Difference between revisions of "Addiction" - New World Encyclopedia

From New World Encyclopedia
Line 265: Line 265:
  
 
The general classes of epigenetic alterations that have been implicated in transgenerational epigenetic inheritance include [[DNA methylation]], [[histone modification]]s, and [[Downregulation and upregulation|downregulation or upregulation]] of [[microRNA]]s.<ref name="Transgenerational epigenetic inheritance in addiction" /> With respect to addiction, more research is needed to determine the specific [[Heredity|heritable]] 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.<ref name="Transgenerational epigenetic inheritance in addiction" /><ref name="pmid26572641" /> Based upon preclinical evidence from [[animal research]], 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.{{#tag:ref|According to a review of experimental animal models that examined the transgenerational epigenetic inheritance of [[epigenetic mark]]s that occur in addiction, alterations in [[histone acetylation]] – specifically, di-acetylation of [[lysine]] [[residue (amino acid)|residues]] 9 and 14 on [[histone 3]] (i.e., [[H3K9ac2]] and [[H3K14ac2]]) in association with [[BDNF]] [[gene promoter]]s – have been shown to occur within the [[medial prefrontal cortex]] (mPFC), [[testes]], and [[sperm]] of cocaine-addicted male rats.<ref name="Transgenerational epigenetic inheritance in addiction" /> These epigenetic alterations in the rat mPFC result in increased BDNF [[gene expression]] within the mPFC, which in turn blunts the [[reward system|rewarding properties]] of cocaine and reduces cocaine [[self-administration]].<ref name="Transgenerational epigenetic inheritance in addiction" /> 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).<ref name="Transgenerational epigenetic inheritance in addiction" /> 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.<ref name="Transgenerational epigenetic inheritance in addiction" /> {{As of|2018|post=,}} neither the heritability of these epigenetic marks in humans nor the behavioral effects of the marks within human mPFC neurons has been established.<ref name="Transgenerational epigenetic inheritance in addiction" />|group="note"}}<ref name="Transgenerational epigenetic inheritance in addiction" /> 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.<ref name="Transgenerational epigenetic inheritance in addiction" /><ref name="pmid26572641" />
 
The general classes of epigenetic alterations that have been implicated in transgenerational epigenetic inheritance include [[DNA methylation]], [[histone modification]]s, and [[Downregulation and upregulation|downregulation or upregulation]] of [[microRNA]]s.<ref name="Transgenerational epigenetic inheritance in addiction" /> With respect to addiction, more research is needed to determine the specific [[Heredity|heritable]] 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.<ref name="Transgenerational epigenetic inheritance in addiction" /><ref name="pmid26572641" /> Based upon preclinical evidence from [[animal research]], 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.{{#tag:ref|According to a review of experimental animal models that examined the transgenerational epigenetic inheritance of [[epigenetic mark]]s that occur in addiction, alterations in [[histone acetylation]] – specifically, di-acetylation of [[lysine]] [[residue (amino acid)|residues]] 9 and 14 on [[histone 3]] (i.e., [[H3K9ac2]] and [[H3K14ac2]]) in association with [[BDNF]] [[gene promoter]]s – have been shown to occur within the [[medial prefrontal cortex]] (mPFC), [[testes]], and [[sperm]] of cocaine-addicted male rats.<ref name="Transgenerational epigenetic inheritance in addiction" /> These epigenetic alterations in the rat mPFC result in increased BDNF [[gene expression]] within the mPFC, which in turn blunts the [[reward system|rewarding properties]] of cocaine and reduces cocaine [[self-administration]].<ref name="Transgenerational epigenetic inheritance in addiction" /> 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).<ref name="Transgenerational epigenetic inheritance in addiction" /> 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.<ref name="Transgenerational epigenetic inheritance in addiction" /> {{As of|2018|post=,}} neither the heritability of these epigenetic marks in humans nor the behavioral effects of the marks within human mPFC neurons has been established.<ref name="Transgenerational epigenetic inheritance in addiction" />|group="note"}}<ref name="Transgenerational epigenetic inheritance in addiction" /> 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.<ref name="Transgenerational epigenetic inheritance in addiction" /><ref name="pmid26572641" />
−
 
−
==Mechanisms==
 
−
Addiction is a disorder of the brain's [[reward system]] which arises through [[transcriptional]] and [[epigenetic]] mechanisms and develops over time from 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.).<ref name="Cellular basis" /><ref name="What the ΔFosB?" /><ref name="Natural and drug addictions" /> [[FOSB#DeltaFosB|DeltaFosB]] (ΔFosB), a gene [[transcription factor]], is a critical component and common factor in the development of virtually all forms of behavioral and drug addictions.<ref name="What the ΔFosB?" /><ref name="Natural and drug addictions" /><ref name="G9a reverses ΔFosB plasticity" /><ref name="Nestler" /> 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 [[overexpression]] of ΔFosB in the [[D1-type]] [[medium spiny neuron]]s of the [[nucleus accumbens]].<ref name="Cellular basis" /><ref name="What the ΔFosB?" /><ref name="Natural and drug addictions" /><ref name="G9a reverses ΔFosB plasticity" /> Due to the causal relationship between ΔFosB expression and addictions, it is used [[preclinical research|preclinically]] as an addiction [[biomarker (medicine)|biomarker]].<ref name="Cellular basis" /><ref name="What the ΔFosB?">{{cite journal | author = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = Am. J. Drug Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–37 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | quote = <br />The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker.&nbsp;...<br />Conclusions<br />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, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ''molecular switch'' (34). 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.}}</ref><ref name="G9a reverses ΔFosB plasticity">{{cite journal | vauthors = Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T | title = Epigenetic regulation in drug addiction | journal = Ann. Agric. Environ. Med. | volume = 19 | issue = 3 | pages = 491–96 | year = 2012 | pmid = 23020045 | doi = | quote = For these reasons, 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. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken&nbsp;... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription}}</ref> ΔFosB expression in these neurons directly and positively regulates drug [[self-administration]] and [[#Sensitization|reward sensitization]] through [[positive reinforcement]], while decreasing sensitivity to [[wikt:aversion|aversion]].{{#tag:ref|A decrease in aversion sensitivity, in simpler terms, means that an individual's behavior is less likely to be influenced by undesirable outcomes.|group="note"|name="ΔFosB behaviors"}}<ref name="Cellular basis" /><ref name="What the ΔFosB?" />
 
−
 
−
 
−
[[Cognitive control]] and [[stimulus control]], which is associated with [[operant conditioning|operant]] and [[classical conditioning]], represent opposite processes (i.e., internal vs external or environmental, respectively) that compete over the control of an individual's elicited behaviors.<ref name="Cognitive - stimulus">{{cite journal | vauthors = Washburn DA | title = The Stroop effect at 80: The competition between stimulus control and cognitive control | journal = J Exp Anal Behav | volume = 105 | issue = 1 | pages = 3–13 | year = 2016 | pmid = 26781048 | doi = 10.1002/jeab.194 | quote = 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. }}</ref> Cognitive control, and particularly [[inhibitory control|inhibitory control over behavior]], is impaired in both addiction and [[attention deficit hyperactivity disorder]].<ref name="Executive functions">{{cite journal | author = Diamond A | title = Executive functions | journal = Annu Rev Psychol | volume = 64 | issue = | pages = 135–68 | year = 2013 | pmid = 23020641 | pmc = 4084861 | doi = 10.1146/annurev-psych-113011-143750 | quote = Core EFs are inhibition [response inhibition (self-control&nbsp;– 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).&nbsp;... 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).&nbsp;...<br />EFs can be improved (Diamond & Lee 2011, Klingberg 2010).&nbsp;... 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)&nbsp;... 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.&nbsp;... The subthalamic nucleus appears to play a critical role in preventing such impulsive or premature responding (Frank 2006).}}</ref><ref name="NHM-Cognitive Control">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-148127-4 | pages = 313–21 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control | quote ={{bull}} Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.<br />{{bull}} Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior.&nbsp;...<br />These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is often called "top-down" control or cognitive control of behavior.&nbsp;... 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).&nbsp;...<br />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.&nbsp;... 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).&nbsp;... <!--Inhibitory control brain structures—>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.&nbsp;... 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.}}</ref> Stimulus-driven behavioral responses (i.e., stimulus control) that are associated with a particular [[rewarding stimulus]] tend to dominate one's behavior in an addiction.<ref name="NHM-Cognitive Control" />
 
−
{{Transcription factor glossary|width=610px}}
 
−
{{Psychostimulant addiction|Colorcode=yes|align=right}}
 
−
Chronic addictive drug use causes alterations in [[gene expression]] in the [[mesocorticolimbic projection]].<ref name="Nestler" /><ref name="Nestler, Hyman, and Malenka 2">{{cite journal |vauthors=Hyman SE, Malenka RC, Nestler EJ |title=Neural mechanisms of addiction: the role of reward-related learning and memory |journal=Annu. Rev. Neurosci. |volume=29 |issue= |pages=565–98 |year=2006 |pmid=16776597 |doi=10.1146/annurev.neuro.29.051605.113009 |url=}}</ref><ref name="Addiction genetics">{{cite journal |vauthors=Steiner H, Van Waes V |title=Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants |journal=Prog. Neurobiol. |volume=100 |issue= |pages=60–80 |date=January 2013 |pmid=23085425 |pmc=3525776 |doi=10.1016/j.pneurobio.2012.10.001 |url=}}</ref> The most important [[transcription factor]]s that produce these alterations are [[ΔFosB]], [[cyclic adenosine monophosphate|cAMP]] response element binding protein ([[cAMP response element binding protein|CREB]]), and nuclear factor kappa B ([[nuclear factor kappa B|NF-κB]]).<ref name="Nestler" /> ΔFosB is the most significant biomolecular mechanism in addiction because the [[overexpression]] of ΔFosB in the [[D1-type]] [[medium spiny neuron]]s in the [[nucleus accumbens]] is [[necessary and sufficient]] for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug [[self-administration]] and [[#Sensitization|reward sensitization]]) seen in drug addiction.<ref name="Nestler" /> ΔFosB expression in [[nucleus accumbens]] [[D1-type]] [[medium spiny neuron]]s directly and positively regulates drug [[self-administration]] and [[#Sensitization|reward sensitization]] through [[positive reinforcement]] while decreasing sensitivity to [[wikt:aversion|aversion]].<ref name="ΔFosB behaviors" group="note" /><ref name="Cellular basis" /><ref name="What the ΔFosB?" /> ΔFosB has been implicated in mediating addictions to many different drugs and drug classes, including [[alcoholism|alcohol]], [[amphetamine]] and other [[substituted amphetamines]], [[cannabinoid]]s, [[cocaine]], [[methylphenidate]], [[nicotine]], [[opiates]], [[phenylcyclidine]], and [[propofol]], among others.<ref name="What the ΔFosB?" /><!--Preceding review covers ΔFosB in propofol addiction—><ref name="Nestler" /><ref name="Nestler, Hyman, and Malenka 2" /><ref name="Alcoholism ΔFosB">{{cite web | title=Alcoholism – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 | work=KEGG Pathway | accessdate=10 April 2014 | author=Kanehisa Laboratories | date=2 August 2013}}</ref><ref name="MPH ΔFosB">{{cite journal | vauthors = Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P | title = Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens | journal = Proc. Natl. Acad. Sci. USA | volume = 106 | issue = 8 | pages = 2915–20 | date = February 2009 | pmid = 19202072 | pmc = 2650365 | doi = 10.1073/pnas.0813179106 | quote = <!--Despite decades of clinical use of methylphenidate for ADHD, concerns have been raised that long-term treatment of children with this medication may result in subsequent drug abuse and addiction.&nbsp;... Thus, although oral administration of clinical doses of methylphenidate is not associated with euphoria or with abuse problems, nontherapeutic use of high doses or i.v. administration may lead to addiction (39, 40).—>}}</ref> [[ΔJunD]], a transcription factor, and [[EHMT2|G9a]], a [[histone methyltransferase]], both oppose the function of ΔFosB and inhibit increases in its expression.<ref name="Cellular basis" /><ref name="Nestler" /><ref name="Nestler 2014 epigenetics" /> Increases in nucleus accumbens ΔJunD expression (via [[viral vector]]-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).<ref name="G9a reverses ΔFosB plasticity" /><ref name="Nestler" />
 
