Editing Amphetamine (section)

===Enhancing performance===

====Cognitive performance====
In 2015, a [[systematic review]] and a [[meta-analysis]] of high quality [[clinical trial]]s found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including [[working memory]], long-term [[episodic memory]], [[inhibitory control]], and some aspects of [[Attention#Clinical model|attention]], in normal healthy adults;<ref name="Unambiguous PFC D1 A2">{{cite journal | vauthors = Spencer RC, Devilbiss DM, Berridge CW | title = The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex | journal =Biological Psychiatry| volume = 77 | issue = 11 | pages = 940–950 | date = June 2015 | pmid = 25499957 | doi = 10.1016/j.biopsych.2014.09.013 | quote = The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors.&nbsp;... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function).&nbsp;... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses. | pmc=4377121| url = https://rdw.rowan.edu/cgi/viewcontent.cgi?article=1056&context=som_facpub }}</ref><ref name="Cognitive and motivational effects">{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal =Journal of Cognitive Neuroscience| pages = 1069–1089 | date = June 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | volume=27 | issue = 6 | s2cid = 15788121 | url = https://repository.upenn.edu/neuroethics_pubs/130 | quote = Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities.&nbsp;... The results of this meta-analysis&nbsp;... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.}}</ref> these cognition-enhancing effects of amphetamine are known to be partially mediated through the [[indirect agonist|indirect activation]] of both [[dopamine receptor D1|dopamine D<sub>1</sub> receptor]] and [[Alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic receptor]] in the [[prefrontal cortex]].<ref name="Malenka_2009" /><ref name="Unambiguous PFC D1 A2" /> A systematic review from 2014 found that low doses of amphetamine also improve [[memory consolidation]], in turn leading to improved [[Recall (memory)|recall of information]].<ref name="Cognition enhancement 2014 systematic review">{{cite journal | vauthors = Bagot KS, Kaminer Y | title = Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review | journal =Addiction| volume = 109 | issue = 4 | pages = 547–557 | date = April 2014 | pmid = 24749160 | pmc = 4471173 | doi = 10.1111/add.12460 | quote = Amphetamine has been shown to improve consolidation of information (0.02&nbsp;≥&nbsp;P&nbsp;≤&nbsp;0.05), leading to improved recall.}}</ref> Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.<ref name="Malenka_2009" /><ref name="pmid11337538">{{cite journal |vauthors=Devous MD, Trivedi MH, Rush AJ |title=Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers |journal=Journal of Nuclear Medicine |volume=42 |issue=4 |pages=535–542 |date=April 2001 |pmid=11337538}}</ref> Amphetamine and other ADHD stimulants also improve [[Incentive salience|task saliency]] (motivation to perform a task) and increase [[arousal]] (wakefulness), in turn promoting goal-directed behavior.<ref name="Malenka_2009" /><ref name="Malenka NAcc">{{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 = 266 | edition = 2nd | chapter = Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu | quote = Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.}}</ref><ref name="Continuum">{{cite journal |vauthors=Wood S, Sage JR, Shuman T, Anagnostaras SG |title=Psychostimulants and cognition: a continuum of behavioral and cognitive activation |journal=Pharmacological Reviews|volume=66 |issue=1 |pages=193–221 |date=January 2014 |pmid=24344115 |pmc=3880463 |doi=10.1124/pr.112.007054}}</ref> Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.<ref name="Malenka_2009">{{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 = 318, 321 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control | quote = Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD.&nbsp;... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks&nbsp;... through indirect stimulation of dopamine and norepinephrine receptors.&nbsp;...<br />Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.