Editing Amphetamine (section)

====Biomolecular mechanisms====
Chronic use of amphetamine at excessive doses causes alterations in [[gene expression]] in the [[mesocorticolimbic projection]], which arise through [[transcriptional]] and [[epigenetic]] mechanisms.<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=Annual Review of Neuroscience|volume=29 |pages=565–598 |date=July 2006 |pmid=16776597 |doi=10.1146/annurev.neuro.29.051605.113009|s2cid=15139406 }}</ref><ref name="Addiction genetics" /> The most important [[transcription factor]]s{{#tag:ref|Transcription factors are proteins that increase or decrease the [[gene expression|expression]] of specific genes.<ref name="NHM-Transcription factor">{{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, US | isbn = 9780071481274 | page = 94 | edition = 2nd | chapter = Chapter 4: Signal Transduction in the Brain | quote= <!-- All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug. -->}}</ref>|group="note"}} that produce these alterations are ''Delta FBJ murine osteosarcoma viral oncogene homolog B'' ([[ΔFosB]]), ''[[Cyclic adenosine monophosphate|cAMP]] response element binding protein'' ([[cAMP response element binding protein|CREB]]), and ''nuclear factor-kappa B'' ([[NF-κB]]).<ref name="Nestler" /> ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB [[overexpression]] (i.e., an abnormally high level of gene expression which produces a pronounced gene-related [[phenotype]]) in the [[D1-type]] [[medium spiny neuron]]s in the [[nucleus accumbens]] is [[necessary and sufficient]]{{#tag:ref|In simpler terms, this ''necessary and sufficient'' relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.|group="note"}} for many of the neural adaptations and regulates multiple behavioral effects (e.g., [[reward sensitization]] and escalating drug [[self-administration]]) involved in addiction.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /><ref name="Nestler" /> Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /> It has been implicated in addictions to [[alcoholism|alcohol]], [[cannabinoid]]s, [[cocaine]], [[methylphenidate]], [[nicotine]], [[opioid]]s, [[phencyclidine]], [[propofol]], and [[substituted amphetamines]], among others.{{#tag:ref|<ref name="What the ΔFosB?" /><!--Preceding review covers ΔFosB in propofol addiction --><ref name="Natural and drug addictions" /><ref name="Nestler" /><ref name="Alcoholism ΔFosB">{{cite web | title=Alcoholism – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 | website=KEGG Pathway | access-date=31 October 2014 | author=Kanehisa Laboratories | date=29 October 2014}}</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 =Proceedings of the National Academy of Sciences| volume = 106 | issue = 8 | pages = 2915–2920 | 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. However, meta analysis of available data suggests that treatment of ADHD with stimulant drugs may have a significant protective effect, reducing the risk for addictive substance use (36, 37). Studies with juvenile rats have also indicated that repeated exposure to methylphenidate does not necessarily lead to enhanced drug-seeking behavior in adulthood (38). However, the recent increase of methylphenidate use as a cognitive enhancer by the general public has again raised concerns because of its potential for abuse and addiction (3, 6–10). 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). --> | bibcode = 2009PNAS..106.2915K| doi-access = free | title-link = doi }}</ref>|group="sources"}}

