote-back-ref">↩</a></li>
<li id="fn:94">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:94" class="footnote-back-ref">↩</a></li>
<li id="fn:95">Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494</a> <a href="#fnref:95" class="footnote-back-ref">↩</a></li>
<li id="fn:96">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:96" class="footnote-back-ref">↩</a></li>
<li id="fn:97">Douglas KR, Chan G, Gelernter J, Arias AJ, Anton RF, Weiss RD, et al. (January 2010). "Adverse childhood events as risk factors for substance dependence: partial mediation by mood and anxiety disorders". Addictive Behaviors. 35 (1): 7–13. doi:10.1016/j.addbeh.2009.07.004. PMC 2763992. PMID 19720467. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763992" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763992</a> <a href="#fnref:97" class="footnote-back-ref">↩</a></li>
<li id="fn:98">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:98" class="footnote-back-ref">↩</a></li>
<li id="fn:99">Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494</a> <a href="#fnref:99" class="footnote-back-ref">↩</a></li>
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<li id="fn:149">Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494</a> <a href="#fnref:149" class="footnote-back-ref">↩</a></li>
<li id="fn:150">Yuan TF, Li A, Sun X, Ouyang H, Campos C, Rocha NB, et al. (2015). "Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism". Mol. Neurobiol. 53 (9): 6367–76. doi:10.1007/s12035-015-9526-2. hdl:10400.22/7331. PMID 26572641. S2CID 25694221. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:150" class="footnote-back-ref">↩</a></li>
<li id="fn:151">Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494</a> <a href="#fnref:151" class="footnote-back-ref">↩</a></li>
<li id="fn:152">Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494</a> <a href="#fnref:152" class="footnote-back-ref">↩</a></li>
<li id="fn:153">Yuan TF, Li A, Sun X, Ouyang H, Campos C, Rocha NB, et al. (2015). "Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism". Mol. Neurobiol. 53 (9): 6367–76. doi:10.1007/s12035-015-9526-2. hdl:10400.22/7331. PMID 26572641. S2CID 25694221. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:153" class="footnote-back-ref">↩</a></li>
<li id="fn:154">According to a review of experimental animal models that examined the transgenerational epigenetic inheritance of epigenetic marks that occur in addiction, alterations in histone acetylation – specifically, di-acetylation of lysine residues 9 and 14 on histone 3 (i.e., H3K9ac2 and H3K14ac2) in association with BDNF gene promoters – have been shown to occur within the medial prefrontal cortex (mPFC), testes, and sperm of cocaine-addicted male rats.[47] These epigenetic alterations in the rat mPFC result in increased BDNF gene expression within the mPFC, which in turn blunts the rewarding properties of cocaine and reduces cocaine self-administration.[47] The male but not female offspring of these cocaine-exposed rats inherited both epigenetic marks (i.e., di-acetylation of lysine residues 9 and 14 on histone 3) within mPFC neurons, the corresponding increase in BDNF expression within mPFC neurons, and the behavioral phenotype associated with these effects (i.e., a reduction in cocaine reward, resulting in reduced cocaine-seeking by these male offspring).[47] Consequently, the transmission of these two cocaine-induced epigenetic alterations (i.e., H3K9ac2 and H3K14ac2) in rats from male fathers to male offspring served to reduce the offspring's risk of developing an addiction to cocaine.[47] As of 2018, neither the heritability of these epigenetic marks in humans nor the behavioral effects of the marks within human mPFC neurons has been established.[47] <a href="/w/index.php?title=Epigenetic_mark&action=edit&redlink=1" target="_blank">/w/index.php?title=Epigenetic_mark&action=edit&redlink=1</a> <a href="#fnref:154" class="footnote-back-ref">↩</a></li>
<li id="fn:155">Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494</a> <a href="#fnref:155" class="footnote-back-ref">↩</a></li>
<li id="fn:156">Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494</a> <a href="#fnref:156" class="footnote-back-ref">↩</a></li>
<li id="fn:157">Yuan TF, Li A, Sun X, Ouyang H, Campos C, Rocha NB, et al. (2015). "Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism". Mol. Neurobiol. 53 (9): 6367–76. doi:10.1007/s12035-015-9526-2. hdl:10400.22/7331. PMID 26572641. S2CID 25694221. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:157" class="footnote-back-ref">↩</a></li>
<li id="fn:158">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:158" class="footnote-back-ref">↩</a></li>
<li id="fn:159">Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[...]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:159" class="footnote-back-ref">↩</a></li>
<li id="fn:160">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:160" class="footnote-back-ref">↩</a></li>
<li id="fn:161">Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[...]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:161" class="footnote-back-ref">↩</a></li>
<li id="fn:162">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:162" class="footnote-back-ref">↩</a></li>
<li id="fn:163">Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–96. PMID 23020045. [...]ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. <a href="http://www.aaem.pl/fulltext.php?ICID=1010966" target="_blank">http://www.aaem.pl/fulltext.php?ICID=1010966</a> <a href="#fnref:163" class="footnote-back-ref">↩</a></li>
<li id="fn:164">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:164" class="footnote-back-ref">↩</a></li>
<li id="fn:165">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:165" class="footnote-back-ref">↩</a></li>
<li id="fn:166">Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[...]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:166" class="footnote-back-ref">↩</a></li>
<li id="fn:167">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:167" class="footnote-back-ref">↩</a></li>
<li id="fn:168">Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–96. PMID 23020045. [...]ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. <a href="http://www.aaem.pl/fulltext.php?ICID=1010966" target="_blank">http://www.aaem.pl/fulltext.php?ICID=1010966</a> <a href="#fnref:168" class="footnote-back-ref">↩</a></li>
<li id="fn:169">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:169" class="footnote-back-ref">↩</a></li>
<li id="fn:170">Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[...]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:170" class="footnote-back-ref">↩</a></li>
<li id="fn:171">Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–96. PMID 23020045. [...]ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. <a href="http://www.aaem.pl/fulltext.php?ICID=1010966" target="_blank">http://www.aaem.pl/fulltext.php?ICID=1010966</a> <a href="#fnref:171" class="footnote-back-ref">↩</a></li>
<li id="fn:172">A decrease in aversion sensitivity, in simpler terms, means that an individual's behavior is less likely to be influenced by undesirable outcomes. <a href="#fnref:172" class="footnote-back-ref">↩</a></li>
<li id="fn:173">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:173" class="footnote-back-ref">↩</a></li>
<li id="fn:174">Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[...]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:174" class="footnote-back-ref">↩</a></li>
<li id="fn:175">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:175" class="footnote-back-ref">↩</a></li>
<li id="fn:176">Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annu. Rev. Neurosci. 29: 565–98. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:176" class="footnote-back-ref">↩</a></li>
<li id="fn:177">Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Prog. Neurobiol. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776. PMID 23085425. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525776" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525776</a> <a href="#fnref:177" class="footnote-back-ref">↩</a></li>
<li id="fn:178">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:178" class="footnote-back-ref">↩</a></li>
<li id="fn:179">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:179" class="footnote-back-ref">↩</a></li>
<li id="fn:180">A decrease in aversion sensitivity, in simpler terms, means that an individual's behavior is less likely to be influenced by undesirable outcomes. <a href="#fnref:180" class="footnote-back-ref">↩</a></li>
<li id="fn:181">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:181" class="footnote-back-ref">↩</a></li>
<li id="fn:182">Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[...]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:182" class="footnote-back-ref">↩</a></li>
<li id="fn:183">Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[...]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:183" class="footnote-back-ref">↩</a></li>
<li id="fn:184">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:184" class="footnote-back-ref">↩</a></li>
<li id="fn:185">Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annu. Rev. Neurosci. 29: 565–98. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:185" class="footnote-back-ref">↩</a></li>
<li id="fn:186">Kanehisa Laboratories (2 August 2013). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 10 April 2014. <a href="http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354" target="_blank">http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354</a> <a href="#fnref:186" class="footnote-back-ref">↩</a></li>