−
 
−
ΔFosB also plays an important role in regulating behavioral responses to [[natural reward]]s, such as palatable food, sex, and exercise.<ref name="Nestler" /><ref name="ΔFosB reward">{{cite journal |vauthors=Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M | title = Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms | journal = Journal of Psychoactive Drugs | volume = 44 | issue = 1 | pages = 38–55 | year = 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112| quote = 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.&nbsp;... 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. }}</ref> Natural rewards, like drugs of abuse, [[inducible gene|induce gene expression]] of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.<ref name="Natural and drug addictions">{{cite journal | author = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–22 |date=December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = 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).&nbsp;... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA&nbsp;... 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).&nbsp;... 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).&nbsp;... 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 patients 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)."}}<br /><!--The following link is outside the template to make it hyperlinked while appearing to be part of the quote.—>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704/table/T1/ Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers]"</ref><ref name="Nestler" /><ref name="ΔFosB reward" /> Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well;<ref name="Nestler">{{cite journal |vauthors=Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–37 |date=November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB has been linked directly to several addiction-related behaviors&nbsp;... 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 exposure<sup>14,22–24</sup>. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also 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 consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. }}</ref><ref name="Natural and drug addictions" /><ref name="ΔFosB reward"/> in particular, ΔFosB in the nucleus accumbens is critical for the [[reinforcing]] effects of sexual reward.<ref name="ΔFosB reward" /> 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-[[sensitization]] effects that are mediated through ΔFosB.<ref name="Natural and drug addictions" /><ref name="Amph-Sex X-sensitization through D1 signaling"><!--Supplemental primary source—>{{cite journal |vauthors=Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM | title = Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator |journal=[[The Journal of Neuroscience]] |volume=33 | issue = 8 | pages = 3434–42 |date=February 2013 | pmid = 23426671 | pmc = 3865508 | doi = 10.1523/JNEUROSCI.4881-12.2013 | quote = Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior.&nbsp;... 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.&nbsp;... 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}}</ref><ref name="Amph-Sex X-sensitization through NMDA signaling"><!--Supplemental primary source—>{{cite journal | vauthors = Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM | title = Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats | journal = Neuropharmacology | volume = 101 | issue = | pages = 154–64 | date = February 2016 | pmid = 26391065 | doi = 10.1016/j.neuropharm.2015.09.023 | quote = }}</ref> 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 also been observed in some individuals taking [[dopaminergic]] medications.<ref name="Natural and drug addictions" />
 
−
 
−
[[ΔFosB]] inhibitors (drugs or treatments that oppose its action) may be an effective treatment for addiction and addictive disorders.<ref name="Malenka_2009_04">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-148127-4 | pages = 384–85 | edition = 2nd | chapter = Chapter 15: Reinforcement and addictive disorders }}</ref>
 
−
 
−
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.<ref name=Salamone>{{cite journal|last=Salamone|first=J.D.|title=Complex motor and sensorimotor function of striatal and accumbens dopamine: Involvement in instrumental behavior processes|journal=Psychopharmacology|year=1992|volume=107|issue=2–3|pages=160–74|doi=10.1007/bf02245133 |pmid=1615120}}</ref><ref name=Kauer>{{cite journal|last=Kauer|first=J.A.|author2=R.C. Malenka|title=Synaptic plasticity and addiction|journal=Nature Reviews Neuroscience |year=2007|issue=11|pages=844–58|doi=10.1038/nrn2234|pmid=17948030|volume=8}}</ref> Altered dopamine [[neurotransmission]] is frequently observed following the development of an addictive state.<ref name="Natural and drug addictions" /> In humans and lab animals that have developed an addiction, alterations in dopamine or [[opioid]] neurotransmission in the nucleus accumbens and other parts of the [[striatum]] are evident.<ref name="Natural and drug addictions" /> Studies have found that use of certain drugs (e.g., [[cocaine]]) affect [[cholinergic neuron]]s that innervate the [[reward system]], in turn affecting dopamine signaling in this region.<ref name=Witten>{{cite journal|last=Witten|first=I|author2=S.-C. Lin|author3=M Brodsky|title=Cholinergic interneurons control local circuit activity and cocaine conditioning|journal=Science|year=2010|volume=330|issue=6011|pages=1677–81|doi=10.1126/science.1193771|pmid=21164015|pmc=3142356|bibcode=2010Sci...330.1677W}}</ref>
 
−
 
−
===Reward system===
 
−
{{main|Reward system}}
 
−
{{expand section|date=August 2015}}
 
−
 
−
====Mesocorticolimbic pathway====
 
−
{{Annotated image 4
 
−
| caption = Top: this depicts the initial effects of high dose exposure to an addictive drug on [[gene expression]] in the [[nucleus accumbens]] for various Fos family proteins (i.e., [[c-Fos]], [[FosB]], [[ΔFosB]], [[Fra1]], and [[Fra2]]).<br />Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these [[phosphorylated]] (35–37&nbsp;[[kilodalton]]) ΔFosB [[isoform]]s persist in the [[D1-type]] [[medium spiny neurons]] of the nucleus accumbens for up to 2&nbsp;months.<!--The following named ref is transcluded in from "Template:Psychostimulant addiction"—><ref name="Nestler2" /><ref name="pmid11572966">{{cite journal |vauthors=Nestler EJ, Barrot M, Self DW | title = DeltaFosB: a sustained molecular switch for addiction | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 20 | pages = 11042–46 |date=September 2001 | pmid = 11572966 | pmc = 58680 | doi = 10.1073/pnas.191352698 | quote = Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in brain after 1–2 months of drug withdrawal&nbsp;... Indeed, ΔFosB is the longest-lived adaptation known to occur in adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn't involve lesions) as well. }}</ref>
 
−
| header = ΔFosB accumulation from excessive drug use
 
−
| header_background = aliceblue
 
−
| alt = ΔFosB accumulation graph
 
−
| image = ΔFosB accumulation.svg
 
−
| align = right
 
−
| icon = none
 
−
| image-width = 400
 
−
| image-left = 0
 
−
| image-top = 0
 
−
| width = 400
 
−
| height = 440
 
−
| annotations =
 
−
}}
 
−
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 [[mesolimbic system|mesolimbic pathway]], or its extension, the [[mesocorticolimbic pathway]], is characterized by the interaction of several areas of the brain.
 
−
* The projections from the [[ventral tegmentum|ventral tegmental area]] (VTA) are a network of [[dopaminergic]] [[neurons]] with [[wikt:colocalize|co-localized]] postsynaptic [[glutamate]] receptors ([[AMPAR]] and [[NMDAR]]). These cells respond when stimuli indicative of a reward are present. The VTA supports learning and sensitization development and releases DA into the [[forebrain]].<ref name="Jones and Bonci">{{cite journal |vauthors=Jones S, Bonci A |title=Synaptic plasticity and drug addiction |journal=Current Opinion in Pharmacology |volume=5 |issue=1 |pages=20–25 |year=2005 |pmid=15661621 |doi=10.1016/j.coph.2004.08.011}}</ref> These neurons also project and release DA into the nucleus accumbens,<ref name="Eisch and Harburg">{{cite journal |vauthors=Eisch AJ, Harburg GC |title=Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology |journal=Hippocampus |volume=16 |issue=3 |pages=271–86 |year=2006 |pmid=16411230 |doi=10.1002/hipo.20161}}</ref> through the [[mesolimbic pathway]]. Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway,<ref name=Rang>{{cite book |author=Rang, H.P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |page=596 |isbn=978-0-443-07145-4}}</ref> in addition to their specific effects.
 
−
* The [[nucleus accumbens]] (NAcc) is one output of the VTA projections. The nucleus accumbens itself consists mainly of [[GABA]]ergic [[medium spiny neuron]]s (MSNs).<ref name="Kourrich">{{cite journal |vauthors=Kourrich S, Rothwell PE, Klug JR, Thomas MJ |title=Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens |journal=J. Neurosci. |volume=27 |issue=30 |pages=7921–28 |year=2007 |pmid=17652583 |pmc=6672735 |doi=10.1523/JNEUROSCI.1859-07.2007}}</ref> The NAcc is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses.<ref name="Jones and Bonci"/> Overexpression of [[ΔFosB]] in the nucleus accumbens is a necessary common factor in essentially all known forms of addiction;<ref name="Cellular basis" /> ΔFosB is a strong positive modulator of [[positively reinforced]] behaviors.<ref name="Cellular basis" />
 
−
* The [[prefrontal cortex]], including the [[anterior cingulate]] and [[orbitofrontal cortex|orbitofrontal]] cortices,<ref name="Kalivas and Volkow">{{cite journal | vauthors = Kalivas PW, Volkow ND | title = The neural basis of addiction: a pathology of motivation and choice | journal = The American Journal of Psychiatry | volume = 162 | issue = 8 | pages = 1403–13 | date = August 2005 | pmid = 16055761 | doi = 10.1176/appi.ajp.162.8.1403 }}</ref> 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.<ref name="Floresco">{{cite journal | vauthors = Floresco SB, Ghods-Sharifi S | title = Amygdala-prefrontal cortical circuitry regulates effort-based decision making | journal = Cerebral Cortex | volume = 17 | issue = 2 | pages = 251–60 | date = February 2007 | pmid = 16495432 | doi = 10.1093/cercor/bhj143 | citeseerx = 10.1.1.335.4681 }}</ref> It is also 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.<ref>{{cite journal | vauthors = Perry CJ, Zbukvic I, Kim JH, Lawrence AJ | title = Role of cues and contexts on drug-seeking behaviour | journal = British Journal of Pharmacology | volume = 171 | issue = 20 | pages = 4636–72 | date = October 2014 | pmid = 24749941 | pmc = 4209936 | doi = 10.1111/bph.12735 }}</ref>
 
−
Other brain structures that are involved in addiction include:
 
−
* The [[basolateral amygdala]] projects into the NAcc and is thought to also be important for motivation.<ref name="Floresco"/>
 
−
* The [[hippocampus]] 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 dopamine levels in NAcc and firing rates of VTA dopaminergic cells.<ref name="Eisch and Harburg"/>
 
−
 
−
====Role of dopamine and glutamate====
 
−
 
−
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.<ref name=arch>{{cite journal | vauthors = Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F | title = Dopamine in drug abuse and addiction: results of imaging studies and treatment implications | journal = Arch. Neurol. | volume = 64 | issue = 11 | pages = 1575–79 | year = 2007 | pmid = 17998440 | doi = 10.1001/archneur.64.11.1575 | url = | doi-access = free }}</ref> 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.<ref name=arch/><ref name=drugs-brain>{{cite web|url=http://www.drugabuse.gov/publications/science-addiction/drugs-brain|title=Drugs, Brains, and Behavior: The Science of Addiction|publisher=National Institute on Drug Abuse}}</ref> Nearly all addictive drugs, directly or indirectly, act upon the brain's reward system by heightening dopaminergic activity.<ref name=addict>{{cite web|url=http://www.drugabuse.gov/infofacts/understand.html|title=Understanding Drug Abuse and Addiction|publisher=National Institute on Drug Abuse|date= November 2012}}</ref>
 