}}</ref><ref name="Continuum" /><ref name="Test taking aid">{{cite web | website = JS Online | author = Twohey M | date = 26 March 2006 | title = Pills become an addictive study aid | access-date = 2 December 2007 | url = http://www.jsonline.com/story/index.aspx?id=410902 | archive-url = https://web.archive.org/web/20070815200239/http://www.jsonline.com/story/index.aspx?id=410902 | archive-date = 15 August 2007}}</ref> Based upon studies of self-reported illicit stimulant use, {{nowrap|5–35%}} of college students use [[drug diversion|diverted]] ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs.<ref name="pmid16999660">{{cite journal |vauthors=Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ | title = Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration | journal =Pharmacotherapy| volume = 26 | issue = 10 | pages = 1501–1510 |date=October 2006 | pmid = 16999660 | pmc = 1794223 | doi = 10.1592/phco.26.10.1501 }}</ref><ref name="Diversion prevalence 1">{{cite journal | vauthors = Weyandt LL, Oster DR, Marraccini ME, Gudmundsdottir BG, Munro BA, Zavras BM, Kuhar B | title = Pharmacological interventions for adolescents and adults with ADHD: stimulant and nonstimulant medications and misuse of prescription stimulants | journal =Psychology Research and Behavior Management| volume = 7 | pages = 223–249 | date = September 2014 | pmid = 25228824 | pmc = 4164338 | doi = 10.2147/PRBM.S47013 | quote = misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well.&nbsp;... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students. | doi-access = free | title-link = doi }}</ref><ref name="Diversion prevalence 2">{{cite journal | vauthors = Clemow DB, Walker DJ | title = The potential for misuse and abuse of medications in ADHD: a review | journal =Postgraduate Medicine| volume = 126 | issue = 5 | pages = 64–81 | date = September 2014 | pmid = 25295651 | doi = 10.3810/pgm.2014.09.2801 | s2cid = 207580823 | quote = Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.}}</ref> However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.<ref name="Malenka_2009" /><ref name="Continuum" />

====Physical performance====
<!-- Do not change this section header to "Physical"; there is already a "Physical" heading located under the "Side effects" section, so changing the heading here will affect section linking. -->
Amphetamine is used by some athletes for its psychological and [[ergogenic aid|athletic performance-enhancing effects]], such as increased endurance and alertness;<ref name="Ergogenics">{{cite journal |vauthors=Liddle DG, Connor DJ | title = Nutritional supplements and ergogenic AIDS | journal =Primary Care: Clinics in Office Practice| volume = 40 | issue = 2 | pages = 487–505 |date=June 2013 | pmid = 23668655 | doi = 10.1016/j.pop.2013.02.009 |quote= Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training&nbsp;...<br />Physiologic and performance effects<br />{{•}}Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation<br />{{•}}Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40<br />{{•}}Improved reaction time<br />{{•}}Increased muscle strength and delayed muscle fatigue<br />{{•}}Increased acceleration<br />{{•}}Increased alertness and attention to task}}</ref><ref name="Westfall">{{cite book |title=Goodman & Gilman's Pharmacological Basis of Therapeutics |vauthors=Westfall DP, Westfall TC |publisher=McGraw-Hill |year=2010 |isbn=9780071624428 |veditors=Brunton LL, Chabner BA, Knollmann BC |edition=12th |location=New York, US |section=Miscellaneous Sympathomimetic Agonists |quote=Dextrorotatory substitution on the α-carbon generally results in a more potent compound. d-Amphetamine is more potent than l-amphetamine in central but not peripheral activity.&nbsp;... In eliciting CNS excitatory effects, the d-isomer (dextroamphetamine) is three to four times more potent than the l-isomer.}}</ref> however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.<ref name="NCAA">{{cite web |date=January 2012 | vauthors = Bracken NM | title=National Study of Substance Use Trends Among NCAA College Student-Athletes | url=http://www.ncaapublications.com/productdownloads/SAHS09.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://www.ncaapublications.com/productdownloads/SAHS09.pdf |archive-date=9 October 2022 |url-status=live | website=NCAA Publications | publisher = National Collegiate Athletic Association | access-date=8 October 2013}}</ref><ref name="WADA & AD regulation">{{cite journal | author = Docherty JR | title = Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) | journal =British Journal of Pharmacology| volume = 154 | issue = 3 | pages = 606–622 | date = June 2008 | pmid = 18500382 | pmc = 2439527 | doi = 10.1038/bjp.2008.124}}</ref> In healthy people at oral therapeutic doses, amphetamine has been shown to increase [[physical strength|muscle strength]],<!