[[ΔJunD]], a transcription factor, and [[EHMT2|G9a]], a [[histone methyltransferase]] enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.<ref name="Cellular basis" /><ref name="Nestler" /><ref name="Nestler 2014 epigenetics">{{cite journal | vauthors = Nestler EJ | title = Epigenetic mechanisms of drug addiction | journal =Neuropharmacology| volume = 76 | issue = Pt B | pages = 259–268 | date = January 2014 | pmid = 23643695 | pmc = 3766384 | doi = 10.1016/j.neuropharm.2013.04.004 | quote = <!-- Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors.&nbsp;... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).<br />G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a).&nbsp;... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. -->}}</ref> Sufficiently overexpressing ΔJunD in the nucleus accumbens with [[viral vector]]s can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).<ref name="Nestler" /> Similarly, accumbal G9a hyperexpression results in markedly increased [[histone]] 3 [[lysine]] [[residue (biochemistry)|residue]] 9 [[Epigenetic methylation|dimethylation]] ([[H3K9me2]]) and blocks the induction of ΔFosB-mediated [[neuroplasticity|neural]] and [[behavioral plasticity]] by chronic drug use,{{#tag:ref|<ref name="Nestler" /><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 = Annals of Agricultural and Environmental Medicine | volume = 19 | issue = 3 | pages = 491–496 | year = 2012 | pmid = 23020045 | url = http://www.aaem.pl/Epigenetic-regulation-in-drug-addiction,71809,0,2.html }}</ref><ref name="HDACi-induced G9a+H3K9me2 primary source">{{cite journal | vauthors = Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ | title = Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation | journal = Nature Neuroscience | volume = 16 | issue = 4 | pages = 434–440 | date = April 2013 | pmid = 23475113 | pmc = 3609040 | doi = 10.1038/nn.3354 }}</ref><ref name="A feat of epigenetic engineering">{{cite journal | vauthors = Whalley K | title = Psychiatric disorders: a feat of epigenetic engineering | journal = Nature Reviews. Neuroscience | volume = 15 | issue = 12 | pages = 768–769 | date = December 2014 | pmid = 25409693 | doi = 10.1038/nrn3869 | s2cid = 11513288 | doi-access = free | title-link = doi }}</ref>|group="sources"}} which occurs via [[H3K9me2]]-mediated [[gene repression|repression]] of [[transcription factor]]s for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., [[CDK5]]).<ref name="Nestler" /><ref name="Nestler 2014 epigenetics" /><ref name="G9a reverses ΔFosB plasticity" /> ΔFosB also plays an important role in regulating behavioral responses to [[natural reward]]s, such as palatable food, sex, and exercise.<ref name="Natural and drug addictions" /><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 | date = March 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.&nbsp;... 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> Since both natural rewards and addictive drugs [[inducible gene|induce the expression]] of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.<ref name="Natural and drug addictions" /><ref name="Nestler">{{cite journal |vauthors=Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal =Nature Reviews Neuroscience| volume = 12 | issue = 11 | pages = 623–637 |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.&nbsp;... ΔFosB serves as one of the master control proteins governing this structural plasticity.}}</ref> Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced [[sexual addiction]]s, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.<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 = 3434–3442 |date=February 2013 | pmid = 23426671 | pmc = 3865508 | doi = 10.1523/JNEUROSCI.4881-12.2013}}</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 | pages = 154–164 | date = February 2016 | pmid = 26391065 | doi = 10.1016/j.neuropharm.2015.09.023| s2cid = 25317397 }}</ref> These sexual addictions are associated with a [[dopamine dysregulation syndrome]] which occurs in some patients taking [[dopaminergic#Supplements and drugs|dopaminergic drugs]].<ref name="Natural and drug addictions" /><ref name="ΔFosB reward" />

The effects of amphetamine on gene regulation are both dose- and route-dependent.<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=Progress in Neurobiology| volume=100 | pages=60–80 | date=January 2013 | pmid=23085425 | pmc=3525776 | doi=10.1016/j.pneurobio.2012.10.001 }}</ref> Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.<ref name="Addiction genetics" /> The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.<ref name="Addiction genetics" /> This suggests that medical use of amphetamine does not significantly affect gene regulation.<ref name="Addiction genetics" />