−
 
−
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 [[synaptic cleft]] can induce receptor [[Downregulation and upregulation|downregulation]] in the neural pathway. Downregulation of [[mesolimbic]] dopamine receptors can result in a decrease in the sensitivity to natural reinforcers.<ref name=arch/>
 
−
 
−
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 [[AMPA]] glutamate receptors and glutamate release in the nucleus accumbens.<ref name="Kalivas and Volkow"/>
 
−
 
−
===Reward sensitization{{anchor|Sensitization|Drug sensitization}}===<!--"Drug sensitization" redirects here, do not change without correcting the redirect—>
 
−
{| class="wikitable" style="text-align:center; float:right; margin-left:1em;"
 
−
|+ Neural and behavioral effects of validated ΔFosB transcriptional targets in the [[striatum]]<ref name="What the ΔFosB?" /><ref name="pmid18640924">{{cite journal |author=Nestler EJ |title=Review. Transcriptional mechanisms of addiction: role of DeltaFosB |journal=Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences |volume=363 |issue=1507 |pages=3245–55 |date=October 2008 |pmid=18640924 |doi=10.1098/rstb.2008.0067 |url= |pmc=2607320|quote=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&nbsp;– cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below.&nbsp;...<br />Examples of validated targets for ΔFosB in nucleus accumbens&nbsp;... GluR2&nbsp;... dynorphin&nbsp;... Cdk5&nbsp;... NFκB&nbsp;... c-Fos}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320/table/tbl3/ Table 3]</ref>
 
−
! scope="col" | Target<br />gene
 
−
! scope="col" | Target<br />[[gene expression|expression]]
 
−
! scope="col" | Neural effects
 
−
! scope="col" | Behavioral effects
 
−
|-
 
−
| scope="row" style="height: 40px"| [[c-Fos]] || ↓ || Molecular switch enabling the chronic<br />induction of ΔFosB{{#tag:ref|In other words, c-Fos [[gene repression|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.<ref name="Cellular basis" /> Prior to 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.<ref name="Cellular basis" />|group="note"}} || –
 
−
|-
 
−
| scope="row" style="height: 40px"| [[dynorphin]] || ↓<br />{{#tag:ref|According to two medical reviews, ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;<ref name="What the ΔFosB?" /><ref name="pmid18640924" /> this table entry reflects only a decrease. |group="note"}} || style="text-align:left" | {{bull}}Downregulation of [[κ-opioid receptor|κ-opioid]] feedback loop || style="text-align:left" | {{bull}}Increased drug reward
 
−
|-
 
−
| scope="row" style="height: 40px"| [[NF-κB]] || ↑ || style="text-align:left" | {{bull}}Expansion of [[Nucleus accumbens|NAcc]] dendritic processes<br />{{bull}}NF-κB inflammatory response in the {{abbr|NAcc|nucleus accumbens}}<br />{{bull}}NF-κB inflammatory response in the {{abbrlink|CP|caudate putamen}}|| style="text-align:left" | {{bull}}Increased drug reward<br />{{bull}}Increased drug reward<br />{{bull}}[[Stereotypy|Locomotor sensitization]]
 
−
|-
 
−
| scope="row" style="height: 40px"| [[GluR2]] || ↑ || style="text-align:left" | {{bull}}Decreased [[sensitization|sensitivity]] to [[glutamate]] || style="text-align:left" | {{bull}}Increased drug reward
 
−
|-
 
−
| scope="row" style="height: 40px"| [[Cdk5]] || ↑ || style="text-align:left" | {{bull}}[[GluR1]] synaptic protein phosphorylation<br />{{bull}}Expansion of {{abbr|NAcc|nucleus accumbens}} dendritic processes || Decreased drug reward<br /><small>(net effect)</small>
 
−
|}
 
−
'''Reward sensitization''' is a process that causes an increase in the amount of reward (specifically, [[incentive salience]]{{#tag:ref|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.<ref name="Incentive salience and motivation review" /><ref name="NAcc function" /> 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.<ref name="Incentive salience and motivation review">{{cite journal | vauthors = Berridge KC | title = From prediction error to incentive salience: mesolimbic computation of reward motivation | journal = Eur. J. Neurosci. | volume = 35 | issue = 7 | pages = 1124–43 | date = April 2012 | pmid = 22487042 | pmc = 3325516 | doi = 10.1111/j.1460-9568.2012.07990.x | quote = 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.&nbsp;... 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 addicts.<br />Cue-triggered ‘wanting’ for the UCS<br />A 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.<br />Cue as attractive motivational magnets<br />When 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&nbsp;... 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.}}</ref>|group="note"}}) 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 [[cue reactivity|cues]] increases.<ref name="NAcc function">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-148127-4 | pages = 147–48, 366–67, 375–76 | edition = 2nd | quote= 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.&nbsp;...<br />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.&nbsp;...<br />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.&nbsp;... 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 human addicts, who state that their desire for drugs (wanting) increases with continued use even when pleasure (liking) decreases because of tolerance.}}</ref><ref name="Incentive salience and motivation review" /><ref name="Reinforcement in addiction" /> Reward sensitization normally occurs following chronically high levels of exposure to the stimulus. [[ΔFosB]] (DeltaFosB) expression in [[D1-type]] [[medium spiny neuron]]s in the [[nucleus accumbens]] has been shown to directly and positively regulate reward sensitization involving drugs and natural rewards.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /><ref name="G9a reverses ΔFosB plasticity" />
 
−
 
−
"Cue-induced wanting" or "cue-triggered wanting", a form of craving that occurs in addiction, is responsible for most of the compulsive behavior that addicts exhibit.<ref name="Incentive salience and motivation review" /><ref name="Reinforcement in addiction">{{Cite book | vauthors = Edwards S | title = Reinforcement principles for addiction medicine; from recreational drug use to psychiatric disorder | journal = Prog. Brain Res. | volume = 223 | issue = | pages = 63–76 | year = 2016 | pmid = 26806771 | doi = 10.1016/bs.pbr.2015.07.005 | quote = 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 addition, cues and contexts that are intimately and repeatedly associated with drug use will often themselves become reinforcing&nbsp;... 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).| series = Progress in Brain Research | isbn = 978-0-444-63545-7 }}</ref> During the development of an addiction, the repeated association of otherwise neutral and even non-rewarding [[stimulation|stimuli]] with drug consumption triggers an [[associative learning]] process that causes these previously neutral stimuli to act as [[Reinforcement#Secondary reinforcers|conditioned positive reinforcers]] of addictive drug use (i.e., these stimuli start to function as [[drug cues]]).<ref name="Incentive salience and motivation review" /><ref name="Pleasure system - incentive sensitization">{{cite journal | vauthors = Berridge KC, Kringelbach ML | title = Pleasure systems in the brain | journal = Neuron | volume = 86 | issue = 3 | pages = 646–64 | date = May 2015 | pmid = 25950633 | doi = 10.1016/j.neuron.2015.02.018 | pmc=4425246}}</ref><ref name="Reinforcement in addiction" /> As conditioned positive reinforcers of drug use, these previously neutral stimuli are assigned incentive salience (which manifests as a craving)&nbsp;– sometimes at pathologically high levels due to reward sensitization&nbsp;– which can [[Pavlovian-instrumental transfer|transfer to the primary reinforcer]] (e.g., the use of an addictive drug) with which it was originally paired.<ref name="Incentive salience and motivation review" /><ref name="Pleasure system - incentive sensitization" /><ref name="Reinforcement in addiction" />
 
−
 
−
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{{#tag:ref|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.|group="note"}} that is mediated through ΔFosB.<ref name="Natural and drug addictions" /><ref name="Amph-Sex X-sensitization through D1 signaling" /><ref name="Amph-Sex X-sensitization through NMDA signaling" /> In contrast to ΔFosB's reward-sensitizing effect, [[CREB]] transcriptional activity decreases user's sensitivity to the rewarding effects of the substance. CREB transcription in the nucleus accumbens is implicated in [[psychological dependence]] and symptoms involving a [[anhedonia|lack of pleasure or motivation]] during [[drug withdrawal]].<ref name="Cellular basis" /><ref name="pmid11572966" /><ref name="pmid18640924" />
 
−
 
−
The set of proteins known as "[[regulators of G protein signaling]]" (RGS), particularly [[RGS4]] and [[RGS9-2]], have been implicated in modulating some forms of opioid sensitization, including reward sensitization.<ref name="RGS opioid">{{cite journal | vauthors = Traynor J | title = μ-Opioid receptors and regulators of G protein signaling (RGS) proteins: from a symposium on new concepts in mu-opioid pharmacology | journal = Drug Alcohol Depend | volume = 121 | issue = 3 | pages = 173–80 | date = March 2012 | pmid = 22129844 | pmc = 3288798 | doi = 10.1016/j.drugalcdep.2011.10.027 | quote = }}</ref>
 
−
{{clear}}
 
−
{{Addiction-related plasticity|title=Summary of addiction-related plasticity}}
 
−
{{clear}}
 
−
 
−
===Neuroepigenetic mechanisms===
 
−
{{See also|Neuroepigenetics|Chromatin remodeling}}
 
−
{{Expand section|the table of drug-induced chromatin modifications from figure 2 of this<ref name="Chromatin states" /> review; an explanation of the relationship between class I [[HDAC]]s—[[H3K9ac]]/[[H3K9ac2]], [[G9a]]—[[H3K9me2]], and transcriptional mechanisms (i.e., phospho-CREB and FosB–ΔFosB)|date=June 2018|small=no}}<!--
 
−
-Should probably mention the following since it's related to both the mechanisms and research sections:
 
−
1) Prolonged inhibition of class I HDACs results in histone hyper-acetylation, which in turn increases G9a expression and H3K9me2 synthesis
 
−
2) G9a catalyzes H3K9 dimethylation (H3K9me2 synthesis)
 
−
3) H3K9me2 is a repressive epigenetic mark that inhibits the induction of DeltaFosB in the NAcc by preventing transcription of the FosB gene
 
−
i.e., +HDACi → ↑ H3 acetylation & ↑H4 acetylation → ↑G9a → ↑H3K9me2 synthesis
 
−
4) The feedback loop involving: +drug → ↑ΔFosB → ↓G9a → ↓H3K9me2 → ↑ΔFosB
 
−
—>
 
−
Altered [[epigenetic]] regulation of [[gene expression]] within the brain's reward system plays a significant and complex role in the development of drug addiction.<ref name="Nestler 2014 epigenetics" /><ref name="Chromatin states" /> Addictive drugs are associated with three types of epigenetic modifications within neurons.<ref name="Nestler 2014 epigenetics" /> These are (1) [[histone modification]]s, (2) [[epigenetic methylation]] of DNA at [[CpG site]]s at (or adjacent to) particular genes, and (3) epigenetic [[Downregulation and upregulation|downregulation or upregulation]] of [[microRNA]]s which have particular target genes.<ref name="Nestler 2014 epigenetics" /><ref name="Nestler" /><ref name="Chromatin states" /> 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 [[histone]] [[Residue (chemistry)#Biochemistry|residues]]<ref name="Chromatin states" /> – most other genes in the NAc cells do not show such changes.<ref name="Nestler 2014 epigenetics" />
 
−
 
−
 
  
 