<li id="fn:187">Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proc. Natl. Acad. Sci. USA. 106 (8): 2915–20. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650365" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650365</a> <a href="#fnref:187" class="footnote-back-ref">↩</a></li>
<li id="fn:188">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:188" class="footnote-back-ref">↩</a></li>
<li id="fn:189">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:189" class="footnote-back-ref">↩</a></li>
<li id="fn:190">Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 (Pt B): 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384</a> <a href="#fnref:190" class="footnote-back-ref">↩</a></li>
<li id="fn:191">Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–96. PMID 23020045. [...]ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. <a href="http://www.aaem.pl/fulltext.php?ICID=1010966" target="_blank">http://www.aaem.pl/fulltext.php?ICID=1010966</a> <a href="#fnref:191" class="footnote-back-ref">↩</a></li>
<li id="fn:192">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:192" class="footnote-back-ref">↩</a></li>
<li id="fn:193">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:193" class="footnote-back-ref">↩</a></li>
<li id="fn:194">Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, et al. (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958</a> <a href="#fnref:194" class="footnote-back-ref">↩</a></li>
<li id="fn:195">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:195" class="footnote-back-ref">↩</a></li>
<li id="fn:196">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:196" class="footnote-back-ref">↩</a></li>
<li id="fn:197">Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, et al. (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958</a> <a href="#fnref:197" class="footnote-back-ref">↩</a></li>
<li id="fn:198">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:198" class="footnote-back-ref">↩</a></li>
<li id="fn:199">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:199" class="footnote-back-ref">↩</a></li>
<li id="fn:200">Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, et al. (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958</a> <a href="#fnref:200" class="footnote-back-ref">↩</a></li>
<li id="fn:201">Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, et al. (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958</a> <a href="#fnref:201" class="footnote-back-ref">↩</a></li>
<li id="fn:202">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:202" class="footnote-back-ref">↩</a></li>
<li id="fn:203">Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508</a> <a href="#fnref:203" class="footnote-back-ref">↩</a></li>
<li id="fn:204">Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). "Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats". Neuropharmacology. 101: 154–64. doi:10.1016/j.neuropharm.2015.09.023. PMID 26391065. S2CID 25317397. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:204" class="footnote-back-ref">↩</a></li>
<li id="fn:205">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:205" class="footnote-back-ref">↩</a></li>
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<li id="fn:209">di Giacomo E, Aliberti F, Pescatore F, Santorelli M, Pessina R, Placenti V, et al. (August 2022). "Disentangling binge eating disorder and food addiction: a systematic review and meta-analysis". Eating and Weight Disorders. 27 (6): 1963–1970. doi:10.1007/s40519-021-01354-7. PMC 9287203. PMID 35041154. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203</a> <a href="#fnref:209" class="footnote-back-ref">↩</a></li>
<li id="fn:210">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:210" class="footnote-back-ref">↩</a></li>
<li id="fn:211">Levy N (2019). "Chapter 5 Addiction: The belief oscillation hypothesis". In Pickard H, Ahmed SH (eds.). The Routledge handbook of philosophy and science of addiction. Wellcome Trust–Funded Monographs and Book Chapters. Oxon (UK): Routledge. doi:10.4324/9781315689197-6. ISBN 978-1-138-90928-1. OCLC 1042341025. PMID 31017751. S2CID 242067468. <a href="978-1-138-90928-1" target="_blank">978-1-138-90928-1</a> <a href="#fnref:211" class="footnote-back-ref">↩</a></li>
<li id="fn:212">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:212" class="footnote-back-ref">↩</a></li>
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<li id="fn:221">Levy N (2019). "Chapter 5 Addiction: The belief oscillation hypothesis". In Pickard H, Ahmed SH (eds.). The Routledge handbook of philosophy and science of addiction. Wellcome Trust–Funded Monographs and Book Chapters. Oxon (UK): Routledge. doi:10.4324/9781315689197-6. ISBN 978-1-138-90928-1. OCLC 1042341025. PMID 31017751. S2CID 242067468. <a href="978-1-138-90928-1" target="_blank">978-1-138-90928-1</a> <a href="#fnref:221" class="footnote-back-ref">↩</a></li>
<li id="fn:222">Kourrich S, Rothwell PE, Klug JR, Thomas MJ (2007). "Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens". J. Neurosci. 27 (30): 7921–28. doi:10.1523/JNEUROSCI.1859-07.2007. PMC 6672735. PMID 17652583. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672735" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672735</a> <a href="#fnref:222" class="footnote-back-ref">↩</a></li>
<li id="fn:223">Jones S, Bonci A (2005). "Synaptic plasticity and drug addiction". Current Opinion in Pharmacology. 5 (1): 20–25. doi:10.1016/j.coph.2004.08.011. PMID 15661621. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:223" class="footnote-back-ref">↩</a></li>
<li id="fn:224">Maxwell AL, Gardiner E, Loxton NJ (9 February 2020). "Investigating the relationship between reward sensitivity, impulsivity, and food addiction: A systematic review". European Eating Disorders Review. 28 (4): 368–384. doi:10.1002/erv.2732. ISSN 1099-0968. PMID 32142199. S2CID 212565361. Retrieved 9 March 2023. <a href="https://doi.org/10.1002/erv.2732" target="_blank">https://doi.org/10.1002/erv.2732</a> <a href="#fnref:224" class="footnote-back-ref">↩</a></li>
<li id="fn:225">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:225" class="footnote-back-ref">↩</a></li>
<li id="fn:226">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:226" class="footnote-back-ref">↩</a></li>
<li id="fn:227">Kalivas PW, Volkow ND (August 2005). "The neural basis of addiction: a pathology of motivation and choice". The American Journal of Psychiatry. 162 (8): 1403–13. doi:10.1176/appi.ajp.162.8.1403. PMID 16055761. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:227" class="footnote-back-ref">↩</a></li>
<li id="fn:228">Maxwell AL, Gardiner E, Loxton NJ (9 February 2020). "Investigating the relationship between reward sensitivity, impulsivity, and food addiction: A systematic review". European Eating Disorders Review. 28 (4): 368–384. doi:10.1002/erv.2732. ISSN 1099-0968. PMID 32142199. S2CID 212565361. Retrieved 9 March 2023. <a href="https://doi.org/10.1002/erv.2732" target="_blank">https://doi.org/10.1002/erv.2732</a> <a href="#fnref:228" class="footnote-back-ref">↩</a></li>
<li id="fn:229">Floresco SB, Ghods-Sharifi S (February 2007). "Amygdala-prefrontal cortical circuitry regulates effort-based decision making". Cerebral Cortex. 17 (2): 251–60. CiteSeerX 10.1.1.335.4681. doi:10.1093/cercor/bhj143. PMID 16495432. <a href="/wiki/CiteSeerX_(identifier)" target="_blank">/wiki/CiteSeerX_(identifier)</a> <a href="#fnref:229" class="footnote-back-ref">↩</a></li>
<li id="fn:230">Perry CJ, Zbukvic I, Kim JH, Lawrence AJ (October 2014). "Role of cues and contexts on drug-seeking behaviour". British Journal of Pharmacology. 171 (20): 4636–72. doi:10.1111/bph.12735. PMC 4209936. PMID 24749941. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209936" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209936</a> <a href="#fnref:230" class="footnote-back-ref">↩</a></li>
<li id="fn:231">Levy N (2019). "Chapter 5 Addiction: The belief oscillation hypothesis". In Pickard H, Ahmed SH (eds.). The Routledge handbook of philosophy and science of addiction. Wellcome Trust–Funded Monographs and Book Chapters. Oxon (UK): Routledge. doi:10.4324/9781315689197-6. ISBN 978-1-138-90928-1. OCLC 1042341025. PMID 31017751. S2CID 242067468. <a href="978-1-138-90928-1" target="_blank">978-1-138-90928-1</a> <a href="#fnref:231" class="footnote-back-ref">↩</a></li>
<li id="fn:232">Floresco SB, Ghods-Sharifi S (February 2007). "Amygdala-prefrontal cortical circuitry regulates effort-based decision making". Cerebral Cortex. 17 (2): 251–60. CiteSeerX 10.1.1.335.4681. doi:10.1093/cercor/bhj143. PMID 16495432. <a href="/wiki/CiteSeerX_(identifier)" target="_blank">/wiki/CiteSeerX_(identifier)</a> <a href="#fnref:232" class="footnote-back-ref">↩</a></li>
<li id="fn:233">Eisch AJ, Harburg GC (2006). "Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology". Hippocampus. 16 (3): 271–86. doi:10.1002/hipo.20161. PMID 16411230. S2CID 23667629. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:233" class="footnote-back-ref">↩</a></li>
<li id="fn:234">Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F (2007). "Dopamine in drug abuse and addiction: results of imaging studies and treatment implications". Arch. Neurol. 64 (11): 1575–79. doi:10.1001/archneur.64.11.1575. PMID 17998440. <a href="https://doi.org/10.1001%2Farchneur.64.11.1575" target="_blank">https://doi.org/10.1001%2Farchneur.64.11.1575</a> <a href="#fnref:234" class="footnote-back-ref">↩</a></li>
<li id="fn:235">Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F (2007). "Dopamine in drug abuse and addiction: results of imaging studies and treatment implications". Arch. Neurol. 64 (11): 1575–79. doi:10.1001/archneur.64.11.1575. PMID 17998440. <a href="https://doi.org/10.1001%2Farchneur.64.11.1575" target="_blank">https://doi.org/10.1001%2Farchneur.64.11.1575</a> <a href="#fnref:235" class="footnote-back-ref">↩</a></li>
