Amfetamina: Różnice pomiędzy wersjami

Długoterminowa poażpodaż odpowiednio wysokich dawek amfetaminy u niektórych [[gatunek (biologia)|gatunków]] [[zwierzęta|zwierząt]] powoduje nieprawidłowy rozwój [[układ dopaminergiczny|układu dopaminergicznego]] i uszkodzenie [[nerw]]ów<ref name="pmid22392347" /><ref name="AbuseAndAbnormalities">{{cytuj pismo| autor=Berman S, O'Neill J, Fears S, Bartzokis G, London ED | tytuł=Abuse of amphetamines and structural abnormalities in the brain | czasopismo=Ann. N. Y. Acad. Sci. | data = 2008 | wolumin= 1141 | wydanie= | strony= 195–220 | pmid=18991959 | doi=10.1196/annals.1441.031 | pmc=2769923}}</ref>. Jednak u ludzi z ADHD farmaceutyczne amfetaminy wydają się poprawiać rozwój mózgu i wzrost nerwów<ref name="Neuroplasticity 1">{{cytuj pismo | autor=Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K | tytuł=Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects | czasopismo=JAMA Psychiatry | wolumin=70 | wydanie=2 | strony=185–198 | data=2013 |pmid=23247506 |doi=10.1001/jamapsychiatry.2013.277}}</ref><ref name="Neuroplasticity 2">{{cytuj pismo | autor=Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J | tytuł=Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies | czasopismo=J. Clin. Psychiatry | wolumin=74 | wydanie=9 | strony=902–917 | data=September 2013 |pmid=24107764 |doi=10.4088/JCP.12r08287 |url= |pmc=3801446}}</ref><ref name="Neuroplasticity 3">{{cytuj pismo | tytuł=Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. | czasopismo=Acta psychiatrica Scand. | data=February 2012 | wolumin=125 | wydanie=2 | strony=114–126 | pmid=22118249 | autor=Frodl T, Skokauskas N | cytat = Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure. | doi=10.1111/j.1600-0447.2011.01786.x}}</ref>. Przeglądy badań z użyciem [[Obrazowanie metodą rezonansu magnetycznego|rezonansu magnetycznego]] wskazują, że długoterminowe leczenie amferaminą zmniejsza nieprawidłowości w budowie i funkcjonowaniu mózgu u pacjentów z ADHD, poprawiając funkcjonowanie kilku regionów mózgu, jak prawe [[jądro ogoniaste]]<ref name="Neuroplasticity 1" /><ref name="Neuroplasticity 2" /><ref name="Neuroplasticity 3" />.

Przeglądy badań klinicznych stymulantów ustaliły bezpieczeństwo i efektywność długoterinowego przyjmowania amfetaminy w leczeniu ADHD<ref name="Millichap" /><ref name="Long-term 2015">{{cytuj pismo | autor = Arnold LE, Hodgkins P, Caci H, Kahle J, Young S | tytuł = Effect of treatment modality on long-term outcomes in attention-deficit/hyperactivity disorder: a systematic review | czasopismo = PLoS ONE | wolumin = 10 | wydanie = 2 | strony = e0116407 | data = 2015 | pmid = 25714373 | pmc = 4340791 | doi = 10.1371/journal.pone.0116407 | cytat = The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.&nbsp;... All reported long-term outcomes were organized into 9 main categories/domains based on common characteristics: 1) academic (e.g., achievement test scores, grades, length of education, repeated grades, education level), 2) antisocial behavior (e.g., school expulsion, delinquency, police contacts, arrests, convictions, incarceration, self-reported crimes, types or severity of offenses, age at first incident, repeat convictions), 3) driving (e.g., traffic violations, automobile accidents, license status, driving simulation rating), 4) non-medicinal drug use/addictive behavior (e.g., substance use, abuse, and/or dependence—from caffeine to illicit drugs; age at initiation; quitting substance use; amount of substance used; non-substance addictions such as gambling), 5) obesity (body mass index, weight), 6) occupation (e.g., employment, military service, income/debt, job performance, job loss/changes, occupation level, socioeconomic status), 7) services use (e.g., school services, health services, emergency room visits, work-related services, financial assistance, justice system), 8) self-esteem (self-esteem questionnaires, suicide ideation, suicide attempts, suicide rate), and 9) social function (e.g., peer, family, and romantic relationships; peer nomination scores; marital status; divorce rate, social skills, living arrangements, activities/hobbies).}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340791/figure/pone.0116407.g003/ Figure 3: Treatment benefit by treatment type and outcome group]</ref><ref name="Long-Term Outcomes Medications">{{cytuj pismo | autor=Huang YS, Tsai MH | tytuł = Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge | czasopismo = CNS Drugs | wolumin = 25 | wydanie = 7 | strony = 539–554 | data=July 2011 | pmid = 21699268 | doi = 10.2165/11589380-000000000-00000 | cytat = Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.}}</ref>. Randomizowane badania kliniczne ciągłej terapii ADHD stymulantammi przez okres 2 lat zademonstrowały efektywność i bezpieczeństwo leczenia<ref name="Millichap" /><ref name="Long-Term Outcomes Medications" />. 2 przeglądy wskazały na efektywność długoterminowej terapii ADHD stymulantami w redukcji osiowych objawów (nadmierna aktywność, deficyt uwagi, impulsywność), polepszaniu [[jakość życia|jakości życia]] i osiągnięć w nauce, a także poprawę w dużej liczbie wyników funkcjonalnych. Obszary największej poprawy długoterminowej ciągłej terapii stymulantami obejmują naukę (poprawa około 55%), prowadzenie pojazdów (100%), niemedyczne używanie leków (47% w przypadku wyników związanych z uzależnieniem), samoocenę (50%) i funkcje społeczne (67%)<ref name="Long-term 2015" />. Największy efekt terapia taka przynosi w nauce ([[Szkolna skala ocen|średnia ocen]], wyniki testów, długość edukacji i jej poziom), samoocenie (ocena kwestionariuszowa samooceny, liczba [[próba samobójcza|prób samobójczych]], współczynniki [[samobójstwo|samobójstw]]) i funkcjach społecznych (np. zdolności społeczne, jakość relacji)<ref name="Long-term 2015" />. Długoterminowe leczenie kombinowane ADHD (np. połączenie podaży stymulantów i terapii behawioralnej) wywołuje jeszcze większe efekty, poprawia większą część zbadanych czynników w każdym zakresie w porównaniu z wyłączą farmakoterapią stymulantem<ref name="Long-term 2015" />. Tak więc poprawie ulegają nauka, zachowania antyspołeczne, prowadzenie pojazdów, niemedyczne używanie leków, otyłość, praca, samoocena, korzystanie z pomocy w nauce, pracy, zdrowotnej, finansowej i prawnej, funkcje społeczne<ref name="Long-term 2015" /><ref name="Long-Term Outcomes Medications" />. Jeden z przeglądów podkreśa dziewięciomiesięczne randomizowane badanie dzieci z ADHD, w którym stwierdzono przyrost [[iloraz inteligencji|IQ]] o 4,5, ciągły wzrost uwagi oraz ciągłą redukcję destrukcyjnych zachowań i hiperaktywności<ref name="Millichap">{{cytuj książkę | autor = Millichap JG | editorwydawca = Millichap JG | tytuł = Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD | rok = 2010 | wydawca = Springer | miejsce = New York, USA | isbn = 9781441913968 | strony = 121–123, 125–127 | wydanie = 2. | rozdział = Chapter 9: Medications for ADHD | cytat = Ongoing research has provided answers to many of the parents’ concerns, and has confirmed the effectiveness and safety of the long-term use of medication.}}</ref>. Inny przegląd wskazał, bazując na prospektywnym badaniu kohortowym, że trwająca całe życie terapia stymulantami rozpoczęta w dzieciństwie jest trwale skuteczna w kontroli objawów ADHD i obniża ryzyko uzależnienia od substancji w dorosłym życiu<ref name="Long-Term Outcomes Medications" />.

W 2015 [[przegląd systematyczny]] i i [[metaanaliza]] wysokiej jakości badań klinicznych wykazały, że używanie niewielkich (terapeutycznych) dawek amfetaminy powoduje umiarkowaną, ale jednoznaczną poprawę zdolności poznawczych, w tym [[pamięć robocza|pamięci roboczej]], długoterminowej [[pamięć epizodyczna|pamięci epizodycznej]], kontroli inhibicyjnej, pewych aspektów uwagi – u zdrowych dorosłych<ref name="Unambiguous PFC D1 A2">{{cytuj pismo | autor = Spencer RC, Devilbiss DM, Berridge CW | tytuł = The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex | czasopismo = Biol. Psychiatry | wolumin = 77 | wydanie = 11 | strony = 940–950 | rok = June 2015 | pmid = 25499957 | doi = 10.1016/j.biopsych.2014.09.013 | cytat = 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). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.&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.}}</ref><ref name="Cognitive and motivational effects">{{cytuj pismo | autor = Ilieva IP, Hook CJ, Farah MJ | tytuł = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | czasopismo = J. Cogn. Neurosci. | wolumin = | wydanie = | strony = 1–21 | data = January 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | cytat = 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>. Zwiększające zdolności poznawcze właściwości amfetaminy polegają na pośredniej aktywacji receptorów D₁ i α₂ w [[kora przedczołowa|korze przedczołowej]]<ref name="Malenka_2009" /><ref name="Unambiguous PFC D1 A2" />. Przegląd systematyczny z 2014 wykazał, że niewielkie dawki amfetaminy mogą poprawiać także [[Konsolidacja (psychologia)|konsolidację pamięci]], w effekcie prowadząc do lepszego [[Przypominanie|przypominania]]<ref name="Cognition enhancement 2014 systematic review">{{cytuj pismo | autor = Bagot KS, Kaminer Y | tytuł = Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review | czasopismo = Addiction | wolumin = 109 | wydanie = 4 | strony = 547–557 | data = April 2014 | pmid = 24749160 | pmc = 4471173 | doi = 10.1111/add.12460 | cytat = Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall.}}</ref>. Dawki terapeutyczne zwiększają również wydajność kory, efekt ten mediuje poprawę amięci operacyjnej u wszystkich osób<ref name="Malenka_2009" /><ref name="pmid11337538">{{cytuj pismo | autor=Devous MD, Trivedi MH, Rush AJ | tytuł=Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers | czasopismo=J. Nucl. Med. | wolumin=42 | wydanie=4 | strony=535–542 | data=April 2001 |pmid=11337538 |doi= |url=}}</ref>. Amfetamina i inne używane w ADHD stymulanty poprawiają również motywację wykonywania zadań oraz zwiększają pobudzenie, promując zachowanie nakierowane na spełnianie zasad (przez wpływ na [[jądro półleżące]])<ref name="Malenka_2009" /><ref name="Malenka NAcc">{{cytuj książkę | autor=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | tytuł = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | rok = 2009 | wydawca = McGraw-Hill Medical | miejsce = New York, USA | isbn = 9780071481274 | strony = 266 | wydanie = 2. | rozdział = Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu | cytat = Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.}}</ref><ref name="Continuum">{{cytuj pismo | autor=Wood S, Sage JR, Shuman T, Anagnostaras SG | tytuł=Psychostimulants and cognition: a continuum of behavioral and cognitive activation | czasopismo=Pharmacol. Rev. | wolumin=66 | wydanie=1 | strony=193–221 | data=January 2014 |pmid=24344115 |doi=10.1124/pr.112.007054}}</ref>. Stymulanty takie jak amfetamina mogą poprawiać wyniki trudnych i nudnych zadań, studenci wykorzystują je podczas nauki i zdawania testów<ref name="Malenka_2009">{{cytuj książkę| autor=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | tytuł = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | rok = 2009 | wydawca = McGraw-Hill Medical | miejsce = New York, USA | isbn = 9780071481274 | strony = 318, 321 | wydanie = 2. | rozdział = Chapter 13: Higher Cognitive Function and Behavioral Control | cytat = 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. ... 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. Drugs used for this purpose include, as stated above, methylphenidate, amphetamines, atomoxetine, and desipramine.}}</ref><ref name="Continuum" /><ref name="Test taking aid">{{cytuj stronę | praca = JS Online | autor = Twohey M | data = 26-03-2006 | tytuł = Pills become an addictive study aid | data dostępu = 2-12-2007 | url = http://www.jsonline.com/story/index.aspx?id=410902 | archiveurl = https://web.archive.org/web/20070815200239/http://www.jsonline.com/story/index.aspx?id=410902 }}</ref>. W oparciu o badania samozgłoszeń nielegalnego użycia stymulantów wiadomo, że 5–35% studentów używa stymulantów przeznaczonych do leczenia ADHD z drugiej ręki, stosując je głównie raczej do poprawy wyników niż rekreacyjnie<ref name="pmid16999660">{{cytuj pismo | autor=Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ | tytuł = Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration | czasopismo = Pharmacotherapy | wolumin = 26 | wydanie = 10 | strony = 1501–1510 | data=October 2006 | pmid = 16999660 | pmc = 1794223 | doi = 10.1592/phco.26.10.1501}}</ref><ref name="Diversion prevalence 1">{{cytuj pismo | autor = Weyandt LL, Oster DR, Marraccini ME, Gudmundsdottir BG, Munro BA, Zavras BM, Kuhar B | tytuł = Pharmacological interventions for adolescents and adults with ADHD: stimulant and nonstimulant medications and misuse of prescription stimulants | czasopismo = Psychol. Res. Behav. Manag. | wolumin = 7 | wydanie = | strony = 223–249 | data = September 2014 | pmid = 25228824 | pmc = 4164338 | doi = 10.2147/PRBM.S47013 | cytat = 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.}}</ref><ref name="Diversion prevalence 2">{{cytuj pismo | autor = Clemow DB, Walker DJ | titletytuł = The potential for misuse and abuse of medications in ADHD: a review | czasopismo = Postgrad. Med. | wolumin = 126 | wydanie = 5 | strony = 64–81 | data = September 2014 | pmid = 25295651 | doi = 10.3810/pgm.2014.09.2801 | cytat = 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>. Jednajże duże dawki amfetaminy, przekraczającce zakres terapeutyczny, mogą zakłócać pamięć roboczą i inne aspekty kontroli kognitywnej<ref name="Malenka_2009" /><ref name="Continuum" />.