==Epidemiology==
 
==Epidemiology==

Revision as of 17:09, 28 May 2020

Currently working on —Jennifer Tanabe (talk) May 2020


Brain positron emission tomography images that compare brain metabolism in a healthy individual and an individual with a cocaine addiction


Addiction is a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences.[7] Despite the involvement of a number of psychosocial factors, a biological process—one that is induced by repeated exposure to an addictive stimulus—is the core pathology that drives the development and maintenance of an addiction.[1][8] The two properties that characterize all addictive stimuli are that they are reinforcing (i.e., they increase the likelihood that a person will seek repeated exposure to them) and intrinsically rewarding (i.e., they are perceived as being inherently positive, desirable, and pleasurable).[1][2][6]

Classic hallmarks of addiction include impaired control over substances or behavior, preoccupation with substance or behavior, and continued use despite consequences.[9] Habits and patterns associated with addiction are typically characterized by immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs).[10]


Types of addiction

Addiction and dependence glossary
* addiction – a biopsychosocial disorder characterized by compulsively seeking to achieve a desired effect, such as intoxication, despite harm and adverse consequences to self and others
  • addictive behavior – a behavior that is both rewarding and reinforcing
  • addictive drug – a drug that is both rewarding and reinforcing
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
  • drug withdrawal – symptoms that occur upon cessation of repeated drug use
  • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
  • psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
  • reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
  • rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
  • sensitization – an amplified response to a stimulus resulting from repeated exposure to it
  • substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
  • tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose


Addiction canonically refers to substance abuse; however, the term connotation has been expanded to include behaviors that may lead to a reward (e.g., gambling, eating, or shopping)[11] since the 1990s. A gene transcription factor known as ΔFosB has been identified as a necessary common factor involved in both behavioral and drug addictions, which are associated with the same set of neural adaptations in the reward system.[12][13][14]

Examples of drug and behavioral addictions include alcoholism, marijuana addiction, amphetamine addiction, cocaine addiction, nicotine addiction, opioid addiction, food addiction, video game addiction, gambling addiction, and sexual addiction. The only behavioral addiction recognized by the DSM-5 and the ICD-10 is gambling addiction. With the introduction of the ICD-11 gaming addiction was appended.[15] The term addiction is misused frequently to refer to other compulsive behaviors or disorders, particularly dependence, in news media.[16] An important distinction between drug addiction and dependence is that drug dependence is a disorder in which cessation of drug use results in an unpleasant state of withdrawal, which can lead to further drug use.[17] Addiction is the compulsive use of a substance or performance of a behavior that is independent of withdrawal. Addiction can occur in the absence of dependence, and dependence can occur in the absence of addiction, although the two often occur together.

Addiction exacts an "astoundingly high financial and human toll" on individuals and society as a whole.[18][19][20] In the United States, the total economic cost to society is greater than that of all types of diabetes and all cancers combined.[20] 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, liver cirrhosis and dementia from chronic alcohol consumption, and meth mouth 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.[18][19][20][21]

Biomolecular mechanisms

ΔFosB, a gene transcription factor, has been identified as playing a critical role in the development of addictive states in both behavioral addictions and drug addictions.[12][13][14] Overexpression of ΔFosB in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction;[12] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, and substituted amphetamines[12][22][23][24] as well as addictions to natural rewards such as sex, exercise, and food.[13][14] A recent study also demonstrated a cross-sensitization between drug reward (amphetamine) and a natural reward (sex) that was mediated by ΔFosB.[25]

Besides increased ΔFosB expression in the nucleus accumbens, there are many other correlations in the neurobiology of behavioral addictions with drug addictions.

Behaviors like gambling have been linked to the new found idea of the brain's capacity to anticipate rewards. The reward system can be triggered by early detectors of the behavior, and trigger dopamine neurons to begin stimulating behaviors. But in some cases, it can lead to many issues due to error, or reward-prediction errors. These errors can act as teaching signals to create a complex behavior task over time.[26]

One of the most important discoveries of addictions has been the drug based reinforcement and, even more important, reward based learning processes. Several structures of the brain are important in the conditioning process of behavioral addiction; these subcortical structures form the brain regions known as the reward system. One of the major areas of study is the amygdala, a brain structure which involves emotional significance and associated learning. Research shows that dopaminergic projections from the ventral tegmental area facilitate a motivational or learned association to a specific behavior.[27] Dopamine neurons take a role in the learning and sustaining of many acquired behaviors. Research specific to Parkinson's disease has led to identifying the intracellular signaling pathways that underlie the immediate actions of dopamine. The most common mechanism of dopamine is to create addictive properties along with certain behaviors.[28] There are three stages to the dopamine reward system: bursts of dopamine, triggering of behavior, and further impact to the behavior. Once electronically signaled, possibly through the behavior, dopamine neurons let out a ‘burst-fire’ of elements to stimulate areas along fast transmitting pathways. The behavior response then perpetuates the striated neurons to further send stimuli. The fast firing of dopamine neurons can be monitored over time by evaluating the amount of extracellular concentrations of dopamine through micro dialysis and brain imaging. This monitoring can lead to a model in which one can see the multiplicity of triggering over a period of time.[26] Once the behavior is triggered, it is hard to work away from the dopamine reward system.

Behavioral addiction

Behavioral addiction[note 1] is a form of addiction that involves a compulsion to engage in a rewarding non-substance-related behavior – sometimes called a natural reward[12][13] – despite any negative consequences to the person's physical, mental, social or financial well-being.[32] An addictive behavior is a behavior, or a stimulus related to a behavior (e.g., sex or food), that is both rewarding and reinforcing, and is associated with the development of an addiction. Addictions involving addictive behaviors are normally referred to as behavioral addictions.

The term behavioral addiction refers to a compulsion to engage in a natural reward – which is a behavior that is inherently rewarding (i.e., desirable or appealing) – despite adverse consequences.[5][13][12] Preclinical evidence has demonstrated that marked increases in the expression of ΔFosB through repetitive and excessive exposure to a natural reward induces the same behavioral effects and neuroplasticity as occurs in a drug addiction.[13][33][34][35]

Reviews of both clinical research in humans and preclinical studies involving ΔFosB have identified compulsive sexual activity – specifically, any form of sexual intercourse – as an addiction (i.e., sexual addiction).[13][33] Moreover, reward cross-sensitization between amphetamine and sexual activity, meaning that exposure to one increases the desire for both, has been shown to occur preclinically and clinically as a dopamine dysregulation syndrome;[13][33][34][35] ΔFosB expression is required for this cross-sensitization effect, which intensifies with the level of ΔFosB expression.[13][34][35]

Reviews of preclinical studies indicate that long-term frequent and excessive consumption of high fat or sugar foods can produce an addiction (food addiction).[13][12]

Gambling provides a natural reward which is associated with compulsive behavior and for which clinical diagnostic manuals, namely the DSM-5, have identified diagnostic criteria for an "addiction".[13] In order for a person's gambling behavior to meet criteria of an addiction, it shows certain characteristics, such as mood modification, compulsivity, and withdrawal. There is evidence from functional neuroimaging that gambling activates the reward system and the mesolimbic pathway in particular.[13][36] Similarly, shopping and playing video games are associated with compulsive behaviors in humans and have also been shown to activate the mesolimbic pathway and other parts of the reward system.[13] Based upon this evidence, gambling addiction, video game addiction, and shopping addiction are classified accordingly.[13][36]

Psychiatric and medical classifications

Diagnostic models do not currently include the criteria necessary to identify behaviors as addictions in a clinical setting. Behavioral addictions have been proposed as a new class in DSM-5, but the only category included is gambling addiction. Internet gaming addiction is included in the appendix as a condition for further study.[37][38]

Behavioral addictions, which are sometimes referred to as impulse control disorders, are increasingly recognized as treatable forms of addiction.[39] The type of excessive behaviors identified as being addictive include gambling, food, chocolate, sexual intercourse, use of pornography, use of computers, playing video games, use of the internet and other digital media, exercise, and shopping.

Researching addiction to food, for example, a 2009 Scripps Research Institute study found evidence that the same molecular mechanisms correlated with human drug addiction also exist in compulsive overeating in obese rats. The dopamine D2 receptor studied is associated with vulnerability to drug addiction in humans. It was found downregulated in obese rats exposed to a high fat diet, and further reductions of the receptor increased compulsive eating. The D2 receptor responds to dopamine, a central neurotransmitter released in anticipation of rewarding, satiating experiences such as those involving food, sex or psychoactive drugs.[40]

In August 2011, the American Society of Addiction Medicine (ASAM) issued a public statement defining all addiction in terms of brain changes. "Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry."[41]

The following excerpts are taken from the organization's FAQs:

The new ASAM definition makes a departure from equating addiction with just substance dependence, by describing how addiction is also related to behaviors that are rewarding. This is the first time that ASAM has taken an official position that addiction is not solely "substance dependence." This definition says that addiction is about functioning and brain circuitry and how the structure and function of the brains of persons with addiction differ from the structure and function of the brains of persons who do not have addiction. It talks about reward circuitry in the brain and related circuitry, but the emphasis is not on the external rewards that act on the reward system. Food and sexual behaviors and gambling behaviors can be associated with the "pathological pursuit of rewards" described in this new definition of addiction.

We all have the brain reward circuitry that makes food and sex rewarding. In fact, this is a survival mechanism. In a healthy brain, these rewards have feedback mechanisms for satiety or 'enough.' In someone with addiction, the circuitry becomes dysfunctional such that the message to the individual becomes ‘more’, which leads to the pathological pursuit of rewards and/or relief through the use of substances and behaviors. So, anyone who has addiction is vulnerable to food and sex addiction.

Since ASAM released its statement, and shortly before its release, additional new studies have come out on Internet addiction. They reveal the same fundamental brain changes seen in other addicts of drugs.[42][43][44][45][46][47] Another 2011 study found that the risk of Internet addiction in men was about three times more than women. Researchers noted,

Internet addiction is a psychosocial disorder and its characteristics are as follows: tolerance, withdrawal symptoms, affective disorders, and problems in social relations. Internet usage creates psychological, social, school and/or work difficulties in a person's life. Eighteen percent of study participants were considered to be pathological Internet users, whose excessive use of the Internet was causing academic, social, and interpersonal problems. Excessive Internet use may create a heightened level of psychological arousal, resulting in little sleep, failure to eat for long periods, and limited physical activity, possibly leading to the user experiencing physical and mental health problems such as depression, OCD, low family relationships and anxiety.[48]

Another growing area is social media addiction. Psychology researchers surveyed 253 undergraduate students at the University of Albany and found that not only is social media (particularly Facebook) itself potentially addictive, those who use it may also be at greater risk for substance abuse.[49]

Treatment

Behavioral addiction is a treatable condition. Treatment options include psychotherapy and psychopharmacotherapy (i.e., medications) or a combination of both. Cognitive behavioral therapy (CBT) is the most common form of psychotherapy used in treating behavioral addictions; it focuses on identifying patterns that trigger compulsive behavior and making lifestyle changes to promote healthier behaviors. Because cognitive behavioral therapy is considered a short term therapy, the number of sessions for treatment normally ranges from five to twenty. During the session, therapists will lead patients through the topics of identifying the issue, becoming aware of one's thoughts surround the issue, identifying any negative or false thinking, and reshaping said negative and false thinking. While CBT does not cure behavioral addiction, it does help with coping with the condition in a healthy way. Currently, there are no medications approved for treatment of behavioral addictions in general, but some medications used for treatment of drug addiction may also be beneficial with specific behavioral addictions.[36] Any unrelated psychiatric disorders should be kept under control, and differentiated from the contributing factors that cause the addiction.