=====Pharmacological treatments=====
<!-- warning! This section is transcluded to other articles (like Adderall), and as such must not invoke reference tags from elsewhere in this article -->
{{Further|Addiction#Research}}
{{As of|December 2019|post=,}} there is no effective [[pharmacotherapy]] for amphetamine addiction.<ref name="NHMH_3e-Physical dependence + psychostimulant addiction treatment">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE, Holtzman DM | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2015 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071827706 | edition = 3rd | chapter = Chapter 16: Reinforcement and Addictive Disorders | quote = Pharmacologic treatment for psychostimulant addiction is generally unsatisfactory. As previously discussed, cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria, anhedonia, and an intense desire to reinitiate drug use.}}</ref><ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" /><ref name="pmid24716825">{{cite journal | vauthors = Stoops WW, Rush CR | title = Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research | journal =Expert Review of Clinical Pharmacology| volume = 7 | issue = 3 | pages = 363–374 | date = May 2014 | pmid = 24716825 | doi = 10.1586/17512433.2014.909283 | quote = Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved. | pmc = 4017926 }}</ref> Reviews from 2015 and 2016 indicated that [[TAAR1]]-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;<ref name="Miller+Grandy 2016" /><ref name="TAAR1 addiction 2015" /> however, {{As of|February 2016|lc=y|post=,}} the only compounds which are known to function as TAAR1-selective agonists are [[experimental drug]]s.<ref name="Miller+Grandy 2016">{{cite journal | vauthors = Grandy DK, Miller GM, Li JX | title = "TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference | journal =Drug and Alcohol Dependence| volume = 159 | pages = 9–16 | date = February 2016 | pmid = 26644139 | doi = 10.1016/j.drugalcdep.2015.11.014 | quote = When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.| pmc = 4724540 }}</ref><ref name="TAAR1 addiction 2015">{{cite journal | vauthors = Jing L, Li JX | title = Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction | journal =European Journal of Pharmacology| volume = 761 | pages = 345–352 | date = August 2015 | pmid = 26092759 | doi = 10.1016/j.ejphar.2015.06.019 | quote = Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction. | pmc=4532615}}</ref> Amphetamine addiction is largely mediated through increased activation of [[dopamine receptor]]s and {{nowrap|[[wikt:colocalize|co-localized]]}} [[NMDA receptor]]s{{#tag:ref|NMDA receptors are voltage-dependent [[ligand-gated ion channels]] that requires simultaneous binding of glutamate and a co-agonist ({{nowrap|[[D-serine|{{smallcaps all|D}}-serine]]}} or [[glycine]]) to open the ion channel.<ref name="NHM-NMDA">{{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, US | isbn = 9780071481274 | pages = 124–125 | edition = 2nd | chapter = Chapter 5: Excitatory and Inhibitory Amino Acids | quote = <!-- At membrane potentials more negative than approximately −50 mV, the Mg<sup>2+</sup> in the extracellular fluid of the brain virtually abolishes ion flux through NMDA receptor channels, even in the presence of glutamate.&nbsp;... The NMDA receptor is unique among all neurotransmitter receptors in that its activation requires the simultaneous binding of two different agonists. In addition to the binding of glutamate at the conventional agonist-binding site, the binding of glycine appears to be required for receptor activation. Because neither of these agonists alone can open this ion channel, glutamate and glycine are referred to as coagonists of the NMDA receptor. The physiologic significance of the glycine binding site is unclear because the normal extracellular concentration of glycine is believed to be saturating. However, recent evidence suggests that D-serine may be the endogenous agonist for this site. -->}}</ref>|group="note"}} in the nucleus accumbens;<ref name="Magnesium" /> [[magnesium|magnesium ions]] inhibit NMDA receptors by blocking the receptor [[calcium channel]].<ref name="Magnesium" /><ref name="NHM-NMDA" /> One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.<ref name="Magnesium" /> [[Dietary supplement|Supplemental magnesium]]{{#tag:ref|The review indicated that [[magnesium aspartate|magnesium {{nowrap|L-aspartate}}]] and [[magnesium chloride]] produce significant changes in addictive behavior;<ref name="Magnesium" /> other forms of magnesium were not mentioned.|group="note"}} treatment has been shown to reduce amphetamine [[self-administration]] (i.e., doses given to oneself) in humans, but it is not an effective [[monotherapy]] for amphetamine addiction.<ref name="Magnesium">{{cite journal |author =Nechifor M |title=Magnesium in drug dependences |journal=Magnesium Research|volume=21 |issue=1 |pages=5–15 |date=March 2008 |pmid=18557129 |doi=10.1684/mrh.2008.0124|doi-broken-date=1 November 2024 |url=https://www.jle.com/10.1684/mrh.2008.0124}}</ref>