Niektórzy sportowcy stosują amfetaminę dla polepszenia wyników sportowych i jej własności psychologicznych, bowiem zwiększa ona wytrzymałość i czujność<ref name="Ergogenics">{{cytuj pismo | autor=Liddle DG, Connor DJ | titletytuł = Nutritional supplements and ergogenic AIDS | czasopismo = Prim. Care | wolumin = 40 | wydanie = 2 | strony = 487–505 | data=June 2013 | pmid = 23668655 | doi = 10.1016/j.pop.2013.02.009 |quotecytat= 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" />. Jednak niemedyczne używanie amfetaminy w sporcie jest zabronione, podlega kolegialnym, narodowym i międzynarodowym agencjom antydopingowym<ref name="NCAA">{{cytuj stronę | data=January 2012 | autor=Bracken NM | titletytuł=National Study of Substance Use Trends Among NCAA College Student-Athletes | url=http://www.ncaapublications.com/productdownloads/SAHS09.pdf | praca=NCAA Publications | wydawca = National Collegiate Athletic Association | data dostępu=8 October 2013}}</ref><ref name="WADA & AD regulation">{{cytuj pismo | autor = Docherty JR | titletytuł = Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) | czasopismo = Br. J. Pharmacol. | wolumin = 154 | wydanie = 3 | strony = 606–622 | data = June 2008 | pmid = 18500382 | pmc = 2439527 | doi = 10.1038/bjp.2008.124 }}</ref>. U zdrowych ludzi terapeutyczne doustne dawki amfetaminy zwiększają [[siła mięśniowa|siłę mięśniową]], [[przyśpieszenie]], wyniki sportowe w warunkach beztlenowych{{r|Ergogenics|Ergogenics2}}, [[wytrzymałość]] (opóźnia ona [[zmęczenie]]{{r|Ergogenics|Ergogenics2|Roelands_2013}}, poprawiając czas reakcji<ref name="Ergogenics" /><ref name="Ergogenics2" /><ref name="Roelands_2013" />. Wytrzymałość i czas reakcji polepszają się głównie poprzez hamowanie wychwytu zwrotnego i wydzielanie dopaminy w OUN<ref name="Ergogenics2" /><ref name="Roelands_2013">{{cytuj pismo | autor=Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R | titletytuł = Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing | czasopismo = Sports Med. | wolumin = 43 | wydanie = 5 | strony = 301–311 | data=May 2013 | pmid = 23456493 | doi = 10.1007/s40279-013-0030-4 | cytat = 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">{{cytuj pismo | autor=Parker KL, Lamichhane D, Caetano MS, Narayanan NS | titletytuł = Executive dysfunction in Parkinson's disease and timing deficits | czasopismo = Front. Integr. Neurosci. | wolumin = 7 | strony = 75 | data = October 2013 | pmid = 24198770 | pmc = 3813949 | doi = 10.3389/fnint.2013.00075 | cytat = 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.}}</ref>. Amfetamina i inne leki dopaminergiczne zwiększają także moc przy stałym poziomie postrzeganego wysiłku przez przekroczenie "przełącznika bezpieczeństwa", pozwalając temepraturze ciała na wzrost, by zyskać dostęp do zasobów normalnie niedostępnych<ref name="Roelands_2013" /><ref name="Central mechanisms affecting exertion">{{cytuj pismo | autor = Rattray B, Argus C, Martin K, Northey J, Driller M | titletytuł = Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance? | czasopismo = Front. Physiol. | wolumin = 6 | wydanie = | strony = 79 | data = March 2015 | pmid = 25852568 | pmc = 4362407 | doi = 10.3389/fphys.2015.00079 | cytat = 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)}}</ref><ref name="Monoamine+drug effects on exercise - fatigue and heat">{{cytuj pismo | autor = Roelands B, De Pauw K, Meeusen R | titletytuł = Neurophysiological effects of exercise in the heat | czasopismo = Scand. J. Med. Sci. Sports | wolumin = 25 Suppl 1 | wydanie = | strony = 65–78 | data = June 2015 | pmid = 25943657 | doi = 10.1111/sms.12350 | url = http://onlinelibrary.wiley.com/doi/10.1111/sms.12350/epdf | data dostępu = 10 March 2016 | cytat = Physical fatigue has classically been attributed to peripheral factors within the muscle (Fitts, 1996), the depletion of muscle glycogen (Bergstrom & Hultman, 1967) or increased cardiovascular, metabolic, and thermoregulatory strain (Abbiss & Laursen, 2005; Meeusen et al., 2006b). In recent decennia however, it became clear that the central nervous system plays an important role in the onset of fatigue during prolonged exercise (Klass et al., 2008), certainly when ambient temperature is increased&nbsp;... 5-HT, DA, and NA have all been implicated in the control of thermoregulation and are thought to mediate thermoregulatory responses, certainly since their neurons innervate the hypothalamus (Roelands & Meeusen, 2010).&nbsp;... 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.&nbsp;... The combined effects of DA and NA on performance in the heat were studied by our research group on a number of occasions.&nbsp;... the administration of bupropion (DA/NA reuptake inhibitor) significantly improved performance. Coinciding with this ergogenic effect, the authors observed core temperatures that were much higher compared with the placebo situation. Interestingly, this occurred without any change in the subjective feelings of thermal sensation or perceived exertion. Similar to the methylphenidate study (Roelands et al., 2008b), bupropion may dampen or override inhibitory signals arising from the central nervous system to cease exercise because of hyperthermia, and enable an individual to continue maintaining a high power output}}</ref>. W dawnach terapeutycznych działania niepożądane amfetaminy nie przeszkadzają osiągnięciom sportowym<ref name="Ergogenics" /><ref name="Ergogenics2" />; jednak przy znacznie większych dawkach subtsancja ta może powodować owazne uszkodzenia, jak [[rabdomioliza|rabdomiolizę]] i [[hipertermia|hipertermię]]<ref name="FDA Abuse & OD" /><ref name="FDA Effects" /><ref name="Ergogenics2">{{cytuj pismo | autor =Parr JW | tytuł=Attention-deficit hyperactivity disorder and the athlete: new advances and understanding | czasopismo=Clin. Sports Med. | wolumin=30 | wydanie=3 | strony=591–610 | data=July 2011 |pmid=21658550 |doi=10.1016/j.csm.2011.03.007 |quotecytat=In 1980, Chandler and Blair⁴⁷ 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.&nbsp;... In 2008, Roelands and colleagues⁵³ studied the effect of reboxetine, a pure NE reuptake inhibitor, similar to atomoxetine, in 9 healthy, well-trained cyclists. They too exercised in both temperate and warm environments. They showed decreased power output and exercise performance at both 18 and 30 degrees centigrade. Their conclusion was that DA reuptake inhibition was the cause of the increased exercise performance seen with drugs that affect both DA and NE (MPH, amphetamine, and bupropion).}}</ref>.

Zgodnie z [[International Programme on Chemical Safety]] (IPCS) i [[United States Food and Drug Administration]] (USFDA) (informacje USFDA pochodzą z informacji z leków, stanowiąc własność intelektualną producenta, zaakceptowaną prze USFDA; przeciwwskazania USFDA nie są koniecznie wprowadzane w celu ograniczenia stosowania leku, ale ograniczenia roszczeń względem koncernów farmaceutycznych<ref name="pmid8545689">{{cytuj pismo | autor = Kessler S | titletytuł = Drug therapy in attention-deficit hyperactivity disorder | czasopismo = South. Med. J. | wolumin = 89 | wydanie = 1 | strony = 33–38 | data = January 1996 | pmid = 8545689 |quotecytat = statements on package inserts are not intended to limit medical practice. Rather they are intended to limit claims by pharmaceutical companies.&nbsp;... the FDA asserts explicitly, and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations. | doi=10.1097/00007611-199601000-00005}}</ref>) amfetamina jest [[przeciwwskazanie|przeciwwskazana]] u ludzi z [[uzależnienie]]m od leków w historii choroby (zgodnie z jednym przeglądem amfetaminę można przepisać pacje pod warunkiem odpowiedniej kontroli, jak wydzielanie dziennych dawek przez przepisującego lek lekarza<ref name="Amph Uses" />, [[choroby układu krążenia]], [[drażliwość]], poważny [[niepokój]]<ref name="FDA Contra Warnings" /><ref name="International" />. Przeciwwskazana jest również u ludzi z obecnym [[Miażdżyca|stwardnieniem tętnic]], [[jaskra|jaskrą]], [[nadczynność tarczycy|nadczynnością tarczycy]] oraz umiarkowanm lub ciężkim [[nadciśnienie tętnicze|nadciśnieniem]]<ref name="FDA Contra Warnings" /><ref name="International">{{cytuj stronę | autor=Heedes G, Ailakis J | titletytuł=Amphetamine (PIM 934) | url=http://www.inchem.org/documents/pims/pharm/pim934.htm | website=INCHEM | wydawca=International Programme on Chemical Safety | data dostępu=24 June 2014}}</ref><ref name="Dexedrine FDA" />. Pacjentom, którzy przebyli rekacje alergiczne na inne stymulanty, bądź zażywającym [[inhibitory monoaminooksydazy]] odradza się przyjmowanie amfetaminy<ref name="FDA Contra Warnings" /><ref name="International" />, chociaż bezpieczne jednoczesne przyjmowanie amfetaminy i inhibitorów MAO zostało już udokumentowane<ref name="Review MAOI-amph">{{cytuj pismo | autor = Feinberg SS | titletytuł = Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication | czasopismo = J. Clin. Psychiatry | wolumin = 65 | wydanie = 11 | strony = 1520–1524 | data = November 2004 | pmid = 15554766 | quotecytat = | doi=10.4088/jcp.v65n1113}}</ref><ref name="Primary MAOI-amph">{{citecytuj journalpismo | autor = Stewart JW, Deliyannides DA, McGrath PJ | titletytuł = How treatable is refractory depression? | czasopismo = J. Affect. Disord. | wolumin = 167 | wydanie = | strony = 148–152 | data = June 2014 | pmid = 24972362 | doi = 10.1016/j.jad.2014.05.047 | quotecytat =}}</ref>. Wymienione agencje stwierdzają także, że każda osoba z [[jadłowstręt psychiczny|jadłowstrętem psychicznym]], [[Zaburzenia afektywne dwubiegunowe|zaburzeniem dwubiegunowym]], epizodem depresyjnym, nadciśnieniem, schorzeniami nerek lub wątroby, [[Objaw Raynauda|objawem Raynauda]], [[drgawki|drgawkami]], schorzeniami [[tarczyca|tarczycy]], [[tiki|tikami]], w tym zespołem Tourette'a powinna monitorować objawy swych zaburzeń podczas przyjmowania amfetaminy<ref name="FDA Contra Warnings" /><ref name="International" />. Dowody z badań przeprowadzonych na ludziach wskazują, że terapeutyczne dawki amfetaminy nie powodują nieprawidłowości rozwojowych u [[płód|płodu]] i [[noworodek|noworodka]], amfetamina nie zalicz się do ludzkich [[teratogen]]ów. Jednak nadużywanie amfetaminy nakłada na płód ryzyko<ref name="International" />. Wykazano przedostawanie się amfetaminy do [[mleko|mleka]], wobec czego IPCS i USFDA radzą matkom unikać [[karmienie piersią|karmienia piersią]] podczas zażywania leku<ref name="FDA Contra Warnings" /><ref name="International" />. Z powodu możliwości odwracalnego zaburzenia wzrostu (u osób o niższym przyroście wzrostu i masy ciała powrotu do normy oczekuje się po krótkotrwałym przerwaniu terapii stymulantem<ref name="Millichap" /><ref name="Long-Term Outcomes Medications" /><ref name="pmid18295156" />, średnia redukcja finalnego wzrostu po ciągłej terapii stymulantami przez 3 lata wynosi 2 cm<ref name="pmid18295156" />) USFDA radzi monitorowanie wzrostu i masy ciała dzieci i młodzieży zażywających farmaceutyczną amfetaminę<ref name="FDA Contra Warnings" />.

Wykazano, że amfetamina wywołuje u ludzi [[Warunkowana preferencja miejsca|warunkowaną preferencję miejsca]] już w dawkach terapeutycznych<ref name="Cochrane Amphetamines ADHD" /><ref name="Human CPP">{{cytuj pismo | autor = Childs E, de Wit H | tytuł = Amphetamine-induced place preference in humans | czasopismo = Biol. Psychiatry | wolumin = 65 | wydanie = 10 | strony = 900–904 | data = May 2009 | pmid = 19111278 | pmc = 2693956 | doi = 10.1016/j.biopsych.2008.11.016 | quotecytat = This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.}}</ref>. Oznacza to, że osoby te nabywają preferencję spędzania czasu w miejscu, gdzie wcześniej przyjmowały amfetaminę<ref name="Human CPP" /><ref name="Addiction glossary" />.

Patologicznie zwiększona aktywność [[szlak mezolimbiczny|szlaku mezolimbicznego]], drogi dopaminergicznej łączącej [[obszar nakrywki brzusznej]] z [[jądro półleżące|jądrem półleżącym]], odgrywa centralną rolę w uzaleznieniu od amfetaminy<ref name="Amphetamine KEGG – ΔFosB">{{cytuj stronę | tytuł=Amphetamine – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05031 | praca=KEGG Pathway | data dostępu=31 October 2014 | autor=Kanehisa Laboratories | data=10 October 2014}}</ref><ref name="Magnesium" />. Osobom regularnie nadużywającym amfetaminy w celach rekreacyjnych grozi wysokie ryzyko rozwinięcia się uzależnienia, jako że powtarzające się epizody przedawkowania stopniowo zwiększają w jądrze półleżącym poziom [[ΔFosB]], przełącznika molekularnego i regulatora białek związanego z zależnością<ref name="What the ΔFosB?" /><ref name="Cellular basis" /><ref name="Nestler_1">{{cytuj pismo | autor=Robison AJ, Nestler EJ | tytuł = Transcriptional and epigenetic mechanisms of addiction | czasopismo = Nat. Rev. Neurosci. | wolumin = 12 | wydanie = 11 | strony = 623–637 | data = November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quotecytat = ΔFosB serves as one of the master control proteins governing this structural plasticity.}}</ref>. Wraz z dostateczną nadeksrpesją ΔFosB w jądrze półleżącym zaczyna zwiekszać się ciężkość zachowań związanych z uzależnieniem (np. kompulsywne szukanie substancji), co dalej zwiększa [[ekspresja genu|ekspresję]]<ref name="What the ΔFosB?">{{cytuj pismo | autor = Ruffle JK | tytuł = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | czasopismo = Am. J. Drug Alcohol Abuse | wolumin = 40 | wydanie = 6 | strony = 428–437 | data = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | quotecytat = ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.}}</ref><ref name="Natural and drug addictions" />. Obecnie nie ma leków efektywnie leczących uzależnienie od amfetaminy, jednak regularne uprawianie długotrwałego wysiłku aerobowego wydaje się redukować ryzyko rozwoju tkiego uzależnieniaref name="Running vs addiction" /><ref name="Exercise, addiction prevention, and ΔFosB">{{cytuj pismo | autor = Zhou Y, Zhao M, Zhou C, Li R | tytuł = Sex differences in drug addiction and response to exercise intervention: From human to animal studies | czasopismo = Front. Neuroendocrinol. | wolumin = | wydanie = | strony = | data = July 2015 | pmid = 26182835 | doi = 10.1016/j.yfrne.2015.07.001 | quotecytat = Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use.&nbsp;... As briefly reviewed above, a large number of human and rodent studies clearly show that there are sex differences in drug addiction and exercise. The sex differences are also found in the effectiveness of exercise on drug addiction prevention and treatment, as well as underlying neurobiological mechanisms. The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.&nbsp;... In particular, more studies on the neurobiological mechanism of exercise and its roles in preventing and treating drug addiction are needed.}}</ref>. Długotrwałe ćwiczenia aerobowe wydają się także efektywnym leczeniem uzależnienia od amfetaminy<ref name="Exercise therapy" group="sources" />; poprawiają wyniki kliniczne i mogą wchodzić w skład terapii łączonej wraz z [[terapia poznawczo-hehawioralna|terapią poznawczo-behawioralną]], obecnie najlepszym klinicznym sposobem leczenia<ref name="Running vs addiction" /><ref name="Exercise Rev 3" /><ref name="Nestler CBT"/>.