Substance use disorder

Substance use disorder (SUD), also known as a drug use disorder, is the persistent use of drugs (including alcohol) despite substantial harm and adverse consequences.[50][51] Substance use disorders are characterized by an array of mental, physical, and behavioral symptoms that may cause problems related to loss of control, strain to one's interpersonal life, hazardous use, tolerance, and withdrawal.[52] Drug classes that are involved in SUD include: alcohol; caffeine; cannabis; hallucinogens (such as arylcyclohexylamines); other hallucinogens (such as LSD); inhalants; opioids; sedatives, hypnotics, or anxiolytics; stimulants; tobacco; and other or unknown substances.[53]

In the current Diagnostic and Statistical Manual of Mental Disorders, DSM-5, substance abuse and substance dependence have been merged into the category of substance use disorders.[54][55] The severity of substance use disorders can vary widely; in the diagnosis of a SUD, the severity of an individual's SUD is qualified as mild, moderate, or severe on the basis of how many of the 11 diagnostic criteria are met. The International Classification of Diseases 11th revision (ICD-11) divides substance use disorders into two categories: (1) harmful pattern of substance use; and (2) substance dependence.[56]

In 2017 globally 271 million people (5.5% of adults) were estimated to have used one or more illicit drugs.[57] Of these 35 million had a substance use disorder.[57] An additional 237 million men and 46 million women have alcohol use disorder as of 2016.[58] In 2017 substance use disorders from illicit substances directly resulted in 585,000 deaths.[57] Direct deaths from drug use, other than alcohol, have increased over 60 percent from 2000 to 2015.[59] Alcohol use resulted in an additional 3 million deaths in 2016.[58]

Diagnosis

Further information: Substance use disorder#Diagnosis

The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the term "substance use disorder" to refer to a spectrum of drug use-related disorders. The DSM-5 eliminates the terms "abuse" 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.[60][3]

The DSM-5 introduced a new diagnostic category for behavioral addictions; however, problem gambling is the only condition included in that category in the 5th edition.[16] Internet gaming disorder is listed as a "condition requiring further study" in the DSM-5.[61]

Past editions have used physical dependence 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 homeostasis – and therefore physical withdrawal symptoms occur upon cessation of use.[62] 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, anxiety, irritability, intense cravings for the substance, nausea, hallucinations, headaches, cold sweats, tremors, and seizures.

Medical researchers who actively study addiction have criticized the DSM classification of addiction for being flawed and involving arbitrary diagnostic criteria.[17] Writing in 2013, the director of the United States National Institute of Mental Health discussed the invalidity of the DSM-5's classification of mental disorders:[63]

While DSM has been described as a "Bible" for the field, it is, at best, a dictionary, creating a set of labels and defining each. The strength of each of the editions of DSM has been "reliability" – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever.

Given that addiction manifests in structural changes to the brain, it is possible that non-invasive neuroimaging scans obtained via MRI could be used to help diagnose addiction in the future.[64] As a diagnostic biomarker, ΔFosB expression could be used to diagnose an addiction in humans, but this would require a brain biopsy and therefore is not used in clinical practice.

Individuals whose drug or alcohol use cause significant impairment or distress may have a substance use disorder (SUD).[52] Diagnosis usually involves an in-depth examination, typically by psychiatrist, psychologist, or drug and alcohol counselor.[65] The most commonly used guidelines are published in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).[65] There are 11 diagnostic criteria which can be broadly categorized into issues arising from substance use related to loss of control, strain to one's interpersonal life, hazardous use, and pharmacologic effects.[52]

DSM-5 guidelines for the diagnosis of a substance use disorder requires that the individual have significant impairment or distress from their pattern of drug use, and at least two of the symptoms listed below in a given year.[52]

  1. Using more of a substance than planned, or using a substance for a longer interval than desired
  2. Inability to cut down despite desire to do so
  3. Spending substantial amount of the day obtaining, using, or recovering from substance use
  4. Cravings or intense urges to use
  5. Repeated usage causes or contributes to an inability to meet important social, or professional obligations
  6. Persistent usage despite user's knowledge that it is causing frequent problems at work, school, or home
  7. Giving up or cutting back on important social, professional, or leisure activities because of use
  8. Using in physically hazardous situations, or usage causing physical or mental harm
  9. Persistent use despite the user's awareness that the substance is causing or at least worsening a physical or mental problem
  10. Tolerance: needing to use increasing amounts of a substance to obtain its desired effects
  11. Withdrawal: characteristic group of physical effects or symptoms that emerge as amount of substance in the body decreases

There are additional qualifiers and exceptions outlined in the DSM. For instance, if an individual is taking opiates as prescribed, they may experience physiologic effects of tolerance and withdrawal, but this would not cause an individual to meet criteria for a SUD without additional symptoms also being present.[52] A medical professional trained to evaluate and treat substance use disorders will take these nuances into account during a diagnostic evaluation.

Treatment

According to a review, "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 cognitive behavioral therapy, individual and group psychotherapy, behavior-modification strategies, twelve-step programs, and residential treatment facilities."[6]


Detoxification

Depending on the severity of use, and the given substance, early treatment of acute withdrawal may include medical detoxification. Of note, acute withdrawal from heavy alcohol use should be done under medical supervision to prevent a potentially deadly withdrawal syndrome known as delirium tremens. See also Alcohol detoxification.

Therapy

Therapists often classify people with chemical dependencies as either interested or not interested in changing. About 11% of Americans with substance use disorder seek treatment, and 40–60% of those people relapse within a year.[66] Treatments usually involve planning for specific ways to avoid the addictive stimulus, and therapeutic interventions intended to help a client learn healthier ways to find satisfaction. Clinical leaders in recent years have attempted to tailor intervention approaches to specific influences that affect addictive behavior, using therapeutic interviews in an effort to discover factors that led a person to embrace unhealthy, addictive sources of pleasure or relief from pain.

Treatments
Behavioral pattern Intervention Goals
Low self-esteem, anxiety, verbal hostility Relationship therapy, client centered approach Increase self-esteem, reduce hostility and anxiety
Defective personal constructs, ignorance of interpersonal means Cognitive restructuring including directive and group therapies Insight
Focal anxiety such as fear of crowds Desensitization Change response to same cue
Undesirable behaviors, lacking appropriate behaviors Aversive conditioning, operant conditioning, counter conditioning Eliminate or replace behavior
Lack of information Provide information Have client act on information
Difficult social circumstances Organizational intervention, environmental manipulation, family counseling Remove cause of social difficulty
Poor social performance, rigid interpersonal behavior Sensitivity training, communication training, group therapy Increase interpersonal repertoire, desensitization to group functioning
Grossly bizarre behavior Medical referral Protect from society, prepare for further treatment
Adapted from: Essentials of Clinical Dependency Counseling, Aspen Publishers

From the applied behavior analysis literature and the behavioral psychology literature, several evidence-based intervention programs have emerged, such as behavioral marital therapy, community reinforcement approach, cue exposure therapy, and contingency management strategies.[67][68] In addition, the same author suggests that social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious.

Medication

Medication-assisted treatment (MAT) refers to the combination of behavioral interventions and medications to treat substance use disorders.[69] Certain medications can be useful in treating severe substance use disorders. In the United States five medications are approved to treat alcohol and opioid use disorders.[70] There are no approved medications for cocaine, methamphetamine, or other substance use disorders as of 2002.[70]

Medications, such as methadone and disulfiram, can be used as part of broader treatment plans to help a patient function comfortably without illicit opioids or alcohol.[71] Medications can be used in treatment to lessen withdrawal symptoms. Evidence has demonstrated the efficacy of MAT at reducing illicit drug use and overdose deaths, improving retention in treatment, and reducing HIV transmission.[72][73][74]


Behavioral therapy

A meta-analytic review on the efficacy of various behavioral therapies for treating drug and behavioral addictions found that cognitive behavioral therapy (e.g., relapse prevention and contingency management), motivational interviewing, and a community reinforcement approach were effective interventions with moderate effect sizes.[75]

Clinical and preclinical evidence indicate that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), actually prevents the development of certain drug addictions and is an effective adjunct treatment for drug addiction, and for psychostimulant addiction in particular.[13][76][77][78][79] Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the reversal of drug induced addiction-related neuroplasticity.[13][77] One review noted that exercise may prevent the development of drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system.[79] Aerobic exercise decreases drug self-administration, reduces the likelihood of relapse, and induces opposite effects on striatal dopamine receptor D2 (DRD2) signaling (increased DRD2 density) to those induced by addictions to several drug classes (decreased DRD2 density).[13][77] Consequently, consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction.[13][77][78]

Medication

Alcohol addiction
Further information: Alcoholism

Alcohol, like opioids, can induce a severe state of physical dependence and produce withdrawal symptoms such as delirium tremens. Because of this, treatment for alcohol addiction usually involves a combined approach dealing with dependence and addiction simultaneously. Benzodiazepines have the largest and the best evidence base in the treatment of alcohol withdrawal and are considered the gold standard of alcohol detoxification.[80]

Pharmacological treatments for alcohol addiction include drugs like naltrexone (opioid antagonist), disulfiram, acamprosate, and topiramate.[81][82] Rather than substituting for alcohol, these drugs are intended to affect the desire to drink, either by directly reducing cravings as with acamprosate and topiramate, or by producing unpleasant effects when alcohol is consumed, as with disulfiram. These drugs can be effective if treatment is maintained, but compliance can be an issue as alcoholic patients often forget to take their medication, or discontinue use because of excessive side effects.[83][84] According to a Cochrane Collaboration review, the opioid antagonist naltrexone has been shown to be an effective treatment for alcoholism, with the effects lasting three to twelve months after the end of treatment.[85]

Cannabinoid addiction

As of 2010, there are no effective pharmacological interventions for cannabinoid addiction.[86] A 2013 review on cannabinoid addiction noted that the development of CB1 receptor agonists that have reduced interaction with β-arrestin 2 signaling might be therapeutically useful.[87]

Nicotine addiction
Further information: Smoking cessation

Another area in which drug treatment has been widely used is in the treatment of nicotine addiction, which usually involves the use of nicotine replacement therapy, nicotinic receptor antagonists, or nicotinic receptor partial agonists.[88][89] Examples of drugs that act on nicotinic receptors and have been used for treating nicotine addiction include antagonists like bupropion and the partial agonist varenicline.[88][89]

Opioid addiction
Further information: Opioid use disorder

Opioids cause physical dependence, and treatment typically addresses both dependence and addiction.