A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in [[randomized controlled trials]] (RCTs) for amphetamine and methamphetamine addiction;<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" /> it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy">{{cite journal | vauthors = Chan B, Freeman M, Kondo K, Ayers C, Montgomery J, Paynter R, Kansagara D | title = Pharmacotherapy for methamphetamine/amphetamine use disorder-a systematic review and meta-analysis | journal = Addiction | volume = 114 | issue = 12 | pages = 2122–2136 | date = December 2019 | pmid = 31328345 | doi = 10.1111/add.14755 | s2cid = 198136436 }}</ref> There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, [[mirtazapine]], [[sertraline]]), antipsychotics ([[aripiprazole]]), anticonvulsants ([[topiramate]], [[baclofen]], [[gabapentin]]), [[naltrexone]], [[varenicline]], [[citicoline]], [[ondansetron]], [[prometa]], [[riluzole]], [[atomoxetine]], dextroamphetamine, and [[modafinil]].<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" />

=====Behavioral treatments=====
A 2018 systematic review and [[network meta-analysis]] of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that [[combination therapy]] with both [[contingency management]] and [[community reinforcement approach]] had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).<ref name="Psychosocial interventions network meta-analysis">{{cite journal | vauthors = De Crescenzo F, Ciabattini M, D'Alò GL, De Giorgi R, Del Giovane C, Cassar C, Janiri L, Clark N, Ostacher MJ, Cipriani A | title = Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis | journal = PLOS Medicine | volume = 15 | issue = 12 | pages = e1002715 | date = December 2018 | pmid = 30586362 | pmc = 6306153 | doi = 10.1371/journal.pmed.1002715 | doi-access = free | title-link = doi }}</ref> Other treatment modalities examined in the analysis included [[monotherapy]] with contingency management or community reinforcement approach, [[cognitive behavioral therapy]], [[12-step program]]s, non-contingent reward-based therapies, [[psychodynamic therapy]], and other combination therapies involving these.<ref name="Psychosocial interventions network meta-analysis" />

Additionally, research on the [[neurobiological effects of physical exercise]] suggests that daily aerobic exercise, especially endurance exercise (e.g., [[marathon running]]), prevents the development of drug addiction and is an effective [[adjunct therapy]] (i.e., a supplemental treatment) for amphetamine addiction.{{#tag:ref|<ref name="Natural and drug addictions" /><ref name="Running vs addiction" /><ref name="Exercise, addiction prevention, and ΔFosB" /><ref name="Exercise Rev 3" /><ref name="Addiction review 2016" />|group="sources"|name="Exercise therapy"}} Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.<ref name="Running vs addiction">{{cite journal |vauthors=Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA | title = Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis | journal =Neuroscience & Biobehavioral Reviews| volume = 37 | issue = 8 | pages = 1622–1644 |date=September 2013 | pmid = 23806439 | pmc = 3788047 | doi = 10.1016/j.neubiorev.2013.06.011 | quote = These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug.&nbsp;... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes&nbsp;... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.}}</ref><ref name="Exercise Rev 3">{{cite journal | vauthors = Linke SE, Ussher M | title = Exercise-based treatments for substance use disorders: evidence, theory, and practicality | journal =The American Journal of Drug and Alcohol Abuse| volume = 41 | issue = 1 | pages = 7–15 | date = January 2015 | pmid = 25397661 | doi = 10.3109/00952990.2014.976708 | quote = The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published.&nbsp;... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects. | pmc=4831948}}</ref><ref name="Addiction review 2016">{{cite journal | vauthors = Carroll ME, Smethells JR | title = Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments | journal =Frontiers in Psychiatry| volume = 6 | pages = 175 | date = February 2016 | pmid = 26903885 | pmc = 4745113 | doi = 10.3389/fpsyt.2015.00175 | quote = Physical Exercise<br />There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction&nbsp;... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse.&nbsp;... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis.&nbsp;... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.| doi-access = free | title-link = doi }}</ref> In particular, [[aerobic exercise]] decreases psychostimulant self-administration, reduces the [[reinstatement]] (i.e., relapse) of drug-seeking, and induces increased [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]] (DRD2) density in the [[striatum]].<ref name="Natural and drug addictions" /><ref name="Addiction review 2016" /> This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.<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 = 1109–1122 | date = December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005).&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). }}</ref> One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or {{nowrap|[[c-Fos]]}} [[immunoreactivity]] in the striatum or other parts of the [[reward system]].<ref name="Exercise, addiction prevention, and ΔFosB" />
{{FOSB addiction table|Table title=Summary of addiction-related plasticity}}