[[Uzależnienie]] stanowi poważne ryzyko w przypadku używania znacznych dawek w celach niemedycznych, nie jest jednak prawdopodobne w przypadku długoterminowego leczenia dawkami terapeutycznymi<ref name="NHM-Addiction doses">{{cytuj książkę | autor = Malenka RC, Nestler EJ, Hyman SE | editorwydawca = Sydor A, Brown RY | tytuł = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | rok = 2009 | wydawca = McGraw-Hill Medical | miejsce = New York | isbn = 9780071481274 | strony = 368 | wydanie = 2. | rozdział = Chapter 15: Reinforcement and Addictive Disorders | quotecytat= INITIAL ACTIONS OF DRUGS OF ABUSE AND NATURAL REINFORCERS<br />.Psychostimulants<br />Cocaine, amphetamines, and methamphetamine are the major psychostimulants of abuse. The related drug methylphenidate is also abused, although it is far less potent. These drugs elicit similar initial subjective effects; differences generally reflect the route of administration and other pharmacokinetic factors. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.}}</ref><ref name="Addiction risk">{{cytuj pismo | autor = Kollins SH | tytuł = A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders | czasopismo = Curr. Med. Res. Opin. | wolumin = 24 | wydanie = 5 | strony = 1345–1357 | data = May 2008 | pmid = 18384709 | doi = 10.1185/030079908X280707 | quotecytat = When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.}}</ref><ref name="EncycOfPsychopharm">{{cytuj książkę | autor = Stolerman IP | editorwydawca = Stolerman IP | tytuł = Encyclopedia of Psychopharmacology | rok = 2010 | wydawca = Springer | miejsce = Berlin, Germany; London, England | isbn = 9783540686989 | strony = 78}}</ref>. Tolerancja rozwija się szybko w przypadku nadużywania, wobec czego okresy wzmożonego używania wymagają coraz większych dawek, by osiągnąć ten sam efekt<ref>{{cytuj stronę| tytuł = Amphetamines: Drug Use and Abuse | praca = Merck Manual Home Edition | wydawca = Merck | url = http://www.merckmanuals.com/home/special_subjects/drug_use_and_abuse/amphetamines.html | data dostępu = 28 February 2007 | archiveurl = https://web.archive.org/web/20070217053619/http://www.merck.com/mmhe/sec07/ch108/ch108g.html | data=February 2003 | archivedate = 17 February 2007}}</ref><ref>{{cytuj pismo | autor=Perez-Mana C, Castells X, Torrens M, Capella D, Farre M | tytuł=Efficacy of psychostimulant drugs for amphetamine abuse or dependence | czasopismo=Cochrane Database Syst. Rev. | wolumin=9 | wydanie= | strony=CD009695 | data=September 2013 |pmid=23996457 |doi=10.1002/14651858.CD009695.pub2 }}</ref>.

Współczesne modele uzależnienia obejmują zmiany [[ekspresja genu|ekspresji genów]] w różnych częściach mózgu, zwłaszcza w [[jądro półleżące|jądrze półleżącym]]<ref name="Nestler, Hyman, and Malenka 2">{{cytuj pismo | autor=Hyman SE, Malenka RC, Nestler EJ | tytuł=Neural mechanisms of addiction: the role of reward-related learning and memory | czasopismo=Annu. Rev. Neurosci. | wolumin=29| strony=565–598 | data=July 2006 |pmid=16776597 |doi=10.1146/annurev.neuro.29.051605.113009 }}</ref><ref name="Nestler" /><ref name="Addiction genetics" />. Najważniejsze [[czynnik transkrypcyjny|czynniki transkrypcyjne]] wywołujące te zmiany to [[ΔFosB]], [[CREB]] i [[NF-κB]]<ref name="Nestler" />. ΔFosB odgrywa kluczową rolę w rozwoju uzależnień od suybstancji, jako że jegoplays a crucial role in the development of drug addictions, since its overexpression in [[D1-type]] [[medium spiny neuron]]s in the nucleus accumbens is [[necessary and sufficient#Definitions|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 most of the behavioral and neural adaptations that arise from addiction<ref name="What the ΔFosB?" /><ref name="Cellular basis" /><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="What the ΔFosB?" /><ref name="Cellular basis" />. 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">{{cytuj stronę | tytuł=Alcoholism – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 | praca=KEGG Pathway | data dostępu=31 October 2014 | autor=Kanehisa Laboratories | data=29 October 2014}}</ref><ref name="MPH ΔFosB">{{cytuj pismo | autor = Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P | tytuł = Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens | czasopismo = Proc. Natl. Acad. Sci. U.S.A. | wolumin = 106 | wydanie = 8 | strony = 2915–2920 | data = February 2009 | pmid = 19202072 | pmc = 2650365 | doi = 10.1073/pnas.0813179106 | quotecytat = <!--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).-->}}</ref>|group="sources"}}

[[ΔJunD]], a transcription factor, and [[EHMT2|G9a]], a [[histone methyltransferase]] enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression)<ref name="Cellular basis" /><ref name="Nestler" /><ref name="Nestler 2014 epigenetics">{{cytuj pismo | autor = Nestler EJ | tytuł = Epigenetic mechanisms of drug addiction | czasopismo = Neuropharmacology | wolumin = 76 Pt B | wydanie = | strony = 259–268 | data = January 2014 | pmid = 23643695 | pmc = 3766384 | doi = 10.1016/j.neuropharm.2013.04.004 | quotecytat = <!-- 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" />. 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">{{cytuj pismo | autor=Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M | tytuł = Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms | czasopismo = J. Psychoactive Drugs | wolumin = 44 | wydanie = 1 | strony = 38–55 | data = March 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112| quotecytat = <!-- 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 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">{{cytuj pismo | autor=Robison AJ, Nestler EJ | tytuł = Transcriptional and epigenetic mechanisms of addiction | czasopismo = Nat. Rev. Neurosci. | wolumin = 12 | wydanie = 11 | strony = 623–637 | data=November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quotecytat = <!-- 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^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is 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^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. -->}}</ref>. Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced [[sex 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-->{{cytuj pismo | autor=Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM | tytuł = Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator | czasopismo = J. Neurosci. | wolumin = 33 | wydanie = 8 | strony = 3434–3442 | data=February 2013 | pmid = 23426671 | pmc = 3865508 | doi = 10.1523/JNEUROSCI.4881-12.2013 | quotecytat =}}</ref><ref name="Amph-Sex X-sensitization through NMDA signaling"><!--Supplemental primary source-->{{cytuj pismo | autor = Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM | tytuł = Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats | czasopismo = Neuropharmacology | wolumin = 101 | wydanie = | strony = 154–164 | data = February 2016 | pmid = 26391065 | doi = 10.1016/j.neuropharm.2015.09.023 | quotecytat =}}</ref>. These sex 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" />.

{{As of|May 2014}}, there is no effective [[pharmacotherapy]] for amphetamine addiction<ref name="pmid24716825">{{cytuj pismo | autor = Stoops WW, Rush CR | tytuł = Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research | czasopismo = Expert Rev Clin Pharmacol | wolumin = 7 | wydanie = 3 | strony = 363–374 | data = May 2014 | pmid = 24716825 | doi = 10.1586/17512433.2014.909283 | quotecytat = Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.}}</ref><ref name="Cochrane 2013 treatments">{{cytuj pismo | autor = Perez-Mana C, Castells X, Torrens M, Capella D, Farre M | tytuł = Efficacy of psychostimulant drugs for amphetamine abuse or dependence | czasopismo = Cochrane Database Syst. Rev. | wolumin = 9 | wydanie = | strony = CD009695 | data = September 2013 | pmid = 23996457 | doi = 10.1002/14651858.CD009695.pub2 | quotecytat = To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment.&nbsp;... Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy}}</ref><ref name="pmid23039267">{{cytuj pismo | autor = Forray A, Sofuoglu M | tytuł = Future pharmacological treatments for substance use disorders | czasopismo = Br. J. Clin. Pharmacol. | wolumin = 77 | wydanie = 2 | strony = 382–400 | data = February 2014 | pmid = 23039267 | pmc = 4014020 | doi = 10.1111/j.1365-2125.2012.04474.x}}</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}}, the only compounds which are known to function as TAAR1-selective agonists are [[experimental drug]]s.<ref name="Miller+Grandy 2016">{{cytuj pismo | autor = Grandy DK, Miller GM, Li JX | tytuł = "TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference | czasopismo = Drug Alcohol Depend. | wolumin = 159 | wydanie = | stronys = 9–16 | data = February 2016 | pmid = 26644139 | doi = 10.1016/j.drugalcdep.2015.11.014 | quotecytat = 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.}}</ref><ref name="TAAR1 addiction 2015">{{cytuj pismo | autor = Jing L, Li JX | tytuł = Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction | czasopismo = Eur. J. Pharmacol. | wolumin = 761 | wydanie = | strony = 345–352 | data = August 2015 | pmid = 26092759 | doi = 10.1016/j.ejphar.2015.06.019 | quotecytat = Taken together,the data reviewed here strongly support that TAAR1 is implicated in the functional regulation of monoaminergic systems, especially dopaminergic system, and that TAAR1 serves as a homeostatic “brake” system that is involved in the modulation of dopaminergic activity. Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction.&nbsp;... Given that TAAR1 is primarily located in the intracellular compartments and existing TAAR1 agonists are proposed to get access to the receptors by translocation to the cell interior (Miller, 2011), future drug design and development efforts may need to take strategies of drug delivery into consideration (Rajendran et al., 2010).}}</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 ([[D-serine|{{smallcaps all|D}}-serine]] or [[glycine]]) to open the ion channel<ref name="NHM-NMDA">{{cytuj książkę | autor=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | tytuł = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | rok = 2009 | wydawca = McGraw-Hill Medical | miejsce = New York, USA | isbn = 9780071481274 | stronys = 124–125 | wydanie = 2nd | rozdział = Chapter 5: Excitatory and Inhibitory Amino Acids | quotecytat = <!-- At membrane potentials more negative than approximately −50 mV, the Mg2+ 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 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">{{cytuj pismo | autor =Nechifor M | tytuł=Magnesium in drug dependences | czasopismo=Magnes. Res. | wolumin=21 | wydanie=1 | strony=5–15 | data=March 2008 |pmid=18557129 |doi= |url=}}</ref>.

[[Cognitive behavioral therapy]] is currently the most effective clinical treatment for psychostimulant addictions<ref name="Nestler CBT">{{cytuj książkę | autor=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | tytuł = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | rok = 2009 | wydawca = McGraw-Hill Medical | miejsce = New York, USA | isbn = 9780071481274 | strony = 386 | wydanie = 2nd | rozdział = Chapter 15: Reinforcement and Addictive Disorders | quotecytat= Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.}}</ref>. 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">{{cytuj pismo | autor=Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA | tytuł = Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis | czasopismo = Neurosci. Biobehav. Rev. | wolumin = 37 | wydanie = 8 | strony = 1622–1644 | data=September 2013 | pmid = 23806439 | pmc = 3788047 | doi = 10.1016/j.neubiorev.2013.06.011 | quotecytat = 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. ... 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 ... 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">{{cytuj pismo | autor = Linke SE, Ussher M | tytuł = Exercise-based treatments for substance use disorders: evidence, theory, and practicality | czasopismo = Am. J. Drug Alcohol Abuse | wolumin = 41 | wydanie = 1 | strony = 7–15 | data = January 2015 | pmid = 25397661 | doi = 10.3109/00952990.2014.976708 | quotecytat = 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.}}</ref><ref name="Addiction review 2016">{{cytuj pismo | autor = Carroll ME, Smethells JR | tytuł = Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments | czasopismo = Front. Psychiatry | wolumin = 6 | wydanie = | stronys = 175 | data = February 2016 | pmid = 26903885 | pmc = 4745113 | doi = 10.3389/fpsyt.2015.00175 | quotecytat = Environmental Enrichment&nbsp;...<br />.In humans, non-drug rewards delivered in a contingency management (CM) format successfully reduced drug dependence&nbsp;... In general, CM programs promote drug abstinence through a combination of positive reinforcement for drug-free urine samples. For instance, voucher-based reinforcement therapy in which medication compliance, therapy session attendance, and negative drug screenings reinforced with vouchers to local business (e.g., movie theater, restaurants, etc.) directly reinforces drug abstinence, provides competing reinforcers, enriches the environment, and it is a robust treatment across a broad range of abused drugs (189).&nbsp;...<br />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;... However, a <abbr title="randomized controlled trial">RTC</abbr> study was recently reported by Rawson et al. (226), whereby they used 8 weeks of exercise as a post-residential treatment for METH addiction, showed a significant reduction in use (confirmed by urine screens) in participants who had been using meth 18 days or less a month.&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.''' [emphasis added]}}</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 D₂]] (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">{{cytuj pismo | autor = Olsen CM | tytuł = Natural rewards, neuroplasticity, and non-drug addictions | czasopismo = Neuropharmacology | wolumin = 61 | wydanie = 7 | strony = 1109–1122 | data = December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quotecytat = 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 [[c-Fos]] [[immunoreactivity]] in the striatum or other parts of the [[reward system]]<ref name="Exercise, addiction prevention, and ΔFosB" />.

According to another Cochrane Collaboration review on [[drug withdrawal|withdrawal]] in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24&nbsp;hours of their last dose."<ref name="Cochrane Withdrawal">{{cytuj pismo | autor=Shoptaw SJ, Kao U, Heinzerling K, Ling W | tytuł = Treatment for amphetamine withdrawal | czasopismo = Cochrane Database Syst. Rev. | wolumin = | wydanie = 2 | stronys = CD003021 | data = April 2009 | pmid = 19370579 | doi = 10.1002/14651858.CD003021.pub2 | editor = Shoptaw SJ | quotecytat = <!-- The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999)&nbsp;... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005)&nbsp;... -->}}</ref> This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.<ref name="Cochrane Withdrawal" /> Amphetamine withdrawal symptoms can include anxiety, [[Craving (withdrawal)|drug craving]], [[Dysphoria|depressed mood]], [[Fatigue (medical)|fatigue]], [[hyperphagia|increased appetite]], increased movement or [[psychomotor retardation|decreased movement]], lack of motivation, sleeplessness or sleepiness, and [[lucid dream]]s.<ref name="Cochrane Withdrawal" /> The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence<ref name="Cochrane Withdrawal" />. Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses<ref name="Dexedrine FDA">{{cytuj stronę | tytuł = Dexedrine Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017078s047lbl.pdf | wydawca = Amedra Pharmaceuticals LLC | praca = United States Food and Drug Administration | data = October 2013 | data dostępu = 4 November 2013}}</ref><ref>{{cytuj stronę | tytuł=Adderall IR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011522s042lbl.pdf | wydawca = Teva Pharmaceuticals USA, Inc. | praca = United States Food and Drug Administration | data=October 2015 | data dostępu=18 May 2016}}</ref><ref>{{cytuj stronę | tytuł = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | wydawca = Shire US Inc | praca = United States Food and Drug Administration | data=December 2013 | data dostępu = 30 December 2013}}</ref>.

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic [[neurotoxicity]], or damage to dopamine neurons, which is characterized by dopamine [[axon terminal|terminal]] [[Neurodegeneration|degeneration]] and reduced transporter and receptor function<ref name="Humans&Animals">{{cytuj pismo| autor=Advokat C| tytuł=Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD | czasopismo=J. Atten. Disord. | data = July 2007 | wolumin= 11 | wydanie= 1 | strony= 8–16 | pmid=17606768 | doi=10.1177/1087054706295605}}</ref><ref name="Amph-induced hyperthermia and neurotoxicity review" />. There is no evidence that amphetamine is directly neurotoxic in humans<ref>{{cytuj stronę | tytuł=Amphetamine | url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+300-62-9 | praca=Hazardous Substances Data Bank | wydawca=United States National Library of Medicine&nbsp;– Toxicology Data Network | data dostępu=26 February 2014 | quotecytat = Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.}}</ref><ref name = "Malenka_2009_02">{{cytuj książkę | autor=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | tytuł = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | rok = 2009 | wydawca = McGraw-Hill Medical | miejsce = New York, USA | isbn = 9780071481274 | strony = 370 | wydanie = 2nd | rozdział = Chapter 15: Reinforcement and addictive disorders | quotecytat = Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.}}</ref>. However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of [[hyperpyrexia]], the excessive formation of [[reactive oxygen species]], and increased [[autoxidation]] of dopamine.{{#tag:ref|<ref name="pmid22392347">{{cytuj pismo | autor=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L | tytuł=Toxicity of amphetamines: an update | czasopismo=Arch. Toxicol. | wolumin=86 | wydanie=8 | strony=1167–1231 | data=August 2012 |pmid=22392347 |doi=10.1007/s00204-012-0815-5 |url=}}</ref><ref name="Amph-induced hyperthermia and neurotoxicity review" /><ref name="Autoxidation1">{{cytuj pismo | autor=Sulzer D, Zecca L | tytuł = Intraneuronal dopamine-quinone synthesis: a review | czasopismo = Neurotox. Res. | wolumin = 1 | wydanie = 3 | strony = 181–195 | data=February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289}}</ref><ref name="Autoxidation2">{{cytuj pismo | autor=Miyazaki I, Asanuma M | tytuł = Dopaminergic neuron-specific oxidative stress caused by dopamine itself | czasopismo = Acta Med. Okayama | wolumin = 62 | wydanie = 3 | stronys = 141–150 | data=June 2008 | pmid = 18596830 | doi =}}</ref>|group="sources"}} [[Animal model]]s of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., [[core body temperature]]&nbsp;≥&nbsp;40&nbsp;°C) is necessary for the development of amphetamine-induced neurotoxicity<ref name="Amph-induced hyperthermia and neurotoxicity review">{{cytuj pismo | autor = Bowyer JF, Hanig JP | tytuł = Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity | czasopismo = Temperature (Austin) | wolumin = 1 | wydanie = 3 | strony = 172–182 | data = November 2014 | pmid = 27626044 | pmc = 5008711 | doi = 10.4161/23328940.2014.982049 | quotecytat = Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40 °C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. Forebrain neurotoxicity can also be indirectly influenced through the effects of AMPH- and METH- induced hyperthermia on vasculature. The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals.&nbsp;... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.}}</ref>. Prolonged elevations of brain temperature above 40&nbsp;°C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing [[blood–brain barrier]] permeability<ref name="Amph-induced hyperthermia and neurotoxicity review" />.