<li id="fn:236">"Drugs, Brains, and Behavior: The Science of Addiction". National Institute on Drug Abuse. 6 July 2020. <a href="http://www.drugabuse.gov/publications/science-addiction/drugs-brain" target="_blank">http://www.drugabuse.gov/publications/science-addiction/drugs-brain</a> <a href="#fnref:236" class="footnote-back-ref">↩</a></li>
<li id="fn:237">di Giacomo E, Aliberti F, Pescatore F, Santorelli M, Pessina R, Placenti V, et al. (August 2022). "Disentangling binge eating disorder and food addiction: a systematic review and meta-analysis". Eating and Weight Disorders. 27 (6): 1963–1970. doi:10.1007/s40519-021-01354-7. PMC 9287203. PMID 35041154. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287203</a> <a href="#fnref:237" class="footnote-back-ref">↩</a></li>
<li id="fn:238">"Understanding Drug Abuse and Addiction". National Institute on Drug Abuse. November 2012. Archived from the original on 16 August 2011. Retrieved 12 February 2015. <a href="https://web.archive.org/web/20110816044828/http://www.drugabuse.gov/infofacts/understand.html" target="_blank">https://web.archive.org/web/20110816044828/http://www.drugabuse.gov/infofacts/understand.html</a> <a href="#fnref:238" class="footnote-back-ref">↩</a></li>
<li id="fn:239">Levy N (2019). "Chapter 5 Addiction: The belief oscillation hypothesis". In Pickard H, Ahmed SH (eds.). The Routledge handbook of philosophy and science of addiction. Wellcome Trust–Funded Monographs and Book Chapters. Oxon (UK): Routledge. doi:10.4324/9781315689197-6. ISBN 978-1-138-90928-1. OCLC 1042341025. PMID 31017751. S2CID 242067468. <a href="978-1-138-90928-1" target="_blank">978-1-138-90928-1</a> <a href="#fnref:239" class="footnote-back-ref">↩</a></li>
<li id="fn:240">Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F (2007). "Dopamine in drug abuse and addiction: results of imaging studies and treatment implications". Arch. Neurol. 64 (11): 1575–79. doi:10.1001/archneur.64.11.1575. PMID 17998440. <a href="https://doi.org/10.1001%2Farchneur.64.11.1575" target="_blank">https://doi.org/10.1001%2Farchneur.64.11.1575</a> <a href="#fnref:240" class="footnote-back-ref">↩</a></li>
<li id="fn:241">Kalivas PW, Volkow ND (August 2005). "The neural basis of addiction: a pathology of motivation and choice". The American Journal of Psychiatry. 162 (8): 1403–13. doi:10.1176/appi.ajp.162.8.1403. PMID 16055761. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:241" class="footnote-back-ref">↩</a></li>
<li id="fn:242">Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[...]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:242" class="footnote-back-ref">↩</a></li>
<li id="fn:243">Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch – from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure – cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-FosTable 3 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320</a> <a href="#fnref:243" class="footnote-back-ref">↩</a></li>
<li id="fn:244">In other words, c-Fos repression allows ΔFosB to more rapidly accumulate within the D1-type medium spiny neurons of the nucleus accumbens because it is selectively induced in this state.[3] Before c-Fos repression, all Fos family proteins (e.g., c-Fos, Fra1, Fra2, FosB, and ΔFosB) are induced together, with ΔFosB expression increasing to a lesser extent.[3] <a href="/wiki/Gene_repression" target="_blank">/wiki/Gene_repression</a> <a href="#fnref:244" class="footnote-back-ref">↩</a></li>
<li id="fn:245">According to two medical reviews, ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;[78][110] this table entry reflects only a decrease.
 <a href="#fnref:245" class="footnote-back-ref">↩</a></li>
<li id="fn:246">Incentive salience, the "motivational salience" for a reward, is a "desire" or "want" attribute, which includes a motivational component, that the brain assigns to a rewarding stimulus.[111][112] As a consequence, incentive salience acts as a motivational "magnet" for a rewarding stimulus that commands attention, induces approach, and causes the rewarding stimulus to be sought out.[111] <a href="/wiki/Motivational_salience" target="_blank">/wiki/Motivational_salience</a> <a href="#fnref:246" class="footnote-back-ref">↩</a></li>
<li id="fn:247">Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (second ed.). New York: McGraw-Hill Medical. pp. 147–48, 366–67, 375–76. ISBN 978-0-07-148127-4. VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). In this example, dopamine modulates the processing of sensorimotor information in diverse neural circuits to maximize the ability of the organism to obtain future rewards. ...The brain reward circuitry that is targeted by addictive drugs normally mediates the pleasure and strengthening of behaviors associated with natural reinforcers, such as food, water, and sexual contact. Dopamine neurons in the VTA are activated by food and water, and dopamine release in the NAc is stimulated by the presence of natural reinforcers, such as food, water, or a sexual partner. ...The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement and the modulation of motoric responses to stimuli that satisfy internal homeostatic needs. The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc. ... If motivational drive is described in terms of wanting, and hedonic evaluation in terms of liking, it appears that wanting can be dissociated from liking and that dopamine may influence these phenomena differently. Differences between wanting and liking are confirmed in reports by humans with addictions, who state that their desire for drugs (wanting) increases with continued use even when pleasure (liking) decreases because of tolerance. <a href="978-0-07-148127-4" target="_blank">978-0-07-148127-4</a> <a href="#fnref:247" class="footnote-back-ref">↩</a></li>
<li id="fn:248">Berridge KC (April 2012). "From prediction error to incentive salience: mesolimbic computation of reward motivation". Eur. J. Neurosci. 35 (7): 1124–43. doi:10.1111/j.1460-9568.2012.07990.x. PMC 3325516. PMID 22487042. Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. ... Associative learning and prediction are important contributors to motivation for rewards. Learning gives incentive value to arbitrary cues such as a Pavlovian conditioned stimulus (CS) that is associated with a reward (unconditioned stimulus or UCS). Learned cues for reward are often potent triggers of desires. For example, learned cues can trigger normal appetites in everyone, and can sometimes trigger compulsive urges and relapse in individuals with addictions.Cue-triggered 'wanting' for the UCSA brief CS encounter (or brief UCS encounter) often primes a pulse of elevated motivation to obtain and consume more reward UCS. This is a signature feature of incentive salience.Cue as attractive motivational magnetsWhen a Pavlovian CS+ is attributed with incentive salience it not only triggers 'wanting' for its UCS, but often the cue itself becomes highly attractive – even to an irrational degree. This cue attraction is another signature feature of incentive salience ... Two recognizable features of incentive salience are often visible that can be used in neuroscience experiments: (i) UCS-directed 'wanting' – CS-triggered pulses of intensified 'wanting' for the UCS reward; and (ii) CS-directed 'wanting' – motivated attraction to the Pavlovian cue, which makes the arbitrary CS stimulus into a motivational magnet. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325516" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325516</a> <a href="#fnref:248" class="footnote-back-ref">↩</a></li>
<li id="fn:249">Edwards S (2016). "Reinforcement principles for addiction medicine; from recreational drug use to psychiatric disorder". Neuroscience for Addiction Medicine: From Prevention to Rehabilitation - Constructs and Drugs. Progress in Brain Research. Vol. 223. pp. 63–76. doi:10.1016/bs.pbr.2015.07.005. ISBN 978-0-444-63545-7. PMID 26806771. An important dimension of reinforcement highly relevant to the addiction process (and particularly relapse) is secondary reinforcement (Stewart, 1992). Secondary reinforcers (in many cases also considered conditioned reinforcers) likely drive the majority of reinforcement processes in humans. In the specific case of drug addiction, cues and contexts that are intimately and repeatedly associated with drug use will themselves become reinforcing ... A fundamental piece of Robinson and Berridge's incentive-sensitization theory of addiction posits that the incentive value or attractive nature of such secondary reinforcement processes, in addition to the primary reinforcers themselves, may persist and even become sensitized over time in league with the development of drug addiction (Robinson and Berridge, 1993). <a href="978-0-444-63545-7" target="_blank">978-0-444-63545-7</a> <a href="#fnref:249" class="footnote-back-ref">↩</a></li>
<li id="fn:250">Levy N (2019). "Chapter 5 Addiction: The belief oscillation hypothesis". In Pickard H, Ahmed SH (eds.). The Routledge handbook of philosophy and science of addiction. Wellcome Trust–Funded Monographs and Book Chapters. Oxon (UK): Routledge. doi:10.4324/9781315689197-6. ISBN 978-1-138-90928-1. OCLC 1042341025. PMID 31017751. S2CID 242067468. <a href="978-1-138-90928-1" target="_blank">978-1-138-90928-1</a> <a href="#fnref:250" class="footnote-back-ref">↩</a></li>
<li id="fn:251">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:251" class="footnote-back-ref">↩</a></li>