Physical dependence is treated using replacement drugs such as suboxone or subutex (both containing the active ingredients buprenorphine) and methadone.[90][91] Although these drugs perpetuate physical dependence, the goal of opiate maintenance is to provide a measure of control over both pain and cravings. Use of replacement drugs increases the addicted individual's ability to function normally and eliminates the negative consequences of obtaining controlled substances illicitly. Once a prescribed dosage is stabilized, treatment enters maintenance or tapering phases. In the United States, opiate replacement therapy is tightly regulated in methadone clinics and under the DATA 2000 legislation. In some countries, other opioid derivatives such as levomethadyl acetate,[92] dihydrocodeine,[93] dihydroetorphine[94] and even heroin[95][96] are used as substitute drugs for illegal street opiates, with different prescriptions being given depending on the needs of the individual patient. Baclofen has led to successful reductions of cravings for stimulants, alcohol, and opioids, and also alleviates alcohol withdrawal syndrome. Many patients have stated they "became indifferent to alcohol" or "indifferent to cocaine" overnight after starting baclofen therapy.[97] Some studies show the interconnection between opioid drug detoxification and overdose mortality.[98]

Psychostimulant addiction

As of May 2014, there is no effective pharmacotherapy for any form of psychostimulant addiction.[6][99][100][101] Reviews from 2015, 2016, and 2018 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[102][103][104] however, as of 2018, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[102][103][104]

Research

Template:Expand section Research indicates that vaccines which utilize anti-drug monoclonal antibodies can mitigate drug-induced positive reinforcement by preventing the drug from moving across the blood–brain barrier;[105] however, current vaccine-based therapies are only effective in a relatively small subset of individuals.[105][106] As of November 2015, vaccine-based therapies are being tested in human clinical trials as a treatment for addiction and preventive measure against drug overdoses involving nicotine, cocaine, and methamphetamine.[105]

The new study shows, that the vaccine may also save lives during a drug overdose. In this instance, the idea is that the body will respond to the vaccine by quickly producing antibodies to prevent the opioids from accessing the brain.[107]

Since addiction involves abnormalities in glutamate and GABAergic neurotransmission,[108][109] receptors associated with these neurotransmitters (e.g., AMPA receptors, NMDA receptors, and GABAB receptors) are potential therapeutic targets for addictions.[108][109][110][111] N-acetylcysteine, which affects metabotropic glutamate receptors and NMDA receptors, has shown some benefit in preclinical and clinical studies involving addictions to cocaine, heroin, and cannabinoids.[108] It may also be useful as an adjunct therapy for addictions to amphetamine-type stimulants, but more clinical research is required.[108]

Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors[note 2] – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged use.[114][115][112][113] These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing addictive behavior in lab animals[note 3] that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;[115][113][116][117] however, few clinical trials involving human addicts and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen.[note 4]

Gene therapy for addiction is an active area of research. One line of gene therapy research involves the use of viral vectors to increase the expression of dopamine D2 receptor proteins in the brain.[119][120][121][122][123]

Risk factors

There are many known risk factors associated with an increased chance of developing a substance use disorder. Children born to parents with SUDs have roughly a two-fold increased risk in developing a SUD compared to children born to parents without any SUDs.[124] Taking highly addictive drugs, and those who develop SUDs in their teens are more likely to have continued symptoms into adulthood.[124] Other common risk factors are being male, being under 25, having other mental health problems, and lack of familial support and supervision.[124] Psychological risk factors include high impulsivity, sensation seeking, neuroticism and openness to experience in combination with low conscientiousness.[125][126]

There are a number of genetic and environmental risk factors for developing an addiction, that vary across the population.[1][127] Genetic and environmental risk factors each account for roughly half of an individual's risk for developing an addiction;[1] the contribution from epigenetic risk factors to the total risk is unknown.[127] 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.[1]

Genetic factors

See also: Alcoholism#Genetic variation

It has long been established that genetic factors along with environmental (e.g., psychosocial) factors are significant contributors to addiction vulnerability.[1][127] Epidemiological studies estimate that genetic factors account for 40–60% of the risk factors for alcoholism.[128] Similar rates of heritability for other types of drug addiction have been indicated by other studies.[129] 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 could then change the structure or functioning of specific brain neurons during development. These altered brain neurons could change 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 genotype.[129]

Overall, the data implicating specific genes in the development of drug addiction is mixed for most genes. One reason for this may be that the case is due to a focus of current research on common variants. Many addiction studies focus on common variants with an allele frequency of greater than 5% in the general population; however, when associated with disease, these only confer a small amount of additional risk with an odds ratio of 1.1–1.3 percent. On the other hand, the rare variant hypothesis states that genes with low frequencies in the population (<1%) confer much greater additional risk in the development of the disease.[130]

Genome-wide association studies (GWAS) are used to examine genetic associations with dependence, addiction, and drug use. These studies employ an unbiased approach to finding genetic associations with specific phenotypes and give equal weight to all regions of DNA, including those with no ostensible relationship to drug metabolism or response. 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. This is not to say that previous findings, or the GWAS findings, are erroneous. The important effects of endophenotypes are typically not capable of being captured by these methods. Furthermore, genes identified in GWAS for drug addiction may be involved either in adjusting brain behavior prior to drug experiences, subsequent to them, or both.[131]

A study that highlights the significant role genetics play in addiction is the twin studies. Twins have similar and sometimes identical genetics. Analyzing these genes in relation to genetics has helped geneticists understand how much of a role genes play in addiction. Studies performed on twins found that rarely did only one twin have an addiction. In most cases where at least one twin suffered from an addiction, both did, and often to the same substance.[132] Cross addiction is when already has a predisposed addiction and then starts to become addicted to something different. 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.[133] In a recent study done by the National Institute on Drug Abuse, from 2002 to 2017, overdose deaths have almost tripled amongst male and females. In 2017, 72,306 overdose deaths happened in the U.S. that were reported.[134]

Environmental factors

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.[1] A number of different environmental factors have been implicated as risk factors for addiction, including various psychosocial stressors;[1] however, an individual's exposure to an addictive drug is by far the most significant environmental risk factor for addiction.[1] The National Institute on Drug Abuse (NIDA) cites lack of parental supervision, the prevalence of peer substance use, drug availability, and poverty as risk factors for substance use among children and adolescents.[135]

Adverse childhood experiences (ACEs) are various forms of maltreatment and household dysfunction experienced in childhood. The Adverse Childhood Experiences Study by the Centers for Disease Control and Prevention has shown a strong dose–response relationship between ACEs and numerous health, social, and behavioral problems throughout a person's lifespan, including those associated with substance abuse.[136] 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 suffering from 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, particularly during adolescence.[136] A study of 900 court cases involving children who experienced abuse found that a vast amount of them went on to suffer from some form of addiction in their adolescence or adult life.[137] 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.[137] 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 also a cause for one to become engaged in alcohol or other drug use.[138]

Age

Adolescence represents a period of unique vulnerability for developing an addiction.[139] 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.[140] 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.[141][142]

Statistics have shown that those who start to drink alcohol at a younger age are more likely to become dependent later on. About 33% of the population tasted their first alcohol between the ages of 15 and 17, while 18% experienced it prior to this. As for alcohol abuse or dependence, the numbers start off high with those who first drank before they were 12 and then drop off after that. For example, 16% of alcoholics began drinking prior to turning 12 years old, while only 9% first touched alcohol between 15 and 17. This percentage is even lower, at 2.6%, for those who first started the habit after they were 21.[143]

Most individuals are exposed to and use addictive drugs for the first time during their teenage years.[144] In the United States, there were just over 2.8 million new users of illicit drugs in 2013 (~7,800 new users per day);[144] among them, 54.1% were under 18 years of age.[144] In 2011, there were approximately 20.6 million people in the United States over the age of 12 with an addiction.[145] Over 90% of those with an addiction began drinking, smoking or using illicit drugs before the age of 18.[145]

Comorbid disorders

Individuals with comorbid (i.e., co-occurring) mental health disorders such as depression, anxiety, attention-deficit/hyperactivity disorder (ADHD) or post-traumatic stress disorder are more likely to develop substance use disorders.[146][147][148] The NIDA cites early aggressive behavior as a risk factor for substance use.[135] A study by the National Bureau of Economic Research 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.[149]

Epigenetic factors

Transgenerational epigenetic inheritance

Epigenetic genes and their products (e.g., proteins) are the key components through which environmental influences can affect the genes of an individual;[127] they also serve as the mechanism responsible for transgenerational epigenetic inheritance, a phenomenon in which environmental influences on the genes of a parent can affect the associated traits and behavioral phenotypes of their offspring (e.g., behavioral responses to environmental stimuli).[127] In addiction, epigenetic mechanisms play a central role in the pathophysiology of the disease;[1] it has been noted that some of the alterations to the epigenome 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).[127][150]

The general classes of epigenetic alterations that have been implicated in transgenerational epigenetic inheritance include DNA methylation, histone modifications, and downregulation or upregulation of microRNAs.[127] With respect to addiction, more research is needed to determine the specific heritable 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.[127][150] Based upon preclinical evidence from animal research, 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.[note 5][127] 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.[127][150]

Epidemiology

Due to cultural variations, the proportion of individuals who develop a drug or behavioral addiction within a specified time period (i.e., the prevalence) varies over time, by country, and across national population demographics (e.g., by age group, socioeconomic status, etc.).[127]

Asia

The prevalence of alcohol dependence is not as high as is seen in other regions. In Asia, not only socioeconomic factors but also biological factors influence drinking behavior.[151]

The overall prevalence of smartphone ownership is 62%, ranging from 41% in China to 84% in South Korea. Moreover, participation in online gaming ranges from 11% in China to 39% in Japan. Hong Kong has the highest number of adolescents reporting daily or above Internet use (68%). 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%.[152]

Australia

The prevalence of substance abuse disorder among Australians was reported at 5.1% in 2009.[153]

Europe

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, 0.77, 0.37 and 0.35% in 2017 cannabis, amphetamine, opioid and cocaine use. The mortality rates for alcohol and illicit drugs were highest in Eastern Europe.[154]

United States

Based upon representative samples of the US youth population in 2011, the lifetime prevalence[note 6] of addictions to alcohol and illicit drugs has been estimated to be approximately 8% and 2–3% respectively.[19] Based upon representative samples of the US adult population in 2011, the 12 month prevalence of alcohol and illicit drug addictions were estimated at roughly 12% and 2–3% respectively.[19] The lifetime prevalence of prescription drug addictions is currently around 4.7%.[155]

As of 2016 about 22 million people in the United States need treatment for an addiction to alcohol, nicotine, or other drugs.[20][156] Only about 10%, or a little over 2 million, receive any form of treatments, and those that do generally do not receive evidence-based care.[20][156] One-third of inpatient hospital costs and 20% of all deaths in the US every year are the result of untreated addictions and risky substance use.[20][156] In spite of the massive overall economic cost to society, which is greater than the cost of diabetes and all forms of cancer combined, most doctors in the US lack the training to effectively address a drug addiction.[20][156]

Another review listed estimates of lifetime prevalence rates for several behavioral addictions in the United States, including 1–2% for compulsive gambling, 5% for sexual addiction, 2.8% for food addiction, and 5–6% for compulsive shopping.[13] A systematic review indicated that 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 United States ranges from 3–6% of the population.[33]

According to a 2017 poll conducted by the Pew Research Center, 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.[157]

In 2019, opioid addiction was acknowledged as a national crisis in the United States.[158] A Washington Post article 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."