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as [[paranoia]] and [[delusion]]s.<ref name="Cochrane" /> A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about&nbsp;5–15% of users fail to recover completely<ref name="Cochrane">{{cytuj pismo | editor =<!--Shoptaw SJ--> Shoptaw SJ, Ali R | autor=Shoptaw SJ, Kao U, Ling W | tytuł = Treatment for amphetamine psychosis | czasopismo = Cochrane Database Syst. Rev. | wolumin = | wydanie = 1 | stronys = CD003026 | data = January 2009 | pmid = 19160215 | doi = 10.1002/14651858.CD003026.pub3 | quotecytat=A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention&nbsp;...<br />.About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983)&nbsp;...<br />Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.}}</ref><ref name="Hofmann">{{cytuj książkę | autor = Hofmann FG | tytuł = A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects | wydawca = Oxford University Press | isbn = 9780195030570 | miejsce = New York, USA | rok = 1983 | strony = 329 | wydanie = 2nd}}</ref> According to the same review, there is at least one trial that shows [[antipsychotic]] medications effectively resolve the symptoms of acute amphetamine psychosis<ref name="Cochrane"/>. Psychosis very rarely arises from therapeutic use<ref name="Stimulant Misuse" /><ref name="FDA Contra Warnings">{{cytuj stronę | tytuł = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | strony = 4–6 | wydawca = Shire US Inc | praca = United States Food and Drug Administration | data = December 2013 | data dostępu = 30 December 2013}}</ref>.

Many types of substances are known to [[drug interaction|interact]] with amphetamine, resulting in altered [[drug action]] or [[Drug metabolism|metabolism]] of amphetamine, the interacting substance, or both.<ref name="FDA Pharmacokinetics" /><ref name="FDA Interactions" /> Inhibitors of the enzymes that metabolize amphetamine (e.g., [[CYP2D6#Ligands|CYP2D6]] and [[Flavin-containing monooxygenase 3#Ligands|FMO3]]) will prolong its [[elimination half-life]], meaning that its effects will last longer<ref name="FMO" /><ref name="FDA Interactions">{{cytuj stronę | titletytuł = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | pagesstrony = 8–10 | publisheropublikowany = Shire US Inc | praca = United States Food and Drug Administration |datedata=December 2013 | data dostępu = 30 December 2013}}</ref>. Amphetamine also interacts with {{abbr|MAOIs|monoamine oxidase inhibitors}}, particularly [[monoamine oxidase A]] inhibitors, since both MAOIs and amphetamine increase [[blood plasma|plasma]] catecholamines (i.e., norepinephrine and dopamine)<ref name="FDA Interactions" />; therefore, concurrent use of both is dangerous<ref name="FDA Interactions" />. Amphetamine modulates the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of [[sedative]]s and [[depressant]]s and increase the effects of [[stimulant]]s and [[antidepressant]]s.<ref name="FDA Interactions" /> Amphetamine may also decrease the effects of [[antihypertensives]] and [[antipsychotic]]s due to its effects on blood pressure and dopamine respectively<ref name="FDA Interactions" />. [[Zinc supplementation]] may reduce the minimum [[Effective dose (pharmacology)|effective dose]] of amphetamine when it is used for the treatment of ADHD.{{#tag:ref|The human [[dopamine transporter]] contains a [[affinity (pharmacology)|high affinity]] extracellular zinc [[binding site]] which, upon zinc binding, inhibits dopamine [[reuptake]] and amplifies amphetamine-induced [[neurotransmitter efflux|dopamine efflux]] ''[[in vitro]]''<ref name="Zinc binding sites + ADHD review">{{citecytuj journalpismo | vauthors = Krause J | titletytuł = SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder | journalczasopismo = Expert Rev. Neurother. | volumewolumin = 8 | issuewydanie = 4 | pagesstrony = 611–625 | datedata = April 2008 | pmid = 18416663 | doi = 10.1586/14737175.8.4.611 | quotecytat = Zinc binds at&nbsp;... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm.}}</ref><ref name="Review - cites 2002 amph-zinc primary study">{{citecytuj journalpismo | vauthors = Sulzer D | titletytuł = How addictive drugs disrupt presynaptic dopamine neurotransmission | journalczasopismo = Neuron | volumewolumin = 69 | issuewydanie = 4 | pagesstrony = 628–649 | datedata = February 2011 | pmid = 21338876 | pmc = 3065181 | doi = 10.1016/j.neuron.2011.02.010 | quotecytat = They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002).}}</ref><ref name="Primary 2002 amph-zinc study">{{citecytuj journalpismo | vauthors = Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH | titletytuł = The role of zinc ions in reverse transport mediated by monoamine transporters | journalczasopismo = J. Biol. Chem. | volumewolumin = 277 | issuewydanie = 24 | pagesstrony = 21505–21513 | datedata = June 2002 | pmid = 11940571 | doi = 10.1074/jbc.M112265200 | quotecytat = The human dopamine transporter (hDAT) contains an endogenous high affinity Zn²⁺ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396).&nbsp;... Although Zn²⁺ inhibited uptake, Zn²⁺ facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET).&nbsp;... Surprisingly, this amphetamine-elicited efflux was markedly enhanced, rather than inhibited, by the addition of 10&nbsp;μM Zn²⁺ to the superfusion buffer (Fig. 2 A, open squares). We stress that Zn²⁺ per se did not affect basal efflux (Fig. 2 A).&nbsp;... In many brain regions, Zn²⁺ is stored in synaptic vesicles and co-released together with glutamate; under basal conditions, the extracellular levels of Zn²⁺ are low (∼10&nbsp;nM; see Refs. 39, 40). Upon neuronal stimulation, however, Zn²⁺ is co-released with the neurotransmitters and, consequently, the free Zn²⁺ concentration may transiently reach values that range from 10–20&nbsp;μM (10) up to 300&nbsp;μM (11). The concentrations of Zn²⁺ shown in this study, required for the stimulation of dopamine release (as well as inhibition of uptake), covered this physiologically relevant range, with maximum stimulation occurring at 3–30&nbsp;μM. It is therefore conceivable that the action of Zn²⁺ on hDAT does not merely reflect a biochemical peculiarity but that it is physiologically relevant.&nbsp;... Thus, when Zn²⁺ is co-released with glutamate, it may greatly augment the efflux of dopamine.}}</ref>. The human [[serotonin transporter]] and [[norepinephrine transporter]] do not contain zinc binding sites<ref name="Primary 2002 amph-zinc study" />.|group="note"}}<ref name="Zinc and PEA">{{citecytuj journalpismo |vauthors=Scassellati C, Bonvicini C, Faraone SV, Gennarelli M | titletytuł = Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses | journalczasopismo = J. Am. Acad. Child Adolesc. Psychiatry | volumewolumin = 51 | issuewydanie = 10 | pagesstrony = 1003–1019.e20 | datedata = October 2012 | pmid = 23021477 | doi = 10.1016/j.jaac.2012.08.015 | quotecytat = Although we did not find a sufficient number of studies suitable for a meta-analysis of PEA and ADHD, three studies^20,57,58 confirmed that urinary levels of PEA were significantly lower in patients with ADHD compared with controls.&nbsp;... Administration of D-amphetamine and methylphenidate resulted in a markedly increased urinary excretion of PEA,^20,60 suggesting that ADHD treatments normalize PEA levels.&nbsp;... Similarly, urinary biogenic trace amine PEA levels could be a biomarker for the diagnosis of ADHD,^20,57,58 for treatment efficacy,^20,60 and associated with symptoms of inattentivenesss.⁵⁹&nbsp;... With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30&nbsp;mg/day of zinc were safe for at least 8&nbsp;weeks, but the clinical effect was equivocal except for the finding of a 37%&nbsp;reduction in amphetamine optimal dose with 30&nbsp;mg per day of zinc.¹¹⁰}}</ref>

Amphetamine has been identified as a potent [[full agonist]] of [[TAAR1|trace amine-associated receptor 1]] (TAAR1), a {{nowrap|[[Gs alpha subunit|G_s-coupled]]}} and {{nowrap|[[Gq alpha subunit|G_q-coupled]]}} [[G protein-coupled receptor]] (GPCR) discovered in 2001, which is important for regulation of brain monoamines<ref name="Miller" /><ref name="TAAR1 IUPHAR">{{cytuj stronę| tytuł=TA₁ receptor|url=http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=364| praca=IUPHAR database| wydawca=International Union of Basic and Clinical Pharmacology| data dostępu=8 December 2014|vauthors=Maguire JJ, Davenport AP |datedata=2 December 2014|quotecytat=<!-- Comments: Tyramine causes an increase in intracellular cAMP in HEK293 or COS-7 cells expressing the TA1 receptor in vitro [4,6,18]. In addition, coupling to a promiscuous Gαq has been observed, resulting in increased intracellular calcium concentration [24]. -->}}</ref>. Activation of {{abbr|TAAR1|trace amine-associated receptor 1}} increases {{abbrlink|cAMP|cyclic adenosine monophosphate}} production via [[adenylyl cyclase]] activation and inhibits [[monoamine transporter]] function<ref name="Miller" /><ref name="pmid11459929">{{citecytuj journalpismo |vauthors=Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C | titletytuł = Trace amines: identification of a family of mammalian G protein-coupled receptors | journalczasopismo = Proc. Natl. Acad. Sci. U.S.A. | volumewolumin = 98 | issuewydanie = 16 | pagesstrony = 8966–8971 |datedata=July 2001 | pmid = 11459929 | pmc = 55357 | doi = 10.1073/pnas.151105198}}</ref>. Monoamine [[autoreceptors]] (e.g., [[D2sh|D₂ short]], [[Alpha-2 adrenergic receptor|presynaptic α₂]], and [[5-HT1A#Autoreceptors|presynaptic 5-HT_1A]]) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines<ref name="Miller" /><ref name="Miller+Grandy 2016" />. Notably, amphetamine and [[trace amine]]s bind to TAAR1, but not monoamine autoreceptors<ref name="Miller" /><ref name="Miller+Grandy 2016" />. Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 {{nowrap|co-localization}} in the associated monoamine neurons<ref name="Miller" />. {{As of|2014|alt=As of 2010,}} {{nowrap|co-localization}} of TAAR1 and the [[dopamine transporter]] (DAT) has been visualized in rhesus monkeys, but {{nowrap|co-localization}} of TAAR1 with the [[norepinephrine transporter]] (NET) and the [[serotonin transporter]] (SERT) has only been evidenced by [[messenger RNA]] (mRNA) expression<ref name="Miller" />.

In addition to the neuronal monoamine [[Membrane transport protein|transporters]], amphetamine also inhibits both vesicular monoamine transporters, [[VMAT1]] and [[VMAT2]], as well as [[SLC1A1]], [[SLC22A3]], and [[SLC22A5]].{{#tag:ref|<ref name="E Weihe" /><ref name="EAAT3">{{citecytuj journalpismo |vauthors=Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG | titletytuł = Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons | journalczasopismo = Neuron | volumewolumin = 83 | issuewydanie = 2 | pagesstrony = 404–416 | datedata = July 2014 | pmid = 25033183 | pmc = 4159050 | doi = 10.1016/j.neuron.2014.05.043 | quotecytat = AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).&nbsp;... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate.&nbsp;... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH}}</ref><ref name="IUPHAR VMATs">{{cytuj stronę| tytuł=SLC18 family of vesicular amine transporters|url=http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=193|website=IUPHAR database| wydawca=International Union of Basic and Clinical Pharmacology| data dostępu=13 November 2015}}</ref><ref name="SLC1A1">{{cytuj stronę | titletytuł=SLC1A1 solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 [ Homo sapiens (human) ] | url=http://www.ncbi.nlm.nih.gov/gene/6505 | website=NCBI Gene | publisheropublikowany=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdatedata dostępu=11 November 2014 | quotecytat = Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons.&nbsp;... internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission.}}</ref><ref name="SLC22A3">{{citecytuj journalpismo |vauthors=Zhu HJ, Appel DI, Gründemann D, Markowitz JS | titletytuł = Interaction of organic cation transporter 3 (SLC22A3) and amphetamine | journalczasopismo = J. Neurochem. | volumewolumin = 114 | issuewydanie = 1 | pagesstrony = 142–149 |datedata=July 2010 | pmid = 20402963 | pmc = 3775896 | doi = 10.1111/j.1471-4159.2010.06738.x | url =}}</ref><ref name="SLC22A5">{{citecytuj journalpismo |vauthors=Rytting E, Audus KL | titletytuł = Novel organic cation transporter 2-mediated carnitine uptake in placental choriocarcinoma (BeWo) cells | journalczasopismo = J. Pharmacol. Exp. Ther. | volumewolumin = 312 | issuewydanie = 1 | pagesstrony = 192–198 |datedata=January 2005 | pmid = 15316089 | doi = 10.1124/jpet.104.072363 | url =}}</ref><ref name="pmid13677912">{{citecytuj journalpismo |vauthors=Inazu M, Takeda H, Matsumiya T | titletytuł = [The role of glial monoamine transporters in the central nervous system] | languagejęzyk = Japanese | journalczasopismo = Nihon Shinkei Seishin Yakurigaku Zasshi | volumewolumin = 23 | issuewydanie = 4 | pagesstrony = 171–178 |datedata=August 2003 | pmid = 13677912 | doi =}}</ref>|group="sources"|name="Reuptake inhibition"}} SLC1A1 is [[excitatory amino acid transporter 3]] (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in [[astrocyte]]s, and SLC22A5 is a high-affinity [[carnitine]] transporter<ref name="Reuptake inhibition" group="sources"/>. Amphetamine is known to strongly induce [[cocaine- and amphetamine-regulated transcript]] (CART) [[gene expression]]<ref name="CART NAcc">{{citecytuj journalpismo |vauthors=Vicentic A, Jones DC | titletytuł = The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction | journalczasopismo = J. Pharmacol. Exp. Ther. | volumewolumin = 320 | issuewydanie = 2 | pagesstrony = 499–506 |datedata=February 2007 | pmid = 16840648 | doi = 10.1124/jpet.105.091512 | quotecytat = The physiological importance of CART was further substantiated in numerous human studies demonstrating a role of CART in both feeding and psychostimulant addiction.&nbsp;... Colocalization studies also support a role for CART in the actions of psychostimulants.&nbsp;... CART and DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB.}}</ref><ref name="PubChem Targets" />, a [[neuropeptide]] involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival ''[[in vitro]]''<ref name="PubChem Targets">{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#section=Biomolecular-Interactions-and-Pathways | praca=PubChem Compound | publisher = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=13 October 2013 | section=Biomolecular Interactions and Pathways}}</ref><ref name="CART functions">{{citecytuj journalpismo |vauthors=Zhang M, Han L, Xu Y | titletytuł = Roles of cocaine- and amphetamine-regulated transcript in the central nervous system | journalczasopismo = Clin. Exp. Pharmacol. Physiol. | volumewolumin = 39 | issuewydanie = 6 | pagesstrony = 586–592 |datedata=June 2012 | pmid = 22077697 | doi = 10.1111/j.1440-1681.2011.05642.x | quotecytat = Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. 3. In fact, little is known about the way in which CART peptide interacts with its receptors, initiates downstream cascades and finally exerts its neuroprotective effect under normal or pathological conditions. The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART}}</ref><ref name="CART">{{citecytuj journalpismo | vauthors = Rogge G, Jones D, Hubert GW, Lin Y, Kuhar MJ | titletytuł = CART peptides: regulators of body weight, reward and other functions | journalczasopismo = Nat. Rev. Neurosci. | volumewolumin = 9 | issuewydanie = 10 | pagesstrony = 747–758 | datedata = October 2008 | pmid = 18802445 | pmc = 4418456 | doi = 10.1038/nrn2493 | quotecytat = Several studies on CART (cocaine- and amphetamine-regulated transcript)-peptide-induced cell signalling have demonstrated that CART peptides activate at least three signalling mechanisms. First, CART 55–102 inhibited voltage-gated L-type Ca2+ channels&nbsp;...}}</ref>. The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique {{nowrap|[[Gi alpha subunit|G_i/G_o-coupled]]}} {{abbr|GPCR|G protein-coupled receptor}}<ref name="CART" /><ref name="pmid21855138">{{citecytuj journalpismo |vauthors=Lin Y, Hall RA, Kuhar MJ | titletytuł = CART peptide stimulation of G protein-mediated signaling in differentiated PC12 cells: identification of PACAP 6–38 as a CART receptor antagonist | journalczasopismo = Neuropeptides | volumewolumin = 45 | issuewydanie = 5 | pagesstrony = 351–358 |datedata=October 2011 | pmid = 21855138 | pmc = 3170513 | doi = 10.1016/j.npep.2011.07.006}}</ref>. Amphetamine also inhibits [[monoamine oxidase]] at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines<ref name="PubChem Header">{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007 | praca=PubChem Compound | publisher = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=17 April 2015 | date=11 April 2015 | section=Compound Summary}}</ref><ref name="BRENDA MAO Homo sapiens">{{cite encyclopedia | title=Monoamine oxidase (Homo sapiens)| url=http://www.brenda-enzymes.info/enzyme.php?ecno=1.4.3.4&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0 | praca=BRENDA | publisher=Technische Universität Braunschweig | accessdate=4 May 2014 | date=1 January 2014}}</ref>. In humans, the only post-synaptic receptor at which amphetamine is known to bind is the [[5-HT1A receptor|{{nowrap|5-HT1A}} receptor]], where it acts as an agonist with [[micromolar]] affinity<ref name="5HT1A secondary" /><ref name="5HT1A Primary" />.