<li id="fn:252">Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades[...]As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:252" class="footnote-back-ref">↩</a></li>
<li id="fn:253">Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–96. PMID 23020045. [...]ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. <a href="http://www.aaem.pl/fulltext.php?ICID=1010966" target="_blank">http://www.aaem.pl/fulltext.php?ICID=1010966</a> <a href="#fnref:253" class="footnote-back-ref">↩</a></li>
<li id="fn:254">Berridge KC (April 2012). "From prediction error to incentive salience: mesolimbic computation of reward motivation". Eur. J. Neurosci. 35 (7): 1124–43. doi:10.1111/j.1460-9568.2012.07990.x. PMC 3325516. PMID 22487042. Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. ... Associative learning and prediction are important contributors to motivation for rewards. Learning gives incentive value to arbitrary cues such as a Pavlovian conditioned stimulus (CS) that is associated with a reward (unconditioned stimulus or UCS). Learned cues for reward are often potent triggers of desires. For example, learned cues can trigger normal appetites in everyone, and can sometimes trigger compulsive urges and relapse in individuals with addictions.Cue-triggered 'wanting' for the UCSA brief CS encounter (or brief UCS encounter) often primes a pulse of elevated motivation to obtain and consume more reward UCS. This is a signature feature of incentive salience.Cue as attractive motivational magnetsWhen a Pavlovian CS+ is attributed with incentive salience it not only triggers 'wanting' for its UCS, but often the cue itself becomes highly attractive – even to an irrational degree. This cue attraction is another signature feature of incentive salience ... Two recognizable features of incentive salience are often visible that can be used in neuroscience experiments: (i) UCS-directed 'wanting' – CS-triggered pulses of intensified 'wanting' for the UCS reward; and (ii) CS-directed 'wanting' – motivated attraction to the Pavlovian cue, which makes the arbitrary CS stimulus into a motivational magnet. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325516" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325516</a> <a href="#fnref:254" class="footnote-back-ref">↩</a></li>
<li id="fn:255">Edwards S (2016). "Reinforcement principles for addiction medicine; from recreational drug use to psychiatric disorder". Neuroscience for Addiction Medicine: From Prevention to Rehabilitation - Constructs and Drugs. Progress in Brain Research. Vol. 223. pp. 63–76. doi:10.1016/bs.pbr.2015.07.005. ISBN 978-0-444-63545-7. PMID 26806771. An important dimension of reinforcement highly relevant to the addiction process (and particularly relapse) is secondary reinforcement (Stewart, 1992). Secondary reinforcers (in many cases also considered conditioned reinforcers) likely drive the majority of reinforcement processes in humans. In the specific case of drug addiction, cues and contexts that are intimately and repeatedly associated with drug use will themselves become reinforcing ... A fundamental piece of Robinson and Berridge's incentive-sensitization theory of addiction posits that the incentive value or attractive nature of such secondary reinforcement processes, in addition to the primary reinforcers themselves, may persist and even become sensitized over time in league with the development of drug addiction (Robinson and Berridge, 1993). <a href="978-0-444-63545-7" target="_blank">978-0-444-63545-7</a> <a href="#fnref:255" class="footnote-back-ref">↩</a></li>
<li id="fn:256">Berridge KC (April 2012). "From prediction error to incentive salience: mesolimbic computation of reward motivation". Eur. J. Neurosci. 35 (7): 1124–43. doi:10.1111/j.1460-9568.2012.07990.x. PMC 3325516. PMID 22487042. Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. ... Associative learning and prediction are important contributors to motivation for rewards. Learning gives incentive value to arbitrary cues such as a Pavlovian conditioned stimulus (CS) that is associated with a reward (unconditioned stimulus or UCS). Learned cues for reward are often potent triggers of desires. For example, learned cues can trigger normal appetites in everyone, and can sometimes trigger compulsive urges and relapse in individuals with addictions.Cue-triggered 'wanting' for the UCSA brief CS encounter (or brief UCS encounter) often primes a pulse of elevated motivation to obtain and consume more reward UCS. This is a signature feature of incentive salience.Cue as attractive motivational magnetsWhen a Pavlovian CS+ is attributed with incentive salience it not only triggers 'wanting' for its UCS, but often the cue itself becomes highly attractive – even to an irrational degree. This cue attraction is another signature feature of incentive salience ... Two recognizable features of incentive salience are often visible that can be used in neuroscience experiments: (i) UCS-directed 'wanting' – CS-triggered pulses of intensified 'wanting' for the UCS reward; and (ii) CS-directed 'wanting' – motivated attraction to the Pavlovian cue, which makes the arbitrary CS stimulus into a motivational magnet. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325516" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325516</a> <a href="#fnref:256" class="footnote-back-ref">↩</a></li>
<li id="fn:257">Berridge KC, Kringelbach ML (May 2015). "Pleasure systems in the brain". Neuron. 86 (3): 646–664. doi:10.1016/j.neuron.2015.02.018. PMC 4425246. PMID 25950633. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425246" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425246</a> <a href="#fnref:257" class="footnote-back-ref">↩</a></li>
<li id="fn:258">Edwards S (2016). "Reinforcement principles for addiction medicine; from recreational drug use to psychiatric disorder". Neuroscience for Addiction Medicine: From Prevention to Rehabilitation - Constructs and Drugs. Progress in Brain Research. Vol. 223. pp. 63–76. doi:10.1016/bs.pbr.2015.07.005. ISBN 978-0-444-63545-7. PMID 26806771. An important dimension of reinforcement highly relevant to the addiction process (and particularly relapse) is secondary reinforcement (Stewart, 1992). Secondary reinforcers (in many cases also considered conditioned reinforcers) likely drive the majority of reinforcement processes in humans. In the specific case of drug addiction, cues and contexts that are intimately and repeatedly associated with drug use will themselves become reinforcing ... A fundamental piece of Robinson and Berridge's incentive-sensitization theory of addiction posits that the incentive value or attractive nature of such secondary reinforcement processes, in addition to the primary reinforcers themselves, may persist and even become sensitized over time in league with the development of drug addiction (Robinson and Berridge, 1993). <a href="978-0-444-63545-7" target="_blank">978-0-444-63545-7</a> <a href="#fnref:258" class="footnote-back-ref">↩</a></li>
<li id="fn:259">Berridge KC (April 2012). "From prediction error to incentive salience: mesolimbic computation of reward motivation". Eur. J. Neurosci. 35 (7): 1124–43. doi:10.1111/j.1460-9568.2012.07990.x. PMC 3325516. PMID 22487042. Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. ... Associative learning and prediction are important contributors to motivation for rewards. Learning gives incentive value to arbitrary cues such as a Pavlovian conditioned stimulus (CS) that is associated with a reward (unconditioned stimulus or UCS). Learned cues for reward are often potent triggers of desires. For example, learned cues can trigger normal appetites in everyone, and can sometimes trigger compulsive urges and relapse in individuals with addictions.Cue-triggered 'wanting' for the UCSA brief CS encounter (or brief UCS encounter) often primes a pulse of elevated motivation to obtain and consume more reward UCS. This is a signature feature of incentive salience.Cue as attractive motivational magnetsWhen a Pavlovian CS+ is attributed with incentive salience it not only triggers 'wanting' for its UCS, but often the cue itself becomes highly attractive – even to an irrational degree. This cue attraction is another signature feature of incentive salience ... Two recognizable features of incentive salience are often visible that can be used in neuroscience experiments: (i) UCS-directed 'wanting' – CS-triggered pulses of intensified 'wanting' for the UCS reward; and (ii) CS-directed 'wanting' – motivated attraction to the Pavlovian cue, which makes the arbitrary CS stimulus into a motivational magnet. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325516" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325516</a> <a href="#fnref:259" class="footnote-back-ref">↩</a></li>
<li id="fn:260">Berridge KC, Kringelbach ML (May 2015). "Pleasure systems in the brain". Neuron. 86 (3): 646–664. doi:10.1016/j.neuron.2015.02.018. PMC 4425246. PMID 25950633. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425246" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425246</a> <a href="#fnref:260" class="footnote-back-ref">↩</a></li>