South America

The realities of opioid use and abuse in Latin America may be deceptive if observations are limited to epidemiological findings. In the United Nations Office on Drugs and Crime report,[159] 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.[160]

Notes

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Cite error: Invalid <ref> tag; no text was provided for refs named Cellular basis
  2. ↑ 2.0 2.1 Cite error: Invalid <ref> tag; no text was provided for refs named Nestler Labs Glossary
  3. ↑ 3.0 3.1 Cite error: Invalid <ref> tag; no text was provided for refs named Brain disease
  4. ↑ (October 2008) The disease of addiction: origins, treatment, and recovery. Disease-a-Month 54 (10): 696–721.
  5. ↑ 5.0 5.1 (2009) "Chapter 15: Reinforcement and Addictive Disorders", Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York: McGraw-Hill Medical, 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.”     
  6. ↑ 6.0 6.1 6.2 6.3 (February 2013) The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans. Subst. Abuse Rehabil. 4: 29–43.
  7. ↑ [1][2][3][4][5][6]
  8. ↑ American Society for Addiction Medicine (2012). Definition of Addiction.
  9. ↑ (August 1992) The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism. JAMA 268 (8): 1012–14.
  10. ↑ (1988). Addictive behaviors: etiology and treatment. Annu Rev Psychol 39: 223–52.
  11. ↑ Holden, Constance (2001-11-02). 'Behavioral' Addictions: Do They Exist?. Science 294 (5544): 980–982.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 (November 2011) Transcriptional and epigenetic mechanisms of addiction. Nat. Rev. Neurosci. 12 (11): 623–637.
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 13.10 13.11 13.12 13.13 13.14 13.15 13.16 13.17 13.18 Olsen CM (December 2011). Natural rewards, neuroplasticity, and non-drug addictions. Neuropharmacology 61 (7): 1109–22.
  14. ↑ 14.0 14.1 14.2 (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.
  15. ↑ Meredith E. Gansner, M. D. (2019-09-12). Gaming Addiction in ICD-11: Issues and Implications (in en).
  16. ↑ 16.0 16.1 American Psychiatric Association (2013). Substance-Related and Addictive Disorders pp. 1–2. American Psychiatric Publishing. Archived from the original on 15 August 2015. Retrieved 10 July 2015.
  17. ↑ 17.0 17.1 (2015) "Chapter 16: Reinforcement and Addictive Disorders", Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd, 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.” 
  18. ↑ 18.0 18.1 (2009) "Chapter 1: Basic Principles of Neuropharmacology", Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York: McGraw-Hill Medical. 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.” 
  19. ↑ 19.0 19.1 19.2 19.3 (June 2012) Epidemiology of Substance Use Disorders. Hum. Genet. 131 (6): 779–89.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 American Board of Medical Specialties recognizes the new subspecialty of addiction medicine (14 March 2016). Retrieved 3 April 2016.
  21. ↑ (2013) "Economic consequences of drug abuse", International Narcotics Control Board Report: 2013. United Nations – International Narcotics Control Board. ISBN 978-92-1-148274-4. Retrieved 28 September 2018. 
  22. ↑ (2006). Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29: 565–598.
  23. ↑ (January 2013) Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants. Prog. Neurobiol. 100: 60–80.
  24. ↑ Kanehisa Laboratories (2 August 2013). Alcoholism – Homo sapiens (human). Retrieved 10 April 2014.
  25. ↑ (February 2013) Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator. J. Neurosci. 33 (8): 3434–42.
  26. ↑ 26.0 26.1 (2007). Reward system and addiction: What dopamine does and doesn't do. Current Opinion in Pharmacology 7 (1): 69–76.
  27. ↑ (2008). The neurobiology and genetics of impulse control disorders: Relationships to drug addictions. Biochemical Pharmacology 75 (1): 63–75.
  28. ↑ (2004). The Neurobiology of Dopamine Signaling. Archives of Neurology 61 (5): 641–4.
  29. ↑ (2007). Diagnostic instruments for behavioural addiction: an overview. Psychosom Med 4: Doc11.
  30. ↑ Potenza MN (September 2006). Should addictive disorders include non-substance-related conditions?. Addiction 101 Suppl 1: 142–51.
  31. ↑ (1996). Understanding the means and objects of addiction: Technology, the internet, and gambling. Journal of Gambling Studies 12 (4): 461–9.
  32. ↑ (31 August 2009) Textbook of Anxiety Disorders. American Psychiatric Pub, 359–. ISBN 978-1-58562-254-2. Retrieved 24 April 2010. 
  33. ↑ 33.0 33.1 33.2 33.3 (2014). Sexual addiction or hypersexual disorder: different terms for the same problem? A review of the literature. Curr. Pharm. Des. 20 (25): 4012–20.
  34. ↑ 34.0 34.1 34.2 Cite error: Invalid <ref> tag; no text was provided for refs named Amph-Sex X-sensitization through D1 signaling
  35. ↑ 35.0 35.1 35.2 Cite error: Invalid <ref> tag; no text was provided for refs named Amph-Sex X-sensitization through NMDA signaling
  36. ↑ 36.0 36.1 36.2 (September 2010) Introduction to behavioral addictions. Am. J. Drug Alcohol Abuse 36 (5): 233–241.
  37. ↑ (2013). Internet gaming addiction: current perspectives. Psychology Research and Behavior Management 6 (6): 125–137.
  38. ↑ Is your child a gaming addict?.
  39. ↑ Grant, Jon: Impulse Control Disorders: A Clinician's Guide to Understanding and Treating Behavioral Addictions
  40. ↑ (2010). Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nature Neuroscience 13 (5): 635–41.
  41. ↑ American Society of Addiction Medicine. Public Policy Statement: Definition of Addiction. https://www.asam.org/resources/definition-of-addiction
  42. ↑ (2012). Abnormal White Matter Integrity in Adolescents with Internet Addiction Disorder: A Tract-Based Spatial Statistics Study. PLoS ONE 7 (1): e30253.
  43. ↑ (2011). Enhanced reward sensitivity and decreased loss sensitivity in Internet addicts: An fMRI study during a guessing task. Journal of Psychiatric Research 45 (11): 1525–9.
  44. ↑ (2011). Male Internet addicts show impaired executive control ability: Evidence from a color-word Stroop task. Neuroscience Letters 499 (2): 114–8.
  45. ↑ (2011). Microstructure Abnormalities in Adolescents with Internet Addiction Disorder. PLoS ONE 6 (6): e20708.
  46. ↑ (2011). Reduced striatal dopamine D2 receptors in people with Internet addiction. NeuroReport 22 (8): 407–11.
  47. ↑ (2011). Functional magnetic resonance imaging of brain of college students with internet addiction. 中南大学学报 （医学版） [Journal of Central South University (Medical sciences)] 36 (8): 744–9.
  48. ↑ (2011). The effect of psychiatric symptoms on the internet addiction disorder in Isfahan's University students. Journal of Research in Medical Sciences 16 (6): 793–800.
  49. ↑ Craving Facebook? UAlbany Study Finds Social Media to be Potentially Addictive, Associated with Substance Abuse.
  50. ↑ (2013) Diagnostic and statistical manual of mental disorders., 5, Arlington, VA: American Psychiatric Association. ISBN 978-0-89042-554-1. OCLC 830807378. 
  51. ↑ NAMI Comments on the APA's Dr aft Revision of the DSM-V Substance Use Disorders. National Alliance on Mental Illness.
  52. ↑ 52.0 52.1 52.2 52.3 52.4 (2013) Diagnostic and statistical manual of mental disorders., 5, American Psychiatric Association. ISBN 978-0-89042-554-1. 
  53. ↑ Substance Abuse and Mental Health Services Administration (June 2016). Substance Use Disorders. Substance Abuse and Mental Health Services Administration (US). 
  54. ↑ Guha, Martin (2014-03-11). Diagnostic and Statistical Manual of Mental Disorders: DSM-5 (5th edition). Reference Reviews 28 (3).
  55. ↑ (August 2013) DSM-5 criteria for substance use disorders: recommendations and rationale. The American Journal of Psychiatry 170 (8): 834–51.
  56. ↑ World Health Organization, ICD-11 for Mortality and Morbidity Statistics (ICD-11 MMS), 2018 version for preparing implementation, rev. April 2019
  57. ↑ 57.0 57.1 57.2 World Drug Report 2019: 35 million people worldwide suffer from drug use disorders while only 1 in 7 people receive treatment.
  58. ↑ 58.0 58.1 (2018) Global status report on alcohol and health 2018. WHO. Retrieved 3 May 2020. 
  59. ↑ Prelaunch.
  60. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Surgeon General severe SUD
  61. ↑ (September 2014) An international consensus for assessing internet gaming disorder using the new DSM-5 approach. Addiction 109 (9): 1399–406.
  62. ↑ (1999). Drugs of abuse and brain gene expression. Psychosom Med 61 (5): 630–50.
  63. ↑ Transforming Diagnosis. National Institute of Mental Health. Retrieved 17 June 2015.
  64. ↑ (2019). Substance Abuse and White Matter: Findings, Limitations, and Future of Diffusion Tensor Imaging Research. Drug and Alcohol Dependence 197 (4): 288–298.
  65. ↑ 65.0 65.1 Drug addiction (substance use disorder) – Symptoms and causes.
  66. ↑ (October 2000)Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284 (13): 1689–95.
  67. ↑ (2006). Evidence-Based Practice in Psychology and Behavior Analysis. The Behavior Analyst Today 7 (3): 335–350.
  68. ↑ (1998). An update on empirically validated therapies. Clinical Psychology 49: 5–14.
  69. ↑ (July 2012) Opioid addiction and abuse in primary care practice: a comparison of methadone and buprenorphine as treatment options. Journal of the National Medical Association 104 (7–8): 342–50.
  70. ↑ 70.0 70.1 American Psychiatric Association. (2002). American Psychiatric Association practice guidelines for the treatment of psychiatric disorders.. The Association. ISBN 0-89042-320-2. OCLC 48656105. 
  71. ↑ Massachusetts. Center for Health Information and Analysis, issuing body.. Access to substance use disorder treatment in Massachusetts. OCLC 911187572. 
  72. ↑ Holt, Dr. Harry (2019-07-15). Stigma Associated with Opioid Use Disorder and Medication Assisted Treatment.
  73. ↑ (May 2013) Opioid agonist treatments and heroin overdose deaths in Baltimore, Maryland, 1995-2009. American Journal of Public Health 103 (5): 917–22.
  74. ↑ Administration (US), Substance Abuse and Mental Health Services (November 2016). EARLY INTERVENTION, TREATMENT, AND MANAGEMENT OF SUBSTANCE USE DISORDERS. US Department of Health and Human Services. 
  75. ↑ (2015). [Psychosocial Treatment of Addictive Disorders – An Overview of Psychotherapeutic Options and their Efficacy]. Fortschr Neurol Psychiatr 83 (4): 201–10.
  76. ↑ (February 2016) Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments. Front. Psychiatry 6: 175.
  77. ↑ 77.0 77.1 77.2 77.3 (September 2013) Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis. Neurosci Biobehav Rev 37 (8): 1622–44.
  78. ↑ 78.0 78.1 (2015). Exercise-based treatments for substance use disorders: evidence, theory, and practicality. Am J Drug Alcohol Abuse 41 (1): 7–15.
  79. ↑ 79.0 79.1 (July 2015) Sex differences in drug addiction and response to exercise intervention: From human to animal studies. Front. Neuroendocrinol. 40: 24–41.
  80. ↑ Sachdeva A, Choudhary M, Chandra M. (Sep 2015) "Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond." PMID: 26500991
  81. ↑ (December 2006) New pharmacological approaches for the treatment of alcoholism. Expert Opinion on Pharmacotherapy 7 (17): 2341–53.
  82. ↑ (October 2006) Choosing the right medication for the treatment of alcoholism. Current Psychiatry Reports 8 (5): 383–88.
  83. ↑ (July 2004) Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 99 (7): 811–28.