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or [[neurotransmission]] of [[dopamine]]<ref name="Miller">{{citecytuj journalpismo | autor = Miller GM | titletytuł = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journalczasopismo = J. Neurochem. | volumewolumin = 116 | issuewydanie = 2 | pagesstrony = 164–176 |datedata=January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x}}</ref>, [[serotonin]]<ref name="Miller" />, [[norepinephrine]]<ref name="Miller" />, [[epinephrine]]<ref name="E Weihe">{{citecytuj journalpismo |vauthors=Eiden LE, Weihe E | titletytuł = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journalczasopismo = Ann. N. Y. Acad. Sci. | volumewolumin = 1216 | issuewydanie = | pagesstrony = 86–98 |datedata=January 2011 | pmid = 21272013 | doi = 10.1111/j.1749-6632.2010.05906.x | quotecytat=<!-- VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR)&nbsp;... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).--> | pmc=4183197}}</ref>, [[histamine]]<ref name="E Weihe" />, [[cocaine and amphetamine regulated transcript|CART peptides]]<ref name="CART NAcc" /><ref name="PubChem Targets" />, [[endogenous opioid]]s<ref name="Amphetamine-induced endogenous opioid release review">{{citecytuj journalpismo | vauthors = Finnema SJ, Scheinin M, Shahid M, Lehto J, Borroni E, Bang-Andersen B, Sallinen J, Wong E, Farde L, Halldin C, Grimwood S | titletytuł = Application of cross-species PET imaging to assess neurotransmitter release in brain | journalczasopismo = Psychopharmacology (Berl.) | volumewolumin = 232 | issuewydanie = 21-22 | pagesstrony = 4129–4157 | datedata = November 2015 | pmid = 25921033 | pmc = 4600473 | doi = 10.1007/s00213-015-3938-6 | quotecytat = More recently, Colasanti and colleagues reported that a pharmacologically induced elevation in endogenous opioid release reduced [¹¹C]carfentanil binding in several regions of the human brain, including the basal ganglia, frontal cortex, and thalamus (Colasanti et al. 2012). Oral administration of d-amphetamine, 0.5&nbsp;mg/kg, 3&nbsp;h before [¹¹C]carfentanil injection, reduced BPND values by 2–10&nbsp;%. The results were confirmed in another group of subjects (Mick et al. 2014). However, Guterstam and colleagues observed no change in [¹¹C]carfentanil binding when d-amphetamine, 0.3&nbsp;mg/kg, was administered intravenously directly before injection of [¹¹C]carfentanil (Guterstam et al. 2013). It has been hypothesized that this discrepancy may be related to delayed increases in extracellular opioid peptide concentrations following amphetamine-evoked monoamine release (Colasanti et al. 2012; Mick et al. 2014).}}</ref><ref name="Opioids">{{citecytuj journalpismo | vauthors = Loseth GE, Ellingsen DM, Leknes S | titletytuł = State-dependent μ-opioid modulation of social motivation | journalczasopismo = Front. Behav. Neurosci. | volumewolumin = 8 | issuewydanie = | pagesstrony = 1–15 | datedata = December 2014 | pmid = 25565999 | pmc = 4264475 | doi = 10.3389/fnbeh.2014.00430 | quotecytat = Similar MOR activation patterns were reported during positive mood induced by an amusing video clip (Koepp et al., 2009) and following amphetamine administration in humans (Colasanti et al., 2012).}}</ref><ref name="Opioids cited primary source">{{citecytuj journalpismo | vauthors = Colasanti A, Searle GE, Long CJ, Hill SP, Reiley RR, Quelch D, Erritzoe D, Tziortzi AC, Reed LJ, Lingford-Hughes AR, Waldman AD, Schruers KR, Matthews PM, Gunn RN, Nutt DJ, Rabiner EA | titletytuł = Endogenous opioid release in the human brain reward system induced by acute amphetamine administration | journalczasopismo = Biol. Psychiatry | volumewolumin = 72 | issuewydanie = 5 | pagesstrony = 371–377 | datedata = September 2012 | pmid = 22386378 | doi = 10.1016/j.biopsych.2012.01.027 | quotecytat =}}</ref>, [[adrenocorticotropic hormone]]<ref name="Human amph effects" /><ref name="Primary: Human HPA axis" />, [[corticosteroid]]s<ref name="Human amph effects" /><ref name="Primary: Human HPA axis" />, and [[glutamate]]<ref name="EAAT3" /><ref name="SLC1A1" />, which it effects through interactions with {{abbr|CART|cocaine- and amphetamine-regulated transcript}}, {{nowrap|{{abbr|5-HT1A|serotonin receptor 1A}}}}, {{abbr|EAAT3|excitatory amino acid transporter 3}}, {{abbr|TAAR1|trace amine-associated receptor 1}}, {{abbr|VMAT1|vesicular monoamine transporter 1}}, {{abbr|VMAT2|vesicular monoamine transporter 2}}, and possibly other [[biological target]]s.{{#tag:ref|<ref name="Miller" /><ref name="E Weihe" /><ref name="IUPHAR VMATs" /><ref name="SLC1A1" /><ref name="CART NAcc" /><ref name="5HT1A secondary" />|group="sources"}}

Dextroamphetamine is a more potent agonist of {{abbr|TAAR1|trace amine-associated receptor 1}} than levoamphetamine<ref name="TAAR1 stereoselective" />. Consequently, dextroamphetamine produces greater {{abbr|CNS|central nervous system}} stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects<ref name="Westfall" /><ref name="TAAR1 stereoselective">{{citecytuj journalpismo |vauthors=Lewin AH, Miller GM, Gilmour B | titletytuł=Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | journalczasopismo=Bioorg. Med. Chem. |datedata=December 2011 | volumewolumin=19 | issuewydanie=23 | pagesstrony=7044–7048 | pmid=22037049 | doi= 10.1016/j.bmc.2011.10.007 | pmc= 3236098}}</ref>.

In certain brain regions, amphetamine increases the concentration of dopamine in the [[synaptic cleft]]<ref name="Miller" />. Amphetamine can enter the [[presynaptic neuron]] either through {{abbr|DAT|dopamine transporter}} or by diffusing across the neuronal membrane directly<ref name="Miller" />. As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter<ref name="Miller" />. Upon entering the presynaptic neuron, amphetamine activates {{abbr|TAAR1|trace amine-associated receptor 1}} which, through [[protein kinase A]] (PKA) and [[protein kinase C]] (PKC) signaling, causes DAT [[phosphorylation]]<ref name="Miller" />. Phosphorylation by either protein kinase can result in DAT [[endocytosis|internalization]] ({{nowrap|non-competitive}} reuptake inhibition), but {{nowrap|PKC-mediated}} phosphorylation alone induces reverse transporter function (dopamine [[wikt:efflux|efflux]])<ref name="Miller" /><ref name="TAAR1 Review">{{citecytuj journalpismo |vauthors=Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP | titletytuł = International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature | journalczasopismo = Pharmacol. Rev. | volumewolumin = 61 | issuewydanie = 1 | pagesstrony = 1–8 |datedata=March 2009 | pmid = 19325074 | pmc = 2830119 | doi = 10.1124/pr.109.001107}}</ref>. Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified [[Ca2+/calmodulin-dependent protein kinase]] (CAMK)-dependent pathway, in turn producing dopamine efflux<ref name="TAAR1 IUPHAR" /><ref name="EAAT3" /><ref name="DAT regulation review">{{citecytuj journalpismo |vauthors=Vaughan RA, Foster JD | titletytuł = Mechanisms of dopamine transporter regulation in normal and disease states | journalczasopismo = Trends Pharmacol. Sci. | volumewolumin = 34 | issuewydanie = 9 | pagesstrony = 489–496 | datedata = September 2013 | pmid = 23968642 | pmc = 3831354 | doi = 10.1016/j.tips.2013.07.005 | quotecytat = <!-- AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72]. -->}}</ref>. Through direct activation of [[G protein-coupled inwardly-rectifying potassium channel]]s, {{abbr|TAAR1|trace amine associated receptor 1}} reduces the [[action potential|firing rate]] of postsynaptic dopamine neurons, preventing a hyper-dopaminergic state<ref name="GIRK">{{citecytuj journalpismo |vauthors=Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB | titletytuł = Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons | journalczasopismo = Front. Syst. Neurosci. | volumewolumin = 5 | issuewydanie = | pagesstrony = 56 | datedata = July 2011 | pmid = 21772817 | pmc = 3131148 | doi = 10.3389/fnsys.2011.00056 | quotecytat = <!-- inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. -->}}</ref><ref name="Genatlas TAAR1">{{cytuj stronę | url = http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=TAAR1 | titletytuł = TAAR1 | autor = mct | datedata = 28 January 2012 | praca = GenAtlas | publisheropublikowany = University of Paris | accessdatedata dostępu = 29 May 2014 | quotecytat=<br />.{{•}} tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA) }}</ref><ref name="TAAR1-Paradoxical">{{citecytuj journalpismo |vauthors=Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC | tytuł=TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity | czasopismo=Proc. Natl. Acad. Sci. U.S.A. | wolumin=108 | wydanie=20 | strony=8485–8490 |datedata=May 2011 |pmid=21525407 |pmc=3101002 |doi=10.1073/pnas.1103029108}}</ref>

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine<ref name="Miller" /><ref name="cognition enhancers" />. Amphetamine affects serotonin via {{abbr|VMAT2|vesicular monoamine transporter 2}} and, like norepinephrine, is thought to phosphorylate {{abbr|SERT|serotonin transporter}} via {{abbr|TAAR1|trace amine-associated receptor 1}}<ref name="Miller" /><ref name="E Weihe" />. Like dopamine, amphetamine has low, micromolar affinity at the human [[5-HT1A receptor]]<ref name="5HT1A secondary">{{cite encyclopedia | title=Amphetamine | url=http://www.t3db.ca/toxins/T3D2706 | website=T3DB | publisher=University of Alberta | accessdate=24 February 2015 | section=Targets}}</ref><ref name="5HT1A Primary">{{citecytuj journalpismo | vauthors = Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS | titletytuł = Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications | journalczasopismo = NIDA Res. Monogr. | volumewolumin = 178 | issuewydanie = | pagesstrony = 440–466 | datedata = March 1998 | pmid = 9686407 | doi = | url =}}</ref>.

Acute amphetamine administration in humans increases [[endogenous opioid]] release in several brain structures in the [[reward system]]<ref name="Amphetamine-induced endogenous opioid release review" /><ref name="Opioids" /><ref name="Opioids cited primary source" />. Extracellular levels of [[Glutamate (neurotransmitter)|glutamate]], the primary [[Neurotransmitter#Excitatory and inhibitory|excitatory neurotransmitter]] in the brain, have been shown to increase in the striatum following exposure to amphetamine<ref name="EAAT3" />. This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of [[EAAT3]], a glutamate reuptake transporter, in dopamine neurons<ref name="EAAT3" /><ref name="SLC1A1" />. Amphetamine also induces the selective release of [[histamine]] from [[mast cell]]s and efflux from [[Tuberomammillary nucleus|histaminergic neurons]] through {{abbr|VMAT2|vesicular monoamine transporter 2}}<ref name="E Weihe" />. Acute amphetamine administration can also increase [[adrenocorticotropic hormone]] and [[corticosteroid]] levels in [[blood plasma]] by stimulating the [[hypothalamic–pituitary–adrenal axis]]<ref name="Evekeo" /><ref name="Human amph effects">{{cytuj książkę | autor=Gunne LM | titletytuł=Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence | datedata=2013 | publisherwydawca=Springer | miejsce=Berlin, Germany; Heidelberg, Germany | isbn=9783642667091 | pagesstrony=247–260 | accessdatedata dostępu=4 December 2015 | rozdział=Effects of Amphetamines in Humans | rozdział-url=https://books.google.com/books?id=gb_uCAAAQBAJ&pg=PA247#v=onepage&q&f=false | quotecytat =}}</ref><ref name="Primary: Human HPA axis">{{citecytuj journalpismo | vauthors = Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L, Brasic J, Wand GS | titletytuł = Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine | journalczasopismo = Neuropsychopharmacology | volumewolumin = 30 | issuewydanie = 4 | pagesstrony = 821–832 | datedata = April 2005 | pmid = 15702139 | doi = 10.1038/sj.npp.1300667 | quotecytat = Findings from several prior investigations have shown that plasma levels of glucocorticoids and ACTH are increased by acute administration of AMPH in both rodents and humans}}</ref>.