<li id="fn:261">Edwards S (2016). "Reinforcement principles for addiction medicine; from recreational drug use to psychiatric disorder". Neuroscience for Addiction Medicine: From Prevention to Rehabilitation - Constructs and Drugs. Progress in Brain Research. Vol. 223. pp. 63–76. doi:10.1016/bs.pbr.2015.07.005. ISBN 978-0-444-63545-7. PMID 26806771. An important dimension of reinforcement highly relevant to the addiction process (and particularly relapse) is secondary reinforcement (Stewart, 1992). Secondary reinforcers (in many cases also considered conditioned reinforcers) likely drive the majority of reinforcement processes in humans. In the specific case of drug addiction, cues and contexts that are intimately and repeatedly associated with drug use will themselves become reinforcing ... A fundamental piece of Robinson and Berridge's incentive-sensitization theory of addiction posits that the incentive value or attractive nature of such secondary reinforcement processes, in addition to the primary reinforcers themselves, may persist and even become sensitized over time in league with the development of drug addiction (Robinson and Berridge, 1993). <a href="978-0-444-63545-7" target="_blank">978-0-444-63545-7</a> <a href="#fnref:261" class="footnote-back-ref">↩</a></li>
<li id="fn:262">In simplest terms, this means that when either amphetamine or sex is perceived as more alluring or desirable through reward sensitization, this effect occurs with the other as well. <a href="#fnref:262" class="footnote-back-ref">↩</a></li>
<li id="fn:263">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:263" class="footnote-back-ref">↩</a></li>
<li id="fn:264">Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508</a> <a href="#fnref:264" class="footnote-back-ref">↩</a></li>
<li id="fn:265">Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). "Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats". Neuropharmacology. 101: 154–64. doi:10.1016/j.neuropharm.2015.09.023. PMID 26391065. S2CID 25317397. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:265" class="footnote-back-ref">↩</a></li>
<li id="fn:266">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:266" class="footnote-back-ref">↩</a></li>
<li id="fn:267">Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11042–46. Bibcode:2001PNAS...9811042N. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966. Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in [the] brain after 1–2 months of drug withdrawal ... Indeed, ΔFosB is the longest-lived adaptation known to occur in [the] adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn't involve lesions) as well. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC58680" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC58680</a> <a href="#fnref:267" class="footnote-back-ref">↩</a></li>
<li id="fn:268">Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch – from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure – cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-FosTable 3 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320</a> <a href="#fnref:268" class="footnote-back-ref">↩</a></li>
<li id="fn:269">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:269" class="footnote-back-ref">↩</a></li>
<li id="fn:270">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:270" class="footnote-back-ref">↩</a></li>
<li id="fn:271">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:271" class="footnote-back-ref">↩</a></li>
<li id="fn:272">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:272" class="footnote-back-ref">↩</a></li>
<li id="fn:273">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:273" class="footnote-back-ref">↩</a></li>
<li id="fn:274">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:274" class="footnote-back-ref">↩</a></li>
<li id="fn:275">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:275" class="footnote-back-ref">↩</a></li>
<li id="fn:276">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:276" class="footnote-back-ref">↩</a></li>
<li id="fn:277">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:277" class="footnote-back-ref">↩</a></li>
<li id="fn:278">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:278" class="footnote-back-ref">↩</a></li>
<li id="fn:279">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:279" class="footnote-back-ref">↩</a></li>
<li id="fn:280">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:280" class="footnote-back-ref">↩</a></li>
<li id="fn:281">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:281" class="footnote-back-ref">↩</a></li>
<li id="fn:282">Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 (Pt B): 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384</a> <a href="#fnref:282" class="footnote-back-ref">↩</a></li>
<li id="fn:283">Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–21. doi:10.1016/j.conb.2014.11.002. PMC 4293340. PMID 25486626. Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293340" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293340</a> <a href="#fnref:283" class="footnote-back-ref">↩</a></li>
<li id="fn:284">Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 (Pt B): 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384</a> <a href="#fnref:284" class="footnote-back-ref">↩</a></li>
<li id="fn:285">Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 (Pt B): 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384</a> <a href="#fnref:285" class="footnote-back-ref">↩</a></li>
<li id="fn:286">Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277</a> <a href="#fnref:286" class="footnote-back-ref">↩</a></li>
<li id="fn:287">Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–21. doi:10.1016/j.conb.2014.11.002. PMC 4293340. PMID 25486626. Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293340" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293340</a> <a href="#fnref:287" class="footnote-back-ref">↩</a></li>
<li id="fn:288">Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–21. doi:10.1016/j.conb.2014.11.002. PMC 4293340. PMID 25486626. Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293340" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293340</a> <a href="#fnref:288" class="footnote-back-ref">↩</a></li>
<li id="fn:289">Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 (Pt B): 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384</a> <a href="#fnref:289" class="footnote-back-ref">↩</a></li>
<li id="fn:290">"Facing Addiction in America: The Surgeon General's Report on Alcohol, Drugs, and Health" (PDF). Office of the Surgeon General. US Department of Health and Human Services. November 2016. pp. 35–37, 45, 63, 155, 317, 338. Retrieved 28 January 2017. <a href="https://addiction.surgeongeneral.gov/sites/default/files/surgeon-generals-report.pdf" target="_blank">https://addiction.surgeongeneral.gov/sites/default/files/surgeon-generals-report.pdf</a> <a href="#fnref:290" class="footnote-back-ref">↩</a></li>
<li id="fn:291">Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135257" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135257</a> <a href="#fnref:291" class="footnote-back-ref">↩</a></li>
<li id="fn:292">American Psychiatric Association (2013). "Substance-Related and Addictive Disorders" (PDF). American Psychiatric Publishing. pp. 1–2. Archived from the original (PDF) on 15 August 2015. Retrieved 8 April 2023. Additionally, the diagnosis of dependence caused much confusion. Most people link dependence with "addiction" when in fact dependence can be a normal body response to a substance. <a href="https://web.archive.org/web/20150815050402/http://www.dsm5.org/Documents/Substance%20Use%20Disorder%20Fact%20Sheet.pdf" target="_blank">https://web.archive.org/web/20150815050402/http://www.dsm5.org/Documents/Substance%20Use%20Disorder%20Fact%20Sheet.pdf</a> <a href="#fnref:292" class="footnote-back-ref">↩</a></li>
<li id="fn:293">Petry NM, Rehbein F, Gentile DA, Lemmens JS, Rumpf HJ, Mößle T, et al. (September 2014). "An international consensus for assessing internet gaming disorder using the new DSM-5 approach". Addiction. 109 (9): 1399–406. doi:10.1111/add.12457. PMID 24456155. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:293" class="footnote-back-ref">↩</a></li>
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<li id="fn:295">Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 978-0-07-182770-6. The official diagnosis of drug addiction by the Diagnostic and Statistic Manual of Mental Disorders (2013), which uses the term substance use disorder, is flawed. Criteria used to make the diagnosis of substance use disorders include tolerance and somatic dependence/withdrawal, even though these processes are not integral to addiction as noted. It is ironic and unfortunate that the manual still avoids use of the term addiction as an official diagnosis, even though addiction provides the best description of the clinical syndrome. <a href="978-0-07-182770-6" target="_blank">978-0-07-182770-6</a> <a href="#fnref:295" class="footnote-back-ref">↩</a></li>
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<li id="fn:324">Barbara Shine (October 2000). "Nicotine Vaccine Moves Toward Clinical Trials". National Institute on Drug Abuse. Archived from the original on 10 August 2006. Retrieved 19 September 2006. <a href="https://web.archive.org/web/20060810101935/http://www.drugabuse.gov/NIDA_Notes/NNVol15N5/Vaccine.html" target="_blank">https://web.archive.org/web/20060810101935/http://www.drugabuse.gov/NIDA_Notes/NNVol15N5/Vaccine.html</a> <a href="#fnref:324" class="footnote-back-ref">↩</a></li>
<li id="fn:325">"Nabi Biopharmaceuticals Website". <a href="http://www.nabi.com" target="_blank">http://www.nabi.com</a> <a href="#fnref:325" class="footnote-back-ref">↩</a></li>
<li id="fn:326">Hatsukami DK, Rennard S, Jorenby D, Fiore M, Koopmeiners J, de Vos A, et al. (2005). "Safety and immunogenicity of a nicotine conjugate vaccine in current smokers". Clinical Pharmacology & Therapeutics. 78 (5): 456–467. doi:10.1016/j.clpt.2005.08.007. PMID 16321612. S2CID 1218556. <a href="/w/index.php?title=Dorothy_Hatsukami&action=edit&redlink=1" target="_blank">/w/index.php?title=Dorothy_Hatsukami&action=edit&redlink=1</a> <a href="#fnref:326" class="footnote-back-ref">↩</a></li>