  84. ↑ (November 2005) Medications for treating alcohol dependence. American Family Physician 72 (9): 1775–80.
  85. ↑ (December 2010) Opioid antagonists for alcohol dependence. The Cochrane Database of Systematic Reviews (12): CD001867.
  86. ↑ (April 2010) Cognitive function as an emerging treatment target for marijuana addiction. Exp Clin Psychopharmacol 18 (2): 109–19.
  87. ↑ (August 2013) Molecular mechanisms of cannabinoid addiction. Curr. Opin. Neurobiol. 23 (4): 487–92.
  88. ↑ 88.0 88.1 (2007). Emerging pharmacotherapies for smoking cessation. Am J Health Syst Pharm 64 (16): 1693–98.
  89. ↑ 89.0 89.1 (2014) Nicotinic receptor antagonists as treatments for nicotine abuse, Advances in Pharmacology, 513–51. DOI:10.1016/B978-0-12-420118-7.00013-5. ISBN 978-0-12-420118-7. 
  90. ↑ (2000). A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N. Engl. J. Med. 343 (18): 1290–97.
  91. ↑ (2007). Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol Assess 11 (9): 1–171, iii–iv.
  92. ↑ (2005). Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence. Exp Clin Psychopharmacol 13 (4): 293–302.
  93. ↑ (2006). Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial. Addiction 101 (12): 1752–59.
  94. ↑ Qin Bo-Yi (1998). Advances in dihydroetorphine: From analgesia to detoxification. Drug Development Research 39 (2): 131–34. Link
  95. ↑ (1998). Feasibility of prescribing injectable heroin and methadone to opiate-dependent drug users: associated health gains and harm reductions. Med. J. Aust. 168 (12): 596–600.
  96. ↑ (2007). Pathways into receiving a prescription for diamorphine (heroin) for the treatment of opiate dependence in the United kingdom. Eur Addict Res 13 (3): 144–47.
  97. ↑ (2007). Pharmacotherapy of dual substance abuse and dependence. CNS Drugs 21 (3): 213–37.
  98. ↑ Strang J, McCambridge J. (May 2003) "Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study" PMID: 12727768
  99. ↑ (May 2014) Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research. Expert Rev Clin Pharmacol 7 (3): 363–74.
  100. ↑ (September 2013) Efficacy of psychostimulant drugs for amphetamine abuse or dependence. Cochrane Database Syst. Rev. 9 (9): CD009695.
  101. ↑ (February 2014) Future pharmacological treatments for substance use disorders. Br. J. Clin. Pharmacol. 77 (2): 382–400.
  102. ↑ 102.0 102.1 (February 2016) "TAARgeting Addiction" – The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference. Drug Alcohol Depend. 159: 9–16.
  103. ↑ 103.0 103.1 (August 2015) Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction. Eur. J. Pharmacol. 761: 345–52.
  104. ↑ 104.0 104.1 (December 2018) Drug addiction: a curable mental disorder?. Acta Pharmacologica Sinica 39 (12): 1823–1829.
  105. ↑ 105.0 105.1 105.2 (November 2015) Is immunotherapy an opportunity for effective treatment of drug addiction?. Vaccine 33 (48): 6545–51.
  106. ↑ (June 2015) The frequency of naive and early-activated hapten-specific B cell subsets dictates the efficacy of a therapeutic vaccine against prescription opioid abuse. J. Immunol. 194 (12): 5926–36.
  107. ↑ Painter A. (2019) "Researchers working to develop vaccines to fight opioid addiction" Vtnews.vt.edu
  108. ↑ 108.0 108.1 108.2 108.3 (March 2016) Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction. Eur. J. Pharmacol. 780: 129–35.
  109. ↑ 109.0 109.1 (February 2016) Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity. Neurosci Biobehav Rev 61: 35–52.
  110. ↑ (April 2015) [GABAB receptor as therapeutic target for drug addiction: from baclofen to positive allosteric modulators]. Psychiatr. Pol. 49 (2): 215–23.
  111. ↑ (January 2015) GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators. Neuropharmacology 88: 36–47.
  112. ↑ 112.0 112.1 (February 2015) The Epigenetic Mechanisms of Amphetamine. J. Addict. Prev. 2015 (Suppl 1).
  113. ↑ 113.0 113.1 113.2 113.3 (February 2015) Regulation of chromatin states by drugs of abuse. Curr. Opin. Neurobiol. 30: 112–21.
  114. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named G9a reverses ΔFosB plasticity
  115. ↑ 115.0 115.1 115.2 (January 2014) Epigenetic mechanisms of drug addiction. Neuropharmacology 76 Pt B: 259–68.
  116. ↑ 116.0 116.1 Primary references involving sodium butyrate:
    Template:Bull (April 2013) Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation. Nat. Neurosci. 16 (4): 434–40.
    Template:Bull (July 2015) The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals. Addict Biol 20 (4): 676–89.
    Template:Bull (April 2015) Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats. PLOS One 10 (4): e0124796.
  117. ↑ (August 2015) Molecular mechanisms of synaptic remodeling in alcoholism. Neurosci. Lett. 601: 11–19.
  118. ↑ (2016) Effect of add-on valproate on craving in methamphetamine depended patients: A randomized trial. Advanced Biomedical Research 5: 149.
  119. ↑ Gene Therapy For Addiction: Flooding Brain With 'Pleasure Chemical' Receptors Works On Cocaine, As On Alcohol.
  120. ↑ Abuse, National Institute on Drug (14 January 2016). Gene Transfer Therapy for Cocaine Addiction Passes Tests in Animals.
  121. ↑ (2014). Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice. Vaccine 32 (33): 4155–62.
  122. ↑ Using Adeno-Associated Virus (AAV) Mediated Sustained Expression of an Anti-methamphetamine Antibody Fragment to Alter Methamphetamine Disposition in Mice.
  123. ↑ ATTC – Addiction Science Made Easy.
  124. ↑ 124.0 124.1 124.2 Ferri, Fred (2019). Ferri's Clinical Advisor. Elsevier. 
  125. ↑ (April 2014) Personality traits and vulnerability or resilience to substance use disorders. Trends in Cognitive Sciences 18 (4): 211–7.
  126. ↑ (2019) Personality Traits and Drug Consumption. A Story Told by Data. Springer, Cham. DOI:10.1007/978-3-030-10442-9. ISBN 978-3-030-10441-2. 
  127. ↑ 127.00 127.01 127.02 127.03 127.04 127.05 127.06 127.07 127.08 127.09 127.10 127.11 127.12 127.13 127.14 127.15 (2014). Mechanisms of transgenerational inheritance of addictive-like behaviors. Neuroscience 264: 198–206.
  128. ↑ Mayfield RD, Harris RA,1, Schuckit MA (May 2008) "Genetic factors influencing alcohol dependence" PMID 18362899
  129. ↑ 129.0 129.1 (May 1994) A twin-family study of alcoholism in women. Am J Psychiatry 151 (5): 707–15.
  130. ↑ (2013). Low frequency genetic variants in the μ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine. Neuroscience Letters 542: 71–75.
  131. ↑ (December 2013) Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong?. Pharmacology & Therapeutics 140 (3): 267–79.
  132. ↑ Genetics of alcoholism. Alcohol Health and Research World: 1–11.
  133. ↑ Life, Dr. Steven Melemis, I Want to Change My, "The Genetics of Addiction – Is Addiction a Disease?", I Want to Change My Life.
  134. ↑ Abuse, National Institute on Drug, "Overdose Death Rates", 9 August 2018.
  135. ↑ 135.0 135.1 Abuse, National Institute on Drug, "What are risk factors and protective factors?".
  136. ↑ 136.0 136.1 Adverse Childhood Experiences. Substance Abuse and Mental Health Services Administration. Retrieved 26 September 2016.
  137. ↑ 137.0 137.1 (2011). The role of early life stress as a predictor for alcohol and drug dependence. Psychopharmacology 214 (1): 17–31.
  138. ↑ Environmental Risk Factors.
  139. ↑ (June 2000) The adolescent brain and age-related behavioral manifestations. Neuroscience and Biobehavioral Reviews 24 (4): 417–63.
  140. ↑ (April 2014) Neurobiology of adolescent substance use and addictive behaviors: treatment implications. Adolescent Medicine 25 (1): 15–32.
  141. ↑ (1990). Evaluation of the effectiveness of adolescent drug abuse treatment, assessment of risks for relapse, and promising approaches for relapse prevention. The International Journal of the Addictions 25 (9A–10A): 1085–140.
  142. ↑ (November 2008) Practitioner review: adolescent alcohol use disorders: assessment and treatment issues. Journal of Child Psychology and Psychiatry, and Allied Disciplines 49 (11): 1131–54.
  143. ↑ Age and Substance Abuse – Alcohol Rehab.
  144. ↑ 145.0 145.1 "Addiction Statistics – Facts on Drug and Alcohol Addiction", AddictionCenter.
  145. ↑ SAMHSA. Risk and Protective Factors. Substance Abuse and Mental Health Administration.
  146. ↑ Infographic – Risk Factors of Addiction | Recovery Research Institute.
  147. ↑ Drug addiction Risk factors – Mayo Clinic.
  148. ↑ "The Connection Between Mental Illness and Substance Abuse | Dual Diagnosis", Dual Diagnosis.
  149. ↑ 150.0 150.1 150.2 (2015). Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism. Mol. Neurobiol. 53 (9): 6367–76.
  150. ↑ Chen CC, Yin SJ. (Oct 2008) "Alcohol abuse and related factors in Asia". PMID: 19012127
  151. ↑ Mak KK, Lai CM, Watanabe H. (Nov 2014) "Epidemiology of internet behaviors and addiction among adolescents in six Asian countries". PMID: 25405785
  152. ↑ The Mental Health of Australians 2: Substance Use Disorders in Australia. Department of Health and Ageing, Canberra (May 2009).
  153. ↑ Peacock A, Leung J, Larney S. (Oct 2018) "Global statistics on alcohol, tobacco and illicit drug use: 2017 status report." PMID: 29749059
  154. ↑ (March 2011) Prescription drug abuse: epidemiology, regulatory issues, chronic pain management with narcotic analgesics. Primary Care 38 (1): 71–90.
  155. ↑ 156.0 156.1 156.2 156.3 Nora Volkow (31 March 2016). A Major Step Forward for Addiction Medicine. National Institutes of Health. Retrieved 3 April 2016.
  156. ↑ Gramlich J (26 October 2017). Nearly half of Americans have a family member or close friend who's been addicted to drugs. Pew Research Center. Retrieved 14 January 2018.
  157. ↑ "We were addicted to their pill, but they were addicted to the money", Washington Post. Retrieved 22 July 2019. (written in en)
  158. ↑ World Drug Report 2012 UN, 2012.
  159. ↑ Pacurucu Castillo, José Marcelo, Adrián Hernández, Renato D. Alarcón (2019) "World Opioid and Substance Use Epidemic: A Latin American Perspective" Psychiatryonline.org
Image legend

References
ISBN links support NWE through referral fees

External links

Kyoto Encyclopedia of Genes and Genomes (KEGG) signal transduction pathways:

Credits

New World Encyclopedia writers and editors rewrote and completed the Wikipedia article in accordance with New World Encyclopedia standards. This article abides by terms of the Creative Commons CC-by-sa 3.0 License (CC-by-sa), which may be used and disseminated with proper attribution. Credit is due under the terms of this license that can reference both the New World Encyclopedia contributors and the selfless volunteer contributors of the Wikimedia Foundation. To cite this article click here for a list of acceptable citing formats.The history of earlier contributions by wikipedians is accessible to researchers here:

The history of this article since it was imported to New World Encyclopedia:

Note: Some restrictions may apply to use of individual images which are separately licensed.


Cite error: <ref> tags exist for a group named "note", but no corresponding <references group="note"/> tag was found

Retrieved from https://www.newworldencyclopedia.org/p/index.php?title=Addiction&oldid=1037650

Content is available under Creative Commons Attribution/Share-Alike License; additional terms may apply. See Terms of Use for details.
Copyright Logo
Powered by MediaWiki