The oral [[bioavailability]] of amphetamine varies with gastrointestinal pH<ref name="FDA Interactions" />; it is well absorbed from the gut, and bioavailability is typically over&nbsp;75% for dextroamphetamine<ref name="Drugbank-dexamph">{{cite encyclopedia | titletytuł=Dextroamphetamine | section-url=http://www.drugbank.ca/drugs/DB01576#pharmacology | praca=DrugBank | publisheropublikowany= University of Alberta | accessdatedata dostępu=5 November 2013 | datedata=8 February 2013 | section=Pharmacology}}</ref>. Amphetamine is a weak base with a [[Acid dissociation constant|p''K''_a]] of 9.9<ref name="FDA Pharmacokinetics">{{cytuj stronę | titletytuł = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | pagesstrony = 12–13 | publisheropublikowany = Shire US Inc | praca = United States Food and Drug Administration |datedata=December 2013 | accessdatedata dostępu = 30 December 2013}}</ref>; consequently, when the pH is basic, more of the drug is in its [[lipid]] soluble [[free base]] form, and more is absorbed through the lipid-rich [[cell membranes]] of the gut [[epithelium]]<ref name="FDA Pharmacokinetics" /><ref name="FDA Interactions" />. Conversely, an acidic pH means the drug is predominantly in a water-soluble [[cation]]ic (salt) form, and less is absorbed<ref name="FDA Pharmacokinetics" />. Approximately {{nowrap|15–40%}} of amphetamine circulating in the bloodstream is bound to [[plasma protein]]s.<ref name="Drugbank-amph">{{cite encyclopedia | titletytuł=Amphetamine | section-url=http://www.drugbank.ca/drugs/DB00182#pharmacology | praca=DrugBank | publisheropublikowany= University of Alberta | accessdatedata dostępu=5 November 2013 | datedata=8 February 2013 | section=Pharmacology}}</ref>

The [[Biological half-life|half-life]] of amphetamine enantiomers differ and vary with urine pH.<ref name="FDA Pharmacokinetics" /> At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are {{nowrap|9–11}}&nbsp;hours and {{nowrap|11–14}}&nbsp;hours, respectively<ref name="FDA Pharmacokinetics" />. An acidic diet will reduce the enantiomer half-lives to {{nowrap|8–11}}&nbsp;hours; an alkaline diet will increase the range to {{nowrap|16–31}}&nbsp;hours<ref name="Pubchem Kinetics" /><ref name="pH-dependent half-lives">{{cite encyclopedia | titletytuł=AMPHETAMINE| section=Metabolism/Pharmacokinetics| section-url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+300-62-9| workpraca=United States National Library of Medicine&nbsp;– Toxicology Data Network| publisheropublikowany=Hazardous Substances Data Bank| accessdatedata dostępu=5 January 2014 |quotecytat= Plasma protein binding, rate of absorption, & volumes of distribution of amphetamine isomers are similar.&nbsp;... The biological half-life of amphetamine is greater in drug dependent individuals than in control subjects, & distribution volumes are increased, indicating that greater affinity of tissues for the drug may contribute to development of amphetamine tolerance.&nbsp;... Concentrations of (14)C-amphetamine declined less rapidly in the plasma of human subjects maintained on an alkaline diet (urinary pH > 7.5) than those on an acid diet (urinary pH < 6). Plasma half-lives of amphetamine ranged between 16-31 hr & 8-11 hr, respectively, & the excretion of (14)C in 24 hr urine was 45 & 70%.}}</ref>. The biological half-life is longer and [[distribution (pharmacology)|distribution]] volumes are larger in amphetamine dependent individuals<ref name="pH-dependent half-lives" />. The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3&nbsp;hours and 7&nbsp;hours post-dose respectively<ref name="FDA Pharmacokinetics" />. Amphetamine is eliminated via the kidneys, with {{nowrap|30–40%}} of the drug being excreted unchanged at normal urinary pH.<ref name="FDA Pharmacokinetics" /> When the urinary pH is basic, amphetamine is in its free base form, so less is excreted<ref name="FDA Pharmacokinetics" />. When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of&nbsp;1% to a high of&nbsp;75%, depending mostly upon whether urine is too basic or acidic, respectively<ref name="FDA Pharmacokinetics" />. Amphetamine is usually eliminated within two days of the last oral dose<ref name="Pubchem Kinetics" />.{{if pagename|Adderall=|Dextroamphetamine=|other=&nbsp;

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract<ref name="FDA Vyvanse">{{cytuj stronę | titletytuł = Vyvanse Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021977s036s037lbledt.pdf | pagesstrony = 12–16 | publisheropublikowany = Shire US Inc | workpraca = United States Food and Drug Administration |datedata=January 2015 | accessdatedata dostępu = 24 February 2015}}</ref>; following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via [[hydrolysis]]<ref name="FDA Vyvanse" />. The elimination half-life of lisdexamfetamine is generally less than one hour.<ref name="FDA Vyvanse" />}}

[[CYP2D6]], [[dopamine β-hydroxylase]] (DBH), [[flavin-containing monooxygenase 3]] (FMO3), [[butyrate-CoA ligase]] (XM-ligase), and [[glycine N-acyltransferase]] (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans.{{#tag:ref|<ref name="FDA Pharmacokinetics" /><ref name="Substituted amphetamines, FMO, and DBH">{{cytuj książkę | autor = Glennon RA |veditors=Lemke TL, Williams DA, Roche VF, Zito W | titletytuł=Foye's principles of medicinal chemistry | datedata=2013 | publisheropublikowany=Wolters Kluwer Health/Lippincott Williams & Wilkins | miejsce=Philadelphia, USA | isbn=9781609133450 | pagesstrony=646–648 | wydanie=7th | section-url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646&q=substituted%20derivatives%20substituents%20hydroxyamphetamine%20flavin%20monooxygenase#v=onepage | accessdatedata dostępu=11 September 2015 | section=Phenylisopropylamine stimulants: amphetamine-related agents | quotecytat=The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39).&nbsp;... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase.&nbsp;... Amphetamine can also undergo aromatic hydroxylation to ''p''-hydroxyamphetamine.&nbsp;... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords ''p''-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.}}</ref><ref name="DBH amph primary">{{citecytuj journalpismo | autor = Taylor KB | titletytuł = Dopamine-beta-hydroxylase. Stereochemical course of the reaction | journalczasopismo = J. Biol. Chem. | volumewolumin = 249 | issuewydanie = 2 | pagesstrony = 454–458 | datedata = January 1974 | pmid = 4809526 | accessdatedata dostępu = 6 November 2014 | url = http://www.jbc.org/content/249/2/454.full.pdf | quotecytat = Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.}}</ref><ref name="DBH 4-HA primary">{{citecytuj journalpismo |vauthors=Horwitz D, Alexander RW, Lovenberg W, Keiser HR | titletytuł = Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity | journalczasopismo = Circ. Res. | volumewolumin = 32 | issuewydanie = 5 | pagesstrony = 594–599 | datedata = May 1973 | pmid = 4713201 | doi = 10.1161/01.RES.32.5.594 | quotecytat = Subjects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascular function and normal β-hydroxylation of an administered synthetic substrate, hydroxyamphetamine.}}</ref><ref name="FMO">{{citecytuj journalpismo |vauthors=Krueger SK, Williams DE | titletytuł = Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism | journalczasopismo = Pharmacol. Ther. | volumewolumin = 106 | issuewydanie = 3 | pagesstrony = 357–387 |datedata=June 2005 | pmid = 15922018 | pmc = 1828602 | doi = 10.1016/j.pharmthera.2005.01.001}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ Table 5: N-containing drugs and xenobiotics oxygenated by FMO]</ref><ref name="FMO3-Primary">{{citecytuj journalpismo |vauthors=Cashman JR, Xiong YN, Xu L, Janowsky A | titletytuł = N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication | journalczasopismo = J. Pharmacol. Exp. Ther. | volumewolumin = 288 | issuewydanie = 3 | pagesstrony = 1251–1260 | datedata = March 1999 |pmid = 10027866}}</ref><ref name="Metabolites" /><ref name="Benzoic1" /><ref name="Benzoic2" />| name="amphetamine metabolism" |group = "sources" }} Amphetamine has a variety of excreted metabolic products, including {{nowrap|[[4-hydroxyamphetamine]]}}, {{nowrap|[[4-hydroxynorephedrine]]}}, {{nowrap|[[4-hydroxyphenylacetone]]}}, [[benzoic acid]], [[hippuric acid]], [[norephedrine]], and [[phenylacetone]]<ref name="FDA Pharmacokinetics" /><ref name="Pubchem Kinetics">{{cite encyclopedia | titletytuł=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#section=Pharmacology-and-Biochemistry | workpraca=Pubchem Compound | publisheropublikowany = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdatedata dostępu=12 October 2013 | section=Pharmacology and Biochemistry}}</ref><ref name="Metabolites">{{citecytuj journalpismo |vauthors=Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G | titletytuł = Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection | journalczasopismo = J. Pharm. Biomed. Anal. | volumewolumin = 30 | issuewydanie = 2 | pagesstrony = 247–255 |datedata=September 2002 | pmid = 12191709 | doi =10.1016/S0731-7085(02)00330-8}}</ref>. Among these metabolites, the active [[sympathomimetics]] are {{nowrap|4‑hydroxyamphetamine}}<ref>{{cite encyclopedia | titletytuł=p-Hydroxyamphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3651 | workpraca=PubChem Compound | publisheropublikowany = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdatedata dostępu=15 October 2013 | section=Compound Summary}}</ref>, {{nowrap|4‑hydroxynorephedrine}}<ref>{{cite encyclopedia | titletytuł=p-Hydroxynorephedrine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11099 | workpraca=PubChem Compound | publisheropublikowany = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdatedata dostępu=15 October 2013 | section=Compound Summary}}</ref>, and norephedrine<ref>{{cite encyclopedia | titletytuł=Phenylpropanolamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=26934 | workpraca=PubChem Compound | publisheropublikowany = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdatedata dostępu=15 October 2013 | section=Compound Summary}}</ref>. The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination<ref name="FDA Pharmacokinetics" /><ref name="Pubchem Kinetics" />. The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

{{Amphetamine Pharmacokinetics|header=Metabolic pathways of amphetamine in humans<ref name="amphetamine metabolism" group = "sources" />|caption=The primary active metabolites of amphetamine are {{nowrap|4-hydroxyamphetamine}} and norephedrine<ref name="Metabolites" />; at normal urine pH, about {{nowrap|30–40%}} of amphetamine is excreted unchanged and roughly&nbsp;50% is excreted as the inactive metabolites (bottom row)<ref name="FDA Pharmacokinetics" />. The remaining {{nowrap|10–20%}} is excreted as the active metabolites<ref name="FDA Pharmacokinetics" />. Benzoic acid is metabolized by {{abbr|XM-ligase|butyrate-CoA ligase}} into an intermediate product, [[benzoyl-CoA]]<ref name="Benzoic1">{{cite encyclopedia| titletytuł=butyrate-CoA ligase| section-url=http://www.brenda-enzymes.info/enzyme.php?ecno=6.2.1.2&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0 | workpraca=BRENDA| publisheropublikowany=Technische Universität Braunschweig.| accessdatedata dostępu=7 May 2014| section=Substrate/Product}}</ref>, which is then metabolized by {{abbr|GLYAT|glycine N-acyltransferase}} into hippuric acid.<ref name="Benzoic2">{{cite encyclopedia | titletytuł=glycine N-acyltransferase| section-url=http://www.brenda-enzymes.info/enzyme.php?ecno=2.3.1.13&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0 | workpraca=BRENDA| publisheropublikowany=Technische Universität Braunschweig.| accessdatedata dostępu=7 May 2014| section=Substrate/Product}}</ref>}}

Amphetamine has a very similar structure and function to the [[wikt:endogenous|endogenous]] trace amines, which are naturally occurring [[neurotransmitter]] molecules produced in the human body and brain<ref name="Miller" /><ref name="Trace Amines" />. Among this group, the most closely related compounds are [[phenethylamine]], the parent compound of amphetamine, and {{nowrap|[[N-methylphenethylamine|''N''-methylphenethylamine]]}}, an [[isomer]] of amphetamine (i.e., it has an identical molecular formula)<ref name="Miller" /><ref name="Trace Amines" /><ref name="Renaissance GPCR">{{citecytuj journalpismo |vauthors=Lindemann L, Hoener MC | tytuł=A renaissance in trace amines inspired by a novel GPCR family | czasopismo=Trends Pharmacol. Sci. | wolumin=26 | wydanie=5 | strony=274–281 |datedata=May 2005 |pmid=15860375 |doi=10.1016/j.tips.2005.03.007 | quotecytat = <!-- In addition to the main metabolic pathway, TAs can also be converted by nonspecific N-methyltransferase (NMT) [22] and phenylethanolamine N-methyltransferase (PNMT) [23] to the corresponding secondary amines (e.g. synephrine [14], N-methylphenylethylamine and N-methyltyramine [15]), which display similar activities on TAAR1 (TA1) as their primary amine precursors. -->}}</ref>. In humans, phenethylamine is produced directly from [[L-phenylalanine]] by the [[aromatic amino acid decarboxylase]] (AADC) enzyme, which converts [[L-DOPA]] into dopamine as well.<ref name="Trace Amines" /><ref name="Renaissance GPCR" /> In turn, {{nowrap|''N''‑methylphenethylamine}} is metabolized from phenethylamine by [[phenylethanolamine N-methyltransferase]], the same enzyme that metabolizes norepinephrine into epinephrine<ref name="Trace Amines">{{citecytuj journalpismo | autor = Broadley KJ | titletytuł = The vascular effects of trace amines and amphetamines | journalczasopismo = Pharmacol. Ther. | volumewolumin = 125 | issuewydanie = 3 | pagesstrony = 363–375 |datedata=March 2010 | pmid = 19948186 | doi = 10.1016/j.pharmthera.2009.11.005 | quotecytat = <!-- '''Fig. 2.''' Synthetic and metabolic pathways for endogenous and exogenously administered trace amines and sympathomimetic amines&nbsp;...<br /> Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2)&nbsp;... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone&nbsp;...<br />Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines&nbsp;... this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut&nbsp;...<br /> Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life&nbsp;... -->}}</ref><ref name="Renaissance GPCR" />. Like amphetamine, both phenethylamine and {{nowrap|''N''‑methylphenethylamine}} regulate monoamine neurotransmission via {{abbr|TAAR1|trace amine-associated receptor 1}}<ref name="Miller" /><ref name="Renaissance GPCR" />; unlike amphetamine, both of these substances are broken down by [[monoamine oxidase B]], and therefore have a shorter half-life than amphetamine<ref name="Trace Amines" /><ref name="Renaissance GPCR" />.

Amphetamine is a [[methyl]] [[homologous series|homolog]] of the mammalian neurotransmitter phenethylamine with the chemical formula {{chemical formula|C|9|H|13|N}}. The carbon atom adjacent to the [[primary amine]] is a [[stereogenic center]], and amphetamine is composed of a racemic 1:1 mixture of two [[enantiomer]]ic mirror images<ref name="DrugBank1">{{cite encyclopedia | title=Amphetamine | section-url=http://www.drugbank.ca/drugs/DB00182#identification | section=Identification | work=DrugBank | publisher= University of Alberta | accessdate=13 October 2013 | date=8 February 2013}}</ref>. This racemic mixture can be separated into its optical isomers:{{#tag:ref|Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation<ref name="Enantiomers" />.|group = "note"}} [[levoamphetamine]] and [[dextroamphetamine]]<ref name="DrugBank1" />. At room temperature, the pure free base of amphetamine is a mobile, colorless, and [[Volatility (chemistry)|volatile]] [[liquid]] with a characteristically strong [[amine]] odor, and acrid, burning taste<ref name="Properties">{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#section=Chemical-and-Physical-Properties | work=PubChem Compound | publisher = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=13 October 2013 | section=Chemical and Physical Properties}}</ref>. Frequently prepared solid salts of amphetamine include amphetamine aspartate<ref name="FDA Abuse & OD" />, hydrochloride<ref>{{cite encyclopedia | title=Amphetamine Hydrochloride | url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=92939 | work = Pubchem Compound | publisher = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate = 8 November 2013}}</ref>, phosphate<ref>{{cite encyclopedia | title=Amphetamine Phosphate | url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=62885 | work=Pubchem Compound | publisher = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=8 November 2013}}</ref>, saccharate<ref name="FDA Abuse & OD" />, and sulfate<ref name="FDA Abuse & OD" />, the last of which is the most common amphetamine salt.<ref name="EMC" /> Amphetamine is also the parent compound of [[Substituted amphetamine|its own structural class]], which includes a number of psychoactive [[derivative (chemistry)|derivatives]]<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="DrugBank1" />. In organic chemistry, amphetamine is an excellent [[chiral ligand]] for the [[stereoselective synthesis]] of {{nowrap|[[1,1'-bi-2-naphthol]]}}<ref name="Chiral Ligand">{{citecytuj journalpismo |vauthors=Brussee J, Jansen AC | datedata = May 1983 | titletytuł = A highly stereoselective synthesis of s(−)-[1,1'-binaphthalene]-2,2'-diol | journalczasopismo = Tetrahedron Lett. | volumewolumin = 24 | issuewydanie = 31 | pagesstrony = 3261–3262 | doi = 10.1016/S0040-4039(00)88151-4}}</ref>.