-- Refs:"Ergogenics" & "Ergogenics2" --> acceleration,<!-- Refs:"Ergogenics" & "Ergogenics2" --> athletic performance in [[anaerobic exercise|anaerobic conditions]],<!-- Refs:"Ergogenics" & "Ergogenics2" --> and [[endurance]] (i.e., it delays the onset of [[fatigue (medical)|fatigue]]),<!-- Refs:"Ergogenics" & "Ergogenics2" & "Roelands_2013" --> while improving [[mental chronometry|reaction time]].<ref name="Ergogenics" /><ref name="Ergogenics2" /><ref name="Roelands_2013" /> Amphetamine improves endurance and reaction time primarily through [[Reuptake inhibitor|reuptake inhibition]] and [[Releasing agent|release]] of dopamine in the central nervous system.<ref name="Ergogenics2" /><ref name="Roelands_2013">{{cite journal |vauthors=Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R | title = Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing | journal =Sports Medicine| volume = 43 | issue = 5 | pages = 301–311 |date=May 2013 | pmid = 23456493 | doi = 10.1007/s40279-013-0030-4 | s2cid = 30392999 | quote = In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo.&nbsp;... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is 'off-limits' in a normal (placebo) situation.}}</ref><ref name="Amph-DA reaction time">{{cite journal |vauthors=Parker KL, Lamichhane D, Caetano MS, Narayanan NS | title = Executive dysfunction in Parkinson's disease and timing deficits | journal =Frontiers in Integrative Neuroscience| volume = 7 | page = 75 | date = October 2013 | pmid = 24198770 | pmc = 3813949 | doi = 10.3389/fnint.2013.00075 | quote = Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing. | doi-access = free | title-link = doi }}</ref> Amphetamine and other dopaminergic drugs also increase power output at fixed [[rating of perceived exertion|levels of perceived exertion]] by overriding a "safety switch", allowing the [[Human body temperature|core temperature limit]] to increase in order to access a reserve capacity that is normally off-limits.<ref name="Roelands_2013" /><ref name="Central mechanisms affecting exertion">{{cite journal | vauthors = Rattray B, Argus C, Martin K, Northey J, Driller M | title = Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance? | journal =Frontiers in Physiology| volume = 6 | pages = 79 | date = March 2015 | pmid = 25852568 | pmc = 4362407 | doi = 10.3389/fphys.2015.00079 | quote = Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009).&nbsp;... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)| doi-access = free | title-link = doi }}</ref><ref name="Monoamine+drug effects on exercise - fatigue and heat">{{cite journal | vauthors = Roelands B, De Pauw K, Meeusen R | title = Neurophysiological effects of exercise in the heat | journal =Scandinavian Journal of Medicine & Science in Sports| volume = 25 |issue=Suppl 1 | pages = 65–78 | date = June 2015 | pmid = 25943657 | doi = 10.1111/sms.12350 | s2cid = 22782401 | quote = This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the "safety switch" or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.| doi-access = free | title-link = doi }}</ref> At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;<ref name="Ergogenics" /><ref name="Ergogenics2" /> however, at much higher doses, amphetamine can induce effects that severely impair performance, such as [[rhabdomyolysis|rapid muscle breakdown]] and [[hyperthermia|elevated body temperature]].<ref name="FDA">{{cite web | title=Adderall XR- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate capsule, extended release | website=DailyMed | publisher = Shire US Inc. | date=17 July 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aff45863-ffe1-4d4f-8acf-c7081512a6c0 | access-date=22 December 2019}}</ref><ref name="Ergogenics2">{{cite journal |author =Parr JW |title=Attention-deficit hyperactivity disorder and the athlete: new advances and understanding |journal=Clinics in Sports Medicine|volume=30 |issue=3 |pages=591–610 |date=July 2011 |pmid=21658550 |doi=10.1016/j.csm.2011.03.007 |quote=In 1980, Chandler and Blair<sup>47</sup> showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.}}</ref>