<li id="fn:327">Martell BA, Mitchell E, Poling J, Gonsai K, Kosten TR (July 2005). "Vaccine pharmacotherapy for the treatment of cocaine dependence". Biol. Psychiatry. 58 (2): 158–64. doi:10.1016/j.biopsych.2005.04.032. PMID 16038686. S2CID 22415520. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:327" class="footnote-back-ref">↩</a></li>
<li id="fn:328">"Cocaine vaccine 'stops addiction'". BBC News. 14 June 2004. Retrieved 7 October 2009. <a href="http://news.bbc.co.uk/2/hi/health/3804741.stm" target="_blank">http://news.bbc.co.uk/2/hi/health/3804741.stm</a> <a href="#fnref:328" class="footnote-back-ref">↩</a></li>
<li id="fn:329">"CelticPharma: TA-NIC Nicotine Dependence". Archived from the original on 6 December 2009. Retrieved 27 October 2009. <a href="https://web.archive.org/web/20091206100218/http://www.celticpharma.com/theportfolio/ta-nic.html" target="_blank">https://web.archive.org/web/20091206100218/http://www.celticpharma.com/theportfolio/ta-nic.html</a> <a href="#fnref:329" class="footnote-back-ref">↩</a></li>
<li id="fn:330">"UW researcher explains new vaccine in the works to prevent opioid overdoses". KIRO 7. 19 September 2023. <a href="https://www.kiro7.com/news/local/uw-researcher-explains-new-vaccine-being-made-prevent-opioid-overdoses/HXFQ3AZ2YBAGDIELRDIGKCWN6M/" target="_blank">https://www.kiro7.com/news/local/uw-researcher-explains-new-vaccine-being-made-prevent-opioid-overdoses/HXFQ3AZ2YBAGDIELRDIGKCWN6M/</a> <a href="#fnref:330" class="footnote-back-ref">↩</a></li>
<li id="fn:331">Taylor SB, Lewis CR, Olive MF (February 2013). "The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans". Subst. Abuse Rehabil. 4: 29–43. doi:10.2147/SAR.S39684. PMC 3931688. PMID 24648786. Initial drug use can be attributed to the ability of the drug to act as a reward (ie, a pleasurable emotional state or positive reinforcer), which can lead to repeated drug use and dependence.8,9 A great deal of research has focused on the molecular and neuroanatomical mechanisms of the initial rewarding or reinforcing effect of drugs of abuse. ... At present, no pharmacological therapy has been approved by the FDA to treat psychostimulant addiction. Many drugs have been tested, but none have shown conclusive efficacy with tolerable side effects in humans.172 ... A new emphasis on larger-scale biomarker, genetic, and epigenetic research focused on the molecular targets of mental disorders has been recently advocated.212 In addition, the integration of cognitive and behavioral modification of circuit-wide neuroplasticity (i.e., computer-based training to enhance executive function) may prove to be an effective adjunct-treatment approach for addiction, particularly when combined with cognitive enhancers.198,213–216 Furthermore, in order to be effective, all pharmacological or biologically based treatments for addiction need to be integrated into other established forms of addiction rehabilitation, such as CBT, individual and group psychotherapy, behavior-modification strategies, twelve-step programs, and residential treatment facilities. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931688" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931688</a> <a href="#fnref:331" class="footnote-back-ref">↩</a></li>
<li id="fn:332">Skylstad V, Babirye JN, Kiguli J, Solheim Skar AM, et al. (March 2022). "Are we overlooking alcohol use by younger children?". BMJ Paediatrics Open. 6 (1): e001242. doi:10.1136/bmjpo-2021-001242. PMC 8905875. PMID 36053657. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875</a> <a href="#fnref:332" class="footnote-back-ref">↩</a></li>
<li id="fn:333">Hill R, Harris J (2 November 2021). "Psychological Approaches to Addiction". In Day E (ed.). Seminars in addiction psychiatry (2nd ed.). Cambridge: Cambridge University Press. pp. 147–169. doi:10.1017/9781911623199.009. ISBN 978-1-911623-19-9. S2CID 242036830. <a href="978-1-911623-19-9" target="_blank">978-1-911623-19-9</a> <a href="#fnref:333" class="footnote-back-ref">↩</a></li>
<li id="fn:334">Scott CG (July 2000). "Ethical Issues in Addiction Counseling". Rehabilitation Counseling Bulletin. 43 (4): 209–214. doi:10.1177/003435520004300405. ISSN 0034-3552. PMID 15714702. S2CID 28556555. <a href="http://journals.sagepub.com/doi/10.1177/003435520004300405" target="_blank">http://journals.sagepub.com/doi/10.1177/003435520004300405</a> <a href="#fnref:334" class="footnote-back-ref">↩</a></li>
<li id="fn:335">Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872494</a> <a href="#fnref:335" class="footnote-back-ref">↩</a></li>
<li id="fn:336">Chen CC, Yin SJ (October 2008). "Alcohol abuse and related factors in Asia". International Review of Psychiatry. 20 (5): 425–433. doi:10.1080/09540260802344075. PMID 19012127. S2CID 24571763. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:336" class="footnote-back-ref">↩</a></li>
<li id="fn:337">Mak KK, Lai CM, Watanabe H, Kim DI, Bahar N, Ramos M, et al. (November 2014). "Epidemiology of internet behaviors and addiction among adolescents in six Asian countries". Cyberpsychology, Behavior and Social Networking. 17 (11): 720–728. doi:10.1089/cyber.2014.0139. PMID 25405785. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:337" class="footnote-back-ref">↩</a></li>
<li id="fn:338">Slade T, Johnston A, Teesson M, Whiteford H, Burgess P, Pirkis J, et al. (May 2009). "The Mental Health of Australians 2: Substance Use Disorders in Australia" (PDF). Department of Health and Ageing, Canberra. <a href="/wiki/Maree_Teesson" target="_blank">/wiki/Maree_Teesson</a> <a href="#fnref:338" class="footnote-back-ref">↩</a></li>
<li id="fn:339">Australian Institute of Health and Welfare (AIHW) (2020). National Drug Strategy Household Survey 2019 (Report). doi:10.25816/E42P-A447. <a href="https://www.aihw.gov.au/reports/illicit-use-of-drugs/national-drug-strategy-household-survey-2019/contents/table-of-contents" target="_blank">https://www.aihw.gov.au/reports/illicit-use-of-drugs/national-drug-strategy-household-survey-2019/contents/table-of-contents</a> <a href="#fnref:339" class="footnote-back-ref">↩</a></li>
<li id="fn:340">Australian Institute of Health and Welfare (AIHW) (2020). National Drug Strategy Household Survey 2019 (Report). doi:10.25816/E42P-A447. <a href="https://www.aihw.gov.au/reports/illicit-use-of-drugs/national-drug-strategy-household-survey-2019/contents/table-of-contents" target="_blank">https://www.aihw.gov.au/reports/illicit-use-of-drugs/national-drug-strategy-household-survey-2019/contents/table-of-contents</a> <a href="#fnref:340" class="footnote-back-ref">↩</a></li>
<li id="fn:341">Peacock A, Leung J, Larney S, Colledge S, Hickman M, Rehm J, et al. (October 2018). "Global statistics on alcohol, tobacco and illicit drug use: 2017 status report". Addiction. 113 (10): 1905–1926. doi:10.1111/add.14234. hdl:11343/283940. PMID 29749059. S2CID 13674349. <a href="https://discovery.ucl.ac.uk/id/eprint/10049286/" target="_blank">https://discovery.ucl.ac.uk/id/eprint/10049286/</a> <a href="#fnref:341" class="footnote-back-ref">↩</a></li>
<li id="fn:342">Skylstad V, Babirye JN, Kiguli J, Solheim Skar AM, et al. (March 2022). "Are we overlooking alcohol use by younger children?". BMJ Paediatrics Open. 6 (1): e001242. doi:10.1136/bmjpo-2021-001242. PMC 8905875. PMID 36053657. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905875</a> <a href="#fnref:342" class="footnote-back-ref">↩</a></li>
<li id="fn:343">The lifetime prevalence of an addiction is the percentage of individuals in a population that developed an addiction at some point in their life. <a href="#fnref:343" class="footnote-back-ref">↩</a></li>
<li id="fn:344">Merikangas KR, McClair VL (June 2012). "Epidemiology of Substance Use Disorders". Hum. Genet. 131 (6): 779–89. doi:10.1007/s00439-012-1168-0. PMC 4408274. PMID 22543841. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408274" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408274</a> <a href="#fnref:344" class="footnote-back-ref">↩</a></li>
<li id="fn:345">Merikangas KR, McClair VL (June 2012). "Epidemiology of Substance Use Disorders". Hum. Genet. 131 (6): 779–89. doi:10.1007/s00439-012-1168-0. PMC 4408274. PMID 22543841. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408274" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408274</a> <a href="#fnref:345" class="footnote-back-ref">↩</a></li>
<li id="fn:346">Manubay JM, Muchow C, Sullivan MA (March 2011). "Prescription drug abuse: epidemiology, regulatory issues, chronic pain management with narcotic analgesics". Primary Care. 38 (1): 71–90. doi:10.1016/j.pop.2010.11.006. PMC 3328297. PMID 21356422. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328297" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328297</a> <a href="#fnref:346" class="footnote-back-ref">↩</a></li>
<li id="fn:347">Substance Abuse and Mental Health Services Administration (2022). Key substance use and mental health indicators in the United States: Results from the 2021 National Survey on Drug Use and Health (Report). Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved 24 March 2023. <a href="https://www.samhsa.gov/data/report/2021-nsduh-annual-national-report" target="_blank">https://www.samhsa.gov/data/report/2021-nsduh-annual-national-report</a> <a href="#fnref:347" class="footnote-back-ref">↩</a></li>