The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone"<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="Amphetamine - a substituted amphetamine">{{citecytuj journalpismo | vauthors = Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ | titletytuł = Biosynthesis of amphetamine analogs in plants | journalczasopismo = Trends Plant Sci. | volumewolumin = 17 | issuewydanie = 7 | pagesstrony = 404–412 | datedata = 2012 | pmid = 22502775 | doi = 10.1016/j.tplants.2012.03.004 | quotecytat = Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). Countless variation in functional group substitutions has yielded a collection of synthetic drugs with diverse pharmacological properties as stimulants, empathogens and hallucinogens [3].&nbsp;... Beyond (1''R'',2''S'')-ephedrine and (1''S'',2''S'')-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. The stereochemistry at the α-carbon is often a key determinant of pharmacological activity, with (''S'')-enantiomers being more potent. For example, (''S'')-amphetamine, commonly known as d-amphetamine or dextroamphetamine, displays five times greater psychostimulant activity compared with its (''R'')-isomer [78]. Most such molecules are produced exclusively through chemical syntheses and many are prescribed widely in modern medicine. For example, (''S'')-amphetamine (Figure 4b), a key ingredient in Adderall^&reg; and Dexedrine^&reg;, is used to treat attention deficit hyperactivity disorder (ADHD) [79].&nbsp;... <br />;[Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.}}</ref><ref name="Schep">{{citecytuj journalpismo |vauthors=Schep LJ, Slaughter RJ, Beasley DM | titletytuł=The clinical toxicology of metamfetamine | journalczasopismo=Clin. Toxicol. (Phila.) | volumewolumin=48 | issuewydanie=7 | pagesstrony=675–694 |datedata=August 2010 | pmid=20849327 | doi=10.3109/15563650.2010.516752 | issn=1556-3650}}</ref> specifically, this [[Chemical classification|chemical class]] includes [[derivative (chemistry)|derivative]] compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with [[substituent]]s.<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="Amphetamine - a substituted amphetamine" /><ref name="pmid1855720">{{citecytuj journalpismo | vauthors = Lillsunde P, Korte T | titletytuł = Determination of ring- and N-substituted amphetamines as heptafluorobutyryl derivatives | journalczasopismo = Forensic Sci. Int. | volumewolumin = 49 | issuewydanie = 2 | pagesstrony = 205–213 | datedata = March 1991 | pmid = 1855720 | doi=10.1016/0379-0738(91)90081-s}}</ref> The class includes amphetamine itself, stimulants like methamphetamine, serotonergic [[empathogens]] like [[MDMA]], and [[decongestant]]s like [[ephedrine]], among other subgroups<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="Amphetamine - a substituted amphetamine" /><ref name="Schep" />.

Since the first preparation was reported in 1887<ref name="Vermont"/>, numerous synthetic routes to amphetamine have been developed<ref name="Allen_Ely_2009">{{citecytuj journalpismo | url = http://www.nwafs.org/newsletters/2011_Spring.pdf | titletytuł = Review: Synthetic Methods for Amphetamine |vauthors=Allen A, Ely R | work = | publisherwydawca = Northwest Association of Forensic Scientists | volumewolumin = 37 | issuewydanie = 2 | datedata = April 2009 | pagesstrony = 15–25 | journalczasopismo = Crime Scene | accessdatedata dostępu = 6 December 2014}}</ref><ref name="Allen_Cantrell_1989">{{citecytuj journalpismo |vauthors=Allen A, Cantrell TS | titletytuł = Synthetic reductions in clandestine amphetamine and methamphetamine laboratories: A review | journalczasopismo = Forensic Science International | datedata = August 1989 | volumewolumin = 42 | issuewydanie = 3 | pagesstrony = 183–199 | doi = 10.1016/0379-0738(89)90086-8}}</ref>. The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the [[Leuckart reaction]] (method 1)<ref name="EMC"/><ref name="Amph Synth" />. In the first step, a reaction between phenylacetone and [[formamide]], either using additional [[formic acid]] or formamide itself as a reducing agent, yields {{nowrap|[[N-formylamphetamine|''N''-formylamphetamine]]}}. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.<ref name="Amph Synth" /><ref>{{citecytuj journalpismo | doi = 10.1021/jo01145a001 | titletytuł = The Mechanism of the Leuckart Reaction |datedata=May 1951 |vauthors=Pollard CB, Young DC | journalczasopismo = J. Org. Chem. | volumewolumin = 16 | issuewydanie = 5 | pagesstrony = 661–672}}</ref>

A number of [[chiral resolution]]s have been developed to separate the two enantiomers of amphetamine<ref name = "Allen_Ely_2009"/>. For example, racemic amphetamine can be treated with {{nowrap|d-[[tartaric acid]]}} to form a [[diastereoisomer]]ic salt which is [[fractional crystallization (chemistry)|fractionally]] crystallized to yield dextroamphetamine<ref name = "US2276508">{{ cite patent | country = US | number = 2276508 | status = patent | title = Method for the separation of optically active alpha-methylphenethylamine | pubdate = 17 March 1942 | fdate = 3 November 1939 | pridate = 3 November 1939 | inventor = Nabenhauer FP | assign1 = Smith Kline French}}</ref>. Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale<ref name = "Gray_2007"/>. In addition, several [[enantioselective synthesis|enantioselective]] syntheses of amphetamine have been developed. In one example, [[optically pure]] {{nowrap|(''R'')-1-phenyl-ethanamine}} is condensed with phenylacetone to yield a chiral [[Schiff base]]. In the key step, this intermediate is reduced by [[catalytic hydrogenation]] with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the [[benzylic]] amine bond by hydrogenation yields optically pure dextroamphetamine<ref name = "Gray_2007">{{cytuj książkę |veditors=Johnson DS, Li JJ | autor = Gray DL | titletytuł = The Art of Drug Synthesis | rozdział = Approved Treatments for Attention Deficit Hyperactivity Disorder: Amphetamine (Adderall), Methylphenidate (Ritalin), and Atomoxetine (Straterra) | url = https://books.google.com/books?id=zvruBDAulWEC&lpg=PP1&dq=The%20Art%20of%20Drug%20Synthesis%20(Wiley%20Series%20on%20Drug%20Synthesis)&pg=SA17-PA4#v=onepage&q=amphetamine&f=false | rok = 2007 | publisherwydawca = Wiley-Interscience | miejsce = New York, USA | isbn = 9780471752158 | pagestrony = 247}}</ref>.

A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions<ref name="Allen_Ely_2009"/><ref name="Allen_Cantrell_1989"/>. One example is the [[Friedel–Crafts reaction#Friedel–Crafts alkylation|Friedel–Crafts]] alkylation of [[chlorobenzene]] by [[allyl chloride]] to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2)<ref name="pmid20985610">{{citecytuj journalpismo |vauthors=Patrick TM, McBee ET, Hass HB | titletytuł = Synthesis of arylpropylamines; from allyl chloride | journalczasopismo = J. Am. Chem. Soc. | volumewolumin = 68 | issuewydanie = | pagesstrony = 1009–1011 | datedata = June 1946 | pmid = 20985610 | doi = 10.1021/ja01210a032}}</ref>. Another example employs the [[Ritter reaction]] (method 3). In this route, [[allylbenzene]] is reacted [[acetonitrile]] in sulfuric acid to yield an [[organosulfate]] which in turn is treated with sodium hydroxide to give amphetamine via an [[acetamide]] intermediate<ref name="pmid18105933">{{citecytuj journalpismo |vauthors=Ritter JJ, Kalish J | titletytuł = A new reaction of nitriles; synthesis of t-carbinamines | journalczasopismo = J. Am. Chem. Soc. | volumewolumin = 70 | issuewydanie = 12 | pagesstrony = 4048–4050 | datedata = December 1948 | pmid = 18105933 | doi = 10.1021/ja01192a023}}</ref><ref name=Krimen_Cota_1969>{{citecytuj journalpismo | tytuł=The Ritter Reaction|vauthors=Krimen LI, Cota DJ | journalczasopismo = Organic Reactions | datedata = March 2011 | volumewolumin = 17 | pagestrony = 216 | doi = 10.1002/0471264180.or017.03}}</ref>. A third route starts with {{nowrap|[[ethyl acetoacetate|ethyl 3-oxobutanoate]]}} which through a double alkylation with [[methyl iodide]] followed by [[benzyl chloride]] can be converted into {{nowrap|2-methyl-3-phenyl-propanoic}} acid. This synthetic intermediate can be transformed into amphetamine using either a [[Hofmann rearrangement|Hofmann]] or [[Curtius rearrangement]] (method 4)<ref name = "US2413493">{{ cite patent | country = US | number = 2413493 | status = patent | title = Synthesis of isomer-free benzyl methyl acetoacetic methyl ester | pubdate = 31 December 1946 | fdate = 3 June 1943 | pridate = 3 June 1943 | inventor = Bitler WP, Flisik AC, Leonard N | assign1 = Kay Fries Chemicals Inc}}</ref>.

A significant number of amphetamine syntheses feature a [[Organic redox reaction#Organic reductions|reduction]] of a [[nitro group|nitro]], [[imine]], [[oxime]] or other nitrogen-containing [[functional group]]s.<ref name = "Allen_Cantrell_1989"/> In one such example, a [[Knoevenagel condensation]] of [[benzaldehyde]] with [[nitroethane]] yields {{nowrap|[[phenyl-2-nitropropene]]}}. The double bond and nitro group of this intermediate is [[organic redox reaction|reduced]] using either catalytic [[hydrogenation]] or by treatment with [[lithium aluminium hydride]] (method 5)<ref name="Amph Synth">{{citecytuj webstronę | url = http://www.unodc.org/pdf/scientific/stnar34.pdf | titletytuł = Recommended methods of the identification and analysis of amphetamine, methamphetamine, and their ring-substituted analogues in seized materials | pagesstrony = 9–12 | accessdatedata dostępu = 14 October 2013 | rok = 2006 | workpraca = United Nations Office on Drugs and Crime | publisheropublikowany = United Nations}}</ref><ref name="Delta Isotope">{{citecytuj journalpismo |vauthors=Collins M, Salouros H, Cawley AT, Robertson J, Heagney AC, Arenas-Queralt A | titletytuł = δ¹³C and δ²H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane | journalczasopismo = Rapid Commun. Mass Spectrom. | volumewolumin = 24 | issuewydanie = 11 | pagesstrony = 1653–1658 |datedata=June 2010 | pmid = 20486262 | doi = 10.1002/rcm.4563}}</ref>. Another method is the reaction of [[phenylacetone]] with [[ammonia]], producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6)<ref name="Amph Synth" />.

Amphetamine is frequently measured in urine or blood as part of a [[drug test]] for sports, employment, poisoning diagnostics, and forensics.{{#tag:ref|<ref name="Ergogenics" /><ref name="pmid9700558">{{citecytuj journalpismo |vauthors=Kraemer T, Maurer HH | titletytuł = Determination of amphetamine, methamphetamine and amphetamine-derived designer drugs or medicaments in blood and urine | journalczasopismo = J. Chromatogr. B Biomed. Sci. Appl. | volumewolumin = 713 | issuewydanie = 1 | pagesstrony = 163–187 |datedata=August 1998 | pmid = 9700558 | doi = 10.1016/S0378-4347(97)00515-X}}</ref><ref name="pmid17468860">{{citecytuj journalpismo |vauthors=Kraemer T, Paul LD | titletytuł = Bioanalytical procedures for determination of drugs of abuse in blood | journalczasopismo = Anal. Bioanal. Chem. | volumewolumin = 388 | issuewydanie = 7 | pagesstrony = 1415–1435 |datedata=August 2007 | pmid = 17468860 | doi = 10.1007/s00216-007-1271-6}}</ref><ref name="pmid8075776">{{citecytuj journalpismo |vauthors=Goldberger BA, Cone EJ | titletytuł = Confirmatory tests for drugs in the workplace by gas chromatography-mass spectrometry | journalczasopismo = J. Chromatogr. A. | volumewolumin = 674 | issuewydanie = 1–2 | pagesstrony = 73–86 |datedata=July 1994 | pmid = 8075776 | doi = 10.1016/0021-9673(94)85218-9}}</ref>|group="sources"}} Techniques such as [[immunoassay]], which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs<ref name="NAHMSA_testing" />. Chromatographic methods specific for amphetamine are employed to prevent false positive results<ref name="pmid15516295" />. Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., [[selegiline]]), [[over-the-counter drug]] products that contain [[levomethamphetamine]],{{#tag:ref|The active ingredient in some OTC inhalers in the United States is listed as ''levmetamfetamine'', the [[International Nonproprietary Name|INN]] and [[United States Adopted Name|USAN]] of levomethamphetamine<ref name="FDA levmetamfetamine">{{cite encyclopedia | title=Code of Federal Regulations Title 21: Subchapter D – Drugs for human use | section = Part 341 – cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use | section-url=https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=341.80 | website=United States Food and Drug Administration | accessdate=7 March 2016 | date=April 2015 | quote=Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in each 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.}}</ref><ref>{{cite encyclopedia | title=Levomethamphetamine| section=Identification | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604#section=Identification | work=Pubchem Compound| publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=2 January 2014}}</ref>.|name="OTC levmetamfetamine"|group = "note"}} or illicitly obtained substituted amphetamines<ref name="pmid15516295">{{citecytuj journalpismo |vauthors=Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA | titletytuł = Enantiomeric separation and quantitation of (±)-amphetamine, (±)-methamphetamine, (±)-MDA, (±)-MDMA, and (±)-MDEA in urine specimens by GC-EI-MS after derivatization with (''R'')-(−)- or (''S'')-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (MTPA) | journalczasopismo = J. Anal. Toxicol. | volumewolumin = 28 | issuewydanie = 6 | pagesstrony = 449–455 |datedata=September 2004 | pmid = 15516295 | doi = 10.1093/jat/28.6.449}}</ref><ref name="pmid16105261">{{citecytuj journalpismo |vauthors=Verstraete AG, Heyden FV | titletytuł = Comparison of the sensitivity and specificity of six immunoassays for the detection of amphetamines in urine | journalczasopismo = J. Anal. Toxicol. | volumewolumin = 29 | issuewydanie = 5 | pagesstrony = 359–364 | datedata = August 2005 | pmid = 16105261 | doi =10.1093/jat/29.5.359}}</ref><ref name="Baselt_2011">{{cytuj książkę | autor = Baselt RC | titletytuł = Disposition of Toxic Drugs and Chemicals in Man | rok = 2011 | publisherwydawca = Biomedical Publications | miejsce=Seal Beach, USA | isbn = 9780962652387 | pagesstrony = 85–88 | wydanie = 9th}}</ref>. Several prescription drugs produce amphetamine as a [[metabolite]], including [[benzphetamine]], [[clobenzorex]], [[famprofazone]], [[fenproporex]], [[lisdexamfetamine]], [[mesocarb]], methamphetamine, [[prenylamine]], and [[selegiline]], among others<ref name="Amph Uses" /><ref name="pmid10711406">{{citecytuj journalpismo | autor = Musshoff F | titletytuł = Illegal or legitimate use? Precursor compounds to amphetamine and methamphetamine | journalczasopismo = Drug Metab. Rev. | volumewolumin = 32 | issuewydanie = 1 | pagesstrony = 15–44 |datedata=February 2000 | pmid = 10711406 | doi = 10.1081/DMR-100100562}}</ref><ref name="pmid12024689">{{citecytuj journalpismo | autor = Cody JT | titletytuł = Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results | journalczasopismo = J. Occup. Environ. Med. | volumewolumin = 44 | issuewydanie = 5 | pagesstrony = 435–450 |datedata=May 2002 | pmid = 12024689 | doi = 10.1097/00043764-200205000-00012}}</ref>. These compounds may produce positive results for amphetamine on drug tests<ref name="pmid10711406" /><ref name="pmid12024689" />. Amphetamine is generally only detectable by a standard drug test for approximately 24&nbsp;hours, although a high dose may be detectable for two to four days.<ref name="NAHMSA_testing">{{citecytuj webstronę | titletytuł=Clinical Drug Testing in Primary Care | url=http://162.99.3.213/products/manuals/pdfs/TAP32.pdf | workpraca=Substance Abuse and Mental Health Services Administration | publisheropublikowany=United States Department of Health and Human Services | series=Technical Assistance Publication Series 32 | rok=2012 | accessdatedata dostępu=31 October 2013}}</ref>

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist [[Lazăr Edeleanu]] who named it ''phenylisopropylamine''<ref name="Vermont">{{citecytuj webstronę | url=http://healthvermont.gov/adap/meth/brief_history.aspx | titletytuł=Historical overview of methamphetamine | workpraca=Vermont Department of Health | publisheropublikowany=Government of Vermont | accessdatedata dostępu=29 January 2012}}</ref><ref>{{cytuj książkę | autor = Rassool GH | titletytuł=Alcohol and Drug Misuse: A Handbook for Students and Health Professionals | rok=2009 | publisherwydawca=Routledge | miejsce=London, England | isbn=9780203871171 | pagestrony=113}}</ref><ref name="SynthHistory" />; its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have [[sympathomimetic]] properties<ref name="SynthHistory">{{citecytuj journalpismo |vauthors=Sulzer D, Sonders MS, Poulsen NW, Galli A | tytuł=Mechanisms of neurotransmitter release by amphetamines: a review | czasopismo=Prog. Neurobiol. | wolumin=75 | wydanie=6 | strony=406–433 |datedata=April 2005 |pmid=15955613 |doi=10.1016/j.pneurobio.2005.04.003 |url=}}</ref>. Amphetamine had no pharmacological use until 1934, when [[Smith, Kline and French]] began selling it as an [[inhaler]] under the trade name [[History of Benzedrine|Benzedrine]] as a decongestant<ref name="Benzedrine">{{citecytuj journalpismo | autor=Rasmussen N | titletytuł=Making the first anti-depressant: amphetamine in American medicine, 1929–1950 | journalczasopismo=J . Hist. Med. Allied Sci. | volumewolumin=61 | issuewydanie=3 | pagesstrony=288–323 |datedata=July 2006 | pmid=16492800 | doi=10.1093/jhmas/jrj039}}</ref>. Benzedrine sulfate was introduced three years later and found a wide variety of medical applications, including narcolepsy<ref name="Benzedrine" /><ref name="pmid20997404">{{citecytuj journalpismo | vauthors = Bett WR | titletytuł = Benzedrine sulphate in clinical medicine; a survey of the literature | journalczasopismo = Postgrad. Med. J. | volumewolumin = 22 | issuewydanie = | pagesstrony = 205–218 | datedata = August 1946 | pmid = 20997404 | pmc = 2478360 | doi = 10.1136/pgmj.22.250.205| url =}}</ref>. During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects<ref name="Vermont" /><ref>{{citecytuj journalpismo | autor = Rasmussen N | titletytuł=Medical science and the military: the Allies' use of amphetamine during World War II | journalczasopismo=J. Interdiscip. Hist. | datedata=August 2011 | volumewolumin=42 | issuewydanie=2 | pagesstrony=205–233 | pmid=22073434 | doi=10.1162/JINH_a_00212}}</ref><ref name="pmid22849208">{{citecytuj journalpismo |vauthors=Defalque RJ, Wright AJ | titletytuł = Methamphetamine for Hitler's Germany: 1937 to 1945 | journalczasopismo = Bull. Anesth. Hist. | volumewolumin = 29 | issuewydanie = 2 | pagesstrony = 21–24, 32 |datedata=April 2011 | pmid = 22849208 | doi = 10.1016/s1522-8649(11)50016-2}}</ref>. As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine<ref name="Vermont" />. For example, during the early 1970s in the United States, amphetamine became a [[Schedule II (US)|schedule II controlled substance]] under the [[Controlled Substances Act]]<ref>{{citecytuj webstronę | titletytuł=Controlled Substances Act | url=http://www.fda.gov/regulatoryinformation/legislation/ucm148726.htm | publisheropublikowany=United States Food and Drug Administration | datedata=11 June 2009 | accessdatedata dostępu=4 November 2013}}</ref>. In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors<ref>{{citecytuj webstronę | authorautor = Gyenis A | workpraca = wordsareimportant.com | publisheropublikowany = DHARMA beat | titletytuł = Forty Years of ''On the Road'' 1957–1997| url = http://www.wordsareimportant.com/ontheroad.htm | accessdatedata dostępu = 18 March 2008 | archiveurl = https://web.archive.org/web/20080214171739/http://www.wordsareimportant.com/ontheroad.htm | archivedate = 14 February 2008}}</ref>, musicians<ref>{{citecytuj webstronę | titletytuł = Mixing the Medicine: The unintended consequence of amphetamine control on the Northern Soul Scene | authorautor = Wilson A | url = http://www.internetjournalofcriminology.com/Wilson%20-%20Mixing%20the%20Medicine.pdf | publisheropublikowany = Internet Journal of Criminology | rok = 2008 | accessdatedata dostępu=25 May 2013}}</ref>, mathematicians<ref>{{citecytuj webstronę | titletytuł = Paul Erdos, Mathematical Genius, Human (In That Order) |url = http://www.untruth.org/~josh/math/Paul%20Erd%F6s%20bio-rev2.pdf | authorautor = Hill J | accessdatedata dostępu = 2 November 2013 | datedata = 4 June 2004}}</ref>, and athletes<ref name="Ergogenics" />.

Amphetamine is still illegally synthesized today in [[clandestine chemistry|clandestine labs]] and sold on the [[black market]], primarily in European countries<ref name="WDR2014">{{citecytuj webstronę | titletytuł = World Drug Report 2014 | editor = Mohan J | datedata = June 2014 | pagestrony = 3 | workpraca = United Nations Office on Drugs and Crime | url = https://www.unodc.org/documents/wdr2014/World_Drug_Report_2014_web.pdf | accessdatedata dostępu = 18 August 2014}}</ref>. Among European Union (EU) member states, 1.2&nbsp;million young adults used illicit amphetamine or methamphetamine in 2013.<ref name="EMCDDA 2014">{{citecytuj journalpismo | titletytuł=European drug report 2014: Trends and developments | datedata=May 2014 | pagesstrony=13, 24 | doi=10.2810/32306 | url=http://www.emcdda.europa.eu/attachements.cfm/att_228272_EN_TDAT14001ENN.pdf | accessdatedata dostępu=18 August 2014 | publisherwydawca=European Monitoring Centre for Drugs and Drug Addiction | miejsce=Lisbon, Portugal | format=PDF | issn=2314-9086 | quotecytat=1.2 million or 0.9% of young adults (15–34) used amphetamines in the last year}}</ref> During 2012, approximately 5.9&nbsp;[[metric ton]]s of illicit amphetamine were seized within EU member states<ref name="EMCDDA 2014" />; the "street price" of illicit amphetamine within the EU ranged from [[Euro|€]]6–38&nbsp;per gram during the same period<ref name="EMCDDA 2014" />. Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA<ref name="WDR2014" />.

As a result of the [[United Nations]] 1971 [[Convention on Psychotropic Substances]], amphetamine became a schedule II controlled substance, as defined in the treaty, in all (183) state parties<ref name="UN Convention">{{citecytuj webstronę| tytuł=Convention on psychotropic substances |url=http://treaties.un.org/Pages/ViewDetails.aspx?src=TREATY&mtdsg_no=VI-16&chapter=6&lang=en |archive-url=https://web.archive.org/web/20160331074842/https://treaties.un.org/pages/ViewDetails.aspx?src=TREATY&mtdsg_no=VI-16&chapter=6&lang=en |archive-date=31 March 2016 | praca=United Nations Treaty Collection | wydawca=United Nations | data dostępu=11 November 2013 |deadurl=no |df=dmy}}</ref>. Consequently, it is heavily regulated in most countries<ref name="UNODC2007">{{cytuj książkę | authorautor = United Nations Office on Drugs and Crime | titletytuł = Preventing Amphetamine-type Stimulant Use Among Young People: A Policy and Programming Guide | publisherwydawca = United Nations | miejsce = New York, USA | rok = 2007 | isbn = 9789211482232 | url = http://www.unodc.org/pdf/youthnet/ATS.pdf | accessdatedata dostępu = 11 November 2013}}</ref><ref>{{citecytuj webstronę | titletytuł = List of psychotropic substances under international control | workpraca = International Narcotics Control Board | publisheropublikowany = United Nations | url = http://www.incb.org/pdf/e/list/green.pdf | accessdatedata dostępu = 19 November 2005 | archiveurl = https://web.archive.org/web/20051205125434/http://www.incb.org/pdf/e/list/green.pdf | archivedate= 5 December 2005 |datedata=August 2003}}</ref>. Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use<ref name="urlMoving to Korea brings medical, social changes">{{citecytuj webstronę | url = https://www.koreatimes.co.kr/www/news/nation/2012/10/319_111757.html | titletytuł = Moving to Korea brings medical, social changes | workpraca = The Korean Times | datedata = 25 May 2012 | accessdatedata dostępu = 14 November 2013 | authorautor = Park Jin-seng}}</ref><ref>{{citecytuj webstronę | url = http://www.mhlw.go.jp/english/topics/import/ | titletytuł = Importing or Bringing Medication into Japan for Personal Use | workpraca = Japanese Ministry of Health, Labour and Welfare | accessdatedata dostępu=3 November 2013 | datedata=1 April 2004}}</ref>. In other nations, such as Canada ([[Controlled Drugs and Substances Act|schedule I drug]])<ref name="Canada Control">{{citecytuj webstronę|url=http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-24.html#h-28 | tytuł=Controlled Drugs and Substances Act | praca=Canadian Justice Laws Website | wydawca=Government of Canada | data dostępu=11 November 2013 |deadurl=yes |archiveurl=https://web.archive.org/web/20131122143804/http://laws-lois.justice.gc.ca/eng/acts/C%2D38.8/page-24.html |archivedate=22 November 2013}}</ref>, the Netherlands ([[Opium Law|List I drug]])<ref name="Opiumwet">{{citecytuj webstronę | url = http://wetten.overheid.nl/BWBR0001941/geldigheidsdatum_03-08-2009 | titletytuł = Opiumwet | publisheropublikowany = Government of the Netherlands | accessdatedata dostępu = 3 April 2015}}</ref>, the United States ([[List of Schedule II drugs (US)|schedule II drug]])<ref name="FDA Abuse & OD" />, Australia ([[Standard for the Uniform Scheduling of Medicines and Poisons#Schedule 8 Controlled Drug|schedule 8]])<ref>{{cite encyclopedia | title = Poisons Standard | section = Schedule 8 | section-url = https://www.comlaw.gov.au/Details/F2015L01534/Html/Text#_Toc420496378 | url = https://www.comlaw.gov.au/Details/F2015L01534/Html/Text | publisher = Australian Government Department of Health | accessdate = 15 December 2015 | date = October 2015}}</ref>, Thailand ([[Law of Thailand#Criminal Law|category 1 narcotic]])<ref>{{citecytuj webstronę | url = http://narcotic.fda.moph.go.th/faq/upload/Thai%20Narcotic%20Act%202012.doc._37ef.pdf | archiveurl=https://web.archive.org/web/20140308001155/http://narcotic.fda.moph.go.th/faq/upload/Thai%20Narcotic%20Act%202012.doc._37ef.pdf | titletytuł = Table of controlled Narcotic Drugs under the Thai Narcotics Act | workpraca = Thailand Food and Drug Administration | datedata = 22 May 2013 | accessdatedata dostępu = 11 November 2013 | archivedate=8 March 2014}}</ref>, and United Kingdom ([[Misuse of Drugs Act 1971|class B drug]])<ref>{{citecytuj webstronę | titletytuł = Class A, B and C drugs | workpraca = Home Office, Government of the United Kingdom | url = http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/ | accessdatedata dostępu = 23 July 2007 | archiveurl = https://web.archive.org/web/20070804233232/http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/ | archivedate = 4 August 2007}}</ref>, amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment<ref name="WDR2014" /><ref name="Nonmedical">{{citecytuj journalpismo |vauthors=Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S | titletytuł = Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature | journalczasopismo = J. Am. Acad. Child Adolesc. Psychiatry | volumewolumin = 47 | issuewydanie = 1 | pagesstrony = 21–31 |datedata=January 2008 | pmid = 18174822 | doi = 10.1097/chi.0b013e31815a56f1 | quotecytat=Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile)&nbsp;...<br />.<br />Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.}}</ref>

| Adzenys XR || amphetamine || 3:1&nbsp;<small>(base)</small> || [[Orally disintegrating tablet|ODT]] || 2016 ||<ref name="Adzenys">{{citecytuj webstronę | titletytuł=Adzenys XR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204326s000lbl.pdf | website = United States Food and Drug Administration | publisheropublikowany=Neos Therapeutics, Inc. | accessdatedata dostępu=7 March 2016 | pagestrony=15 | datedata=January 2016 | quotecytat = ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.}}</ref><ref name="FDA Adzenys approval date">{{citecytuj webstronę | titletytuł=Adzenys XR | url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Adzenys&SearchType=BasicSearch | website=United States Food and Drug Administration | accessdatedata dostępu=7 March 2016}}</ref>

| Dyanavel&nbsp;XR || amphetamine || 3.2:1&nbsp;<small>(base)</small> || suspension || 2015 ||<ref name="Dyanavel" /><ref name="FDA Dyanavel approval date">{{citecytuj webstronę | titletytuł=Dyanavel XR| url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Dyanavel&SearchType=BasicSearch | website=United States Food and Drug Administration | accessdatedata dostępu=1 January 2016}}</ref>

| Evekeo || amphetamine&nbsp;sulfate || 1:1&nbsp;<small>(salts)</small> || tablet || 2012 ||<ref name="Evekeo">{{citecytuj webstronę | titletytuł=Evekeo Prescribing Information | url=https://www.evekeo.com/assets/evekeo-pi.pdf | publisheropublikowany=Arbor Pharmaceuticals LLC | accessdatedata dostępu=11 August 2015 | pagesstrony=1–2 | datedata=April 2014}}</ref><ref name="Racemic amph - FDA Evekeo status">{{citecytuj webstronę | titletytuł=Evekeo | url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Evekeo&SearchType=BasicSearch | website=United States Food and Drug Administration | accessdatedata dostępu=11 August 2015}}</ref>

| Vyvanse || lisdexamfetamine&nbsp;dimesylate || 1:0&nbsp;<small>(prodrug)</small> || capsule || 2007 ||<ref name="Amph Uses">{{citecytuj journalpismo |vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ | titletytuł = Amphetamine, past and present – a pharmacological and clinical perspective | journalczasopismo = J. Psychopharmacol. | volumewolumin = 27 | issuewydanie = 6 | pagesstrony = 479–496 |datedata=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 | quotecytat = The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation.&nbsp;... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).}}</ref><ref name="Vyvanse">{{cite encyclopedia | title=Lisdexamfetamine | section-url=http://www.drugbank.ca/drugs/DB01255#identification | work=Drugbank | publisher= University of Alberta | accessdate=13 October 2013 | date=8 February 2013 | section=Identification}}</ref>