<li id="fn:348">"American Board of Medical Specialties recognizes the new subspecialty of addiction medicine" (PDF). American Board of Addiction Medicine. 14 March 2016. Archived from the original (PDF) on 21 March 2021. Retrieved 3 April 2016. Sixteen percent of the non-institutionalized U.S. population age 12 and over – more than 40 million Americans – meets medical criteria for addiction involving nicotine, alcohol or other drugs. This is more than the number of Americans with cancer, diabetes or heart conditions. In 2014, 22.5 million people in the United States needed treatment for addiction involving alcohol or drugs other than nicotine, but only 11.6 percent received any form of inpatient, residential, or outpatient treatment. Of those who do receive treatment, few receive evidence-based care. (There is no information available on how many individuals receive treatment for addiction involving nicotine.)Risky substance use and untreated addiction account for one-third of inpatient hospital costs and 20 percent of all deaths in the United States each year, and cause or contribute to more than 100 other conditions requiring medical care, as well as vehicular crashes, other fatal and non-fatal injuries, overdose deaths, suicides, homicides, domestic discord, the highest incarceration rate in the world and many other costly social consequences. The economic cost to society is greater than the cost of diabetes and all cancers combined. Despite these startling statistics on the prevalence and costs of addiction, few physicians have been trained to prevent or treat it. <a href="https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf" target="_blank">https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf</a> <a href="#fnref:348" class="footnote-back-ref">↩</a></li>
<li id="fn:349">Volkow N (31 March 2016). "A Major Step Forward for Addiction Medicine". National Institute on Drug Abuse. National Institutes of Health. Archived from the original on 5 April 2016. Retrieved 3 April 2016. Only about 10 percent of the 21 million Americans who meet the need for care for an alcohol or drug use disorder receive any form of treatment, and much of the treatment available does not meet standards for evidence-based care. There are many attitudinal and systemic reasons for this treatment gap, including stigma against treating people with addictions and institutional barriers to providing or funding addiction treatment. ... A major milestone was reached on March 14, 2016, when the American Board of Medical Specialties (ABMS) formally announced recognition of the field of Addiction Medicine as a medical subspecialty. ... In a statement issued to mark this milestone, ABAM President Robert J. Sokol summed up its significance: 'This landmark event, more than any other, recognizes addiction as a preventable and treatable disease, helping to shed the stigma that has long plagued it. It sends a strong message to the public that American medicine is committed to providing expert care for this disease and services designed to prevent the risky substance use that precedes it.' <a href="https://web.archive.org/web/20160405133536/https://www.drugabuse.gov/about-nida/noras-blog/2016/03/major-step-forward-addiction-medicine" target="_blank">https://web.archive.org/web/20160405133536/https://www.drugabuse.gov/about-nida/noras-blog/2016/03/major-step-forward-addiction-medicine</a> <a href="#fnref:349" class="footnote-back-ref">↩</a></li>
<li id="fn:350">"American Board of Medical Specialties recognizes the new subspecialty of addiction medicine" (PDF). American Board of Addiction Medicine. 14 March 2016. Archived from the original (PDF) on 21 March 2021. Retrieved 3 April 2016. Sixteen percent of the non-institutionalized U.S. population age 12 and over – more than 40 million Americans – meets medical criteria for addiction involving nicotine, alcohol or other drugs. This is more than the number of Americans with cancer, diabetes or heart conditions. In 2014, 22.5 million people in the United States needed treatment for addiction involving alcohol or drugs other than nicotine, but only 11.6 percent received any form of inpatient, residential, or outpatient treatment. Of those who do receive treatment, few receive evidence-based care. (There is no information available on how many individuals receive treatment for addiction involving nicotine.)Risky substance use and untreated addiction account for one-third of inpatient hospital costs and 20 percent of all deaths in the United States each year, and cause or contribute to more than 100 other conditions requiring medical care, as well as vehicular crashes, other fatal and non-fatal injuries, overdose deaths, suicides, homicides, domestic discord, the highest incarceration rate in the world and many other costly social consequences. The economic cost to society is greater than the cost of diabetes and all cancers combined. Despite these startling statistics on the prevalence and costs of addiction, few physicians have been trained to prevent or treat it. <a href="https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf" target="_blank">https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf</a> <a href="#fnref:350" class="footnote-back-ref">↩</a></li>
<li id="fn:351">Volkow N (31 March 2016). "A Major Step Forward for Addiction Medicine". National Institute on Drug Abuse. National Institutes of Health. Archived from the original on 5 April 2016. Retrieved 3 April 2016. Only about 10 percent of the 21 million Americans who meet the need for care for an alcohol or drug use disorder receive any form of treatment, and much of the treatment available does not meet standards for evidence-based care. There are many attitudinal and systemic reasons for this treatment gap, including stigma against treating people with addictions and institutional barriers to providing or funding addiction treatment. ... A major milestone was reached on March 14, 2016, when the American Board of Medical Specialties (ABMS) formally announced recognition of the field of Addiction Medicine as a medical subspecialty. ... In a statement issued to mark this milestone, ABAM President Robert J. Sokol summed up its significance: 'This landmark event, more than any other, recognizes addiction as a preventable and treatable disease, helping to shed the stigma that has long plagued it. It sends a strong message to the public that American medicine is committed to providing expert care for this disease and services designed to prevent the risky substance use that precedes it.' <a href="https://web.archive.org/web/20160405133536/https://www.drugabuse.gov/about-nida/noras-blog/2016/03/major-step-forward-addiction-medicine" target="_blank">https://web.archive.org/web/20160405133536/https://www.drugabuse.gov/about-nida/noras-blog/2016/03/major-step-forward-addiction-medicine</a> <a href="#fnref:351" class="footnote-back-ref">↩</a></li>
<li id="fn:352">"American Board of Medical Specialties recognizes the new subspecialty of addiction medicine" (PDF). American Board of Addiction Medicine. 14 March 2016. Archived from the original (PDF) on 21 March 2021. Retrieved 3 April 2016. Sixteen percent of the non-institutionalized U.S. population age 12 and over – more than 40 million Americans – meets medical criteria for addiction involving nicotine, alcohol or other drugs. This is more than the number of Americans with cancer, diabetes or heart conditions. In 2014, 22.5 million people in the United States needed treatment for addiction involving alcohol or drugs other than nicotine, but only 11.6 percent received any form of inpatient, residential, or outpatient treatment. Of those who do receive treatment, few receive evidence-based care. (There is no information available on how many individuals receive treatment for addiction involving nicotine.)Risky substance use and untreated addiction account for one-third of inpatient hospital costs and 20 percent of all deaths in the United States each year, and cause or contribute to more than 100 other conditions requiring medical care, as well as vehicular crashes, other fatal and non-fatal injuries, overdose deaths, suicides, homicides, domestic discord, the highest incarceration rate in the world and many other costly social consequences. The economic cost to society is greater than the cost of diabetes and all cancers combined. Despite these startling statistics on the prevalence and costs of addiction, few physicians have been trained to prevent or treat it. <a href="https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf" target="_blank">https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf</a> <a href="#fnref:352" class="footnote-back-ref">↩</a></li>
<li id="fn:353">Volkow N (31 March 2016). "A Major Step Forward for Addiction Medicine". National Institute on Drug Abuse. National Institutes of Health. Archived from the original on 5 April 2016. Retrieved 3 April 2016. Only about 10 percent of the 21 million Americans who meet the need for care for an alcohol or drug use disorder receive any form of treatment, and much of the treatment available does not meet standards for evidence-based care. There are many attitudinal and systemic reasons for this treatment gap, including stigma against treating people with addictions and institutional barriers to providing or funding addiction treatment. ... A major milestone was reached on March 14, 2016, when the American Board of Medical Specialties (ABMS) formally announced recognition of the field of Addiction Medicine as a medical subspecialty. ... In a statement issued to mark this milestone, ABAM President Robert J. Sokol summed up its significance: 'This landmark event, more than any other, recognizes addiction as a preventable and treatable disease, helping to shed the stigma that has long plagued it. It sends a strong message to the public that American medicine is committed to providing expert care for this disease and services designed to prevent the risky substance use that precedes it.' <a href="https://web.archive.org/web/20160405133536/https://www.drugabuse.gov/about-nida/noras-blog/2016/03/major-step-forward-addiction-medicine" target="_blank">https://web.archive.org/web/20160405133536/https://www.drugabuse.gov/about-nida/noras-blog/2016/03/major-step-forward-addiction-medicine</a> <a href="#fnref:353" class="footnote-back-ref">↩</a></li>
<li id="fn:354">Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704</a> <a href="#fnref:354" class="footnote-back-ref">↩</a></li>
<li id="fn:355">Karila L, Wéry A, Weinstein A, Cottencin O, Petit A, Reynaud M, et al. (2014). "Sexual addiction or hypersexual disorder: different terms for the same problem? A review of the literature". Curr. Pharm. Des. 20 (25): 4012–20. doi:10.2174/13816128113199990619. PMID 24001295. S2CID 19042860. Sexual addiction, which is also known as hypersexual disorder, has largely been ignored by psychiatrists, even though the condition causes serious psychosocial problems for many people. A lack of empirical evidence on sexual addiction is the result of the disease's complete absence from versions of the Diagnostic and Statistical Manual of Mental Disorders. ... Existing prevalence rates of sexual addiction-related disorders range from 3% to 6%. Sexual addiction/hypersexual disorder is used as an umbrella construct to encompass various types of problematic behaviors, including excessive masturbation, cybersex, pornography use, sexual behavior with consenting adults, telephone sex, strip club visitation, and other behaviors. The adverse consequences of sexual addiction are similar to the consequences of other addictive disorders. Addictive, somatic and psychiatric disorders coexist with sexual addiction. In recent years, research on sexual addiction has proliferated, and screening instruments have increasingly been developed to diagnose or quantify sexual addiction disorders. In our systematic review of the existing measures, 22 questionnaires were identified. As with other behavioral addictions, the appropriate treatment of sexual addiction should combine pharmacological and psychological approaches. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:355" class="footnote-back-ref">↩</a></li>
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<li id="fn:467">"American Board of Medical Specialties recognizes the new subspecialty of addiction medicine" (PDF). American Board of Addiction Medicine. 14 March 2016. Archived from the original (PDF) on 21 March 2021. Retrieved 3 April 2016. Sixteen percent of the non-institutionalized U.S. population age 12 and over – more than 40 million Americans – meets medical criteria for addiction involving nicotine, alcohol or other drugs. This is more than the number of Americans with cancer, diabetes or heart conditions. In 2014, 22.5 million people in the United States needed treatment for addiction involving alcohol or drugs other than nicotine, but only 11.6 percent received any form of inpatient, residential, or outpatient treatment. Of those who do receive treatment, few receive evidence-based care. (There is no information available on how many individuals receive treatment for addiction involving nicotine.)Risky substance use and untreated addiction account for one-third of inpatient hospital costs and 20 percent of all deaths in the United States each year, and cause or contribute to more than 100 other conditions requiring medical care, as well as vehicular crashes, other fatal and non-fatal injuries, overdose deaths, suicides, homicides, domestic discord, the highest incarceration rate in the world and many other costly social consequences. The economic cost to society is greater than the cost of diabetes and all cancers combined. Despite these startling statistics on the prevalence and costs of addiction, few physicians have been trained to prevent or treat it. <a href="https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf" target="_blank">https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf</a> <a href="#fnref:467" class="footnote-back-ref">↩</a></li>
<li id="fn:468">"American Board of Medical Specialties recognizes the new subspecialty of addiction medicine" (PDF). American Board of Addiction Medicine. 14 March 2016. Archived from the original (PDF) on 21 March 2021. Retrieved 3 April 2016. Sixteen percent of the non-institutionalized U.S. population age 12 and over – more than 40 million Americans – meets medical criteria for addiction involving nicotine, alcohol or other drugs. This is more than the number of Americans with cancer, diabetes or heart conditions. In 2014, 22.5 million people in the United States needed treatment for addiction involving alcohol or drugs other than nicotine, but only 11.6 percent received any form of inpatient, residential, or outpatient treatment. Of those who do receive treatment, few receive evidence-based care. (There is no information available on how many individuals receive treatment for addiction involving nicotine.)Risky substance use and untreated addiction account for one-third of inpatient hospital costs and 20 percent of all deaths in the United States each year, and cause or contribute to more than 100 other conditions requiring medical care, as well as vehicular crashes, other fatal and non-fatal injuries, overdose deaths, suicides, homicides, domestic discord, the highest incarceration rate in the world and many other costly social consequences. The economic cost to society is greater than the cost of diabetes and all cancers combined. Despite these startling statistics on the prevalence and costs of addiction, few physicians have been trained to prevent or treat it. <a href="https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf" target="_blank">https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf</a> <a href="#fnref:468" class="footnote-back-ref">↩</a></li>
<li id="fn:469">Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 1: Basic Principles of Neuropharmacology". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 4. ISBN 978-0-07-148127-4. Drug abuse and addiction exact an astoundingly high financial and human toll on society through direct adverse effects, such as lung cancer and hepatic cirrhosis, and indirect adverse effects –for example, accidents and AIDS – on health and productivity. <a href="978-0-07-148127-4" target="_blank">978-0-07-148127-4</a> <a href="#fnref:469" class="footnote-back-ref">↩</a></li>
<li id="fn:470">Merikangas KR, McClair VL (June 2012). "Epidemiology of Substance Use Disorders". Hum. Genet. 131 (6): 779–89. doi:10.1007/s00439-012-1168-0. PMC 4408274. PMID 22543841. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408274" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408274</a> <a href="#fnref:470" class="footnote-back-ref">↩</a></li>
<li id="fn:471">"American Board of Medical Specialties recognizes the new subspecialty of addiction medicine" (PDF). American Board of Addiction Medicine. 14 March 2016. Archived from the original (PDF) on 21 March 2021. Retrieved 3 April 2016. Sixteen percent of the non-institutionalized U.S. population age 12 and over – more than 40 million Americans – meets medical criteria for addiction involving nicotine, alcohol or other drugs. This is more than the number of Americans with cancer, diabetes or heart conditions. In 2014, 22.5 million people in the United States needed treatment for addiction involving alcohol or drugs other than nicotine, but only 11.6 percent received any form of inpatient, residential, or outpatient treatment. Of those who do receive treatment, few receive evidence-based care. (There is no information available on how many individuals receive treatment for addiction involving nicotine.)Risky substance use and untreated addiction account for one-third of inpatient hospital costs and 20 percent of all deaths in the United States each year, and cause or contribute to more than 100 other conditions requiring medical care, as well as vehicular crashes, other fatal and non-fatal injuries, overdose deaths, suicides, homicides, domestic discord, the highest incarceration rate in the world and many other costly social consequences. The economic cost to society is greater than the cost of diabetes and all cancers combined. Despite these startling statistics on the prevalence and costs of addiction, few physicians have been trained to prevent or treat it. <a href="https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf" target="_blank">https://web.archive.org/web/20210321082744/http://www.abam.net/wp-content/uploads/2016/03/1.-News-Release-ADM.pdf</a> <a href="#fnref:471" class="footnote-back-ref">↩</a></li>
<li id="fn:472">"Economic consequences of drug abuse" (PDF). International Narcotics Control Board Report: 2013 (PDF). United Nations – International Narcotics Control Board. 2013. ISBN 978-92-1-148274-4. Retrieved 28 September 2018. <a href="978-92-1-148274-4" target="_blank">978-92-1-148274-4</a> <a href="#fnref:472" class="footnote-back-ref">↩</a></li>
<li id="fn:473">"Overdose Death Rates". National Institute on Drug Abuse. 9 August 2018. Retrieved 17 September 2018. <a href="https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates" target="_blank">https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates</a> <a href="#fnref:473" class="footnote-back-ref">↩</a></li>
<li id="fn:474">"Overdose Deaths Accelerating During Covid-19". Centers For Disease Control Prevention. 18 December 2020. Retrieved 10 February 2021. <a href="https://www.cdc.gov/media/releases/2020/p1218-overdose-deaths-covid-19.html" target="_blank">https://www.cdc.gov/media/releases/2020/p1218-overdose-deaths-covid-19.html</a> <a href="#fnref:474" class="footnote-back-ref">↩</a></li>
</ol>

Addiction open-in-new

Addiction