View source for Amphetamine

{{Short description|Central nervous system stimulant}}
{{About|mixtures of levoamphetamine and dextroamphetamine|other uses}}
{{Pp-semi-indef|small=yes}}
{{Use dmy dates|date=May 2025}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Watchedfields = correct
| Verifiedfields = correct
| verifiedrevid = 851154960r
| INN = Amfetamine
| image = Amphetamine.svg
| image_class = skin-invert-image
| width = 300
| alt = An image of the amphetamine compound
| width2 = 300

<!-- Clinical data -->| imageL = Dexedrine.png
| widthL = 180
| imageR = Cydril.png
| widthR = 180
| pronounce = {{IPAc-en|audio=En-us-amphetamine.ogg|æ|m|ˈ|f|ɛ|t|ə|m|iː|n}}
| tradename = Evekeo, [[Adderall]],{{#tag:ref|Adderall and other mixed amphetamine salts products such as Mydayis are not [[Racemic mixture|racemic]] amphetamine – they are a mixture composed of equal parts racemate and [[dextroamphetamine]].<br />
''See [[Mixed amphetamine salts]] for more information about the mixture, and [[#Pharmaceutical products|this section]] for information about the various mixtures of amphetamine [[enantiomer]]s marketed.''|name=AdderallDiff|group=note}} [[#Pharmaceutical products|others]]
| MedlinePlus = a616004
| DailyMedID = Amphetamine
| Drugs.com = {{Drugs.com|monograph|amphetamine-sulfate}}
| dependency_liability = [[Physical dependence|Physical]]: None<br />[[Psychological dependence|Psychological]]: Moderate<ref name="Stahl's Essential Psychopharmacology" />
| addiction_liability = Moderate<!-- PLEASE NOTE: countless sources state that amphetamine has a "High" abuse liability. This term is not synonymous with "addiction liability", which is the relative risk (compared to other addictive drugs) of developing an addiction (aka "substance use disorder") when it's used as prescribed or recreationally. -->
| routes_of_administration = Medical: [[Oral administration|Oral]]<br />Recreational: [[Oral administration|Oral]], [[Insufflation (medicine)|insufflation]], [[Rectal administration|rectal]], [[Intramuscular injection|intramuscular]], [[Intravenous therapy|intravenous]]
| class = {{plainlist| 
*[[Stimulant]],
*[[anorectic]]}}
| ATC_prefix = N06
| ATC_suffix = BA01
| ATC_supplemental = {{ATC|N06|BA02}} {{ATC|N06|BA12}}

<!-- Legal status -->| legal_AU = Schedule 8
| legal_BR = A3
| legal_BR_comment = 
| legal_CA = Schedule I
| legal_DE = Anlage III
| legal_NZ = Class B
| legal_UK = Class B
| legal_US = [[List of Schedule II controlled substances (U.S.)|Schedule II]]<ref name=":USAS2">{{Cite web | vauthors = Ingersoll J |date=7 July 1971 |title=Amphetamine, Methamphetamine, and Optical Isomers |url=https://archives.federalregister.gov/issue_slice/1971/7/7/12730-12734.pdf |url-status=live |archive-url= https://archive.today/20241127164332/https://archives.federalregister.gov/issue_slice/1971/7/7/12730-12734.pdf |archive-date=27 November 2024 |access-date=27 November 2024 |website=[[Federal Register]]|publisher=[[Bureau of Narcotics and Dangerous Drugs]]}}</ref>
| legal_UN = Psychotropic Schedule II
| legal_status = <!-- Physiological data -->
| target_tissues = 
| receptors = [[Trace amine-associated receptor 1|TAAR1]], [[VMAT2]], [[5HT1A]]

<!-- Pharmacokinetic data -->| bioavailability = Oral: {{nowrap|~90%}}<ref name="Antunes_2022" />
| protein_bound = {{nowrap|20%}}<ref name="Drugbank-amph" />
| metabolism = [[CYP2D6]],<ref name="FDA Pharmacokinetics" /> [[Dopamine β-hydroxylase|DBH]],<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="DBH amph primary" /> [[Flavin-containing monooxygenase 3|FMO3]]<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="FMO" /><ref name="FMO3-Primary" />
| metabolites = {{nowrap|[[4-hydroxyamphetamine]]}}, {{nowrap|[[4-hydroxynorephedrine]]}}, {{nowrap|[[4-hydroxyphenylacetone]]}}, [[benzoic acid]], [[hippuric acid]], [[norephedrine]], [[phenylacetone]]<ref name="FDA Pharmacokinetics" /><ref name="Metabolites"/>
| onset = {{abbr|IR|Immediate release}} dosing: {{nowrap|30–60}}&nbsp;minutes<ref name="Medscape Adderall Pharmacology">{{cite encyclopedia |title=amphetamine/dextroamphetamine |section=Pharmacology |section-url=https://reference.medscape.com/drug/adderall-mydayis-amphetamine-dextroamphetamine-342997 |publisher=Medscape - WebMD |access-date=21 January 2016 |quote= Onset of action: 30–60 min}}</ref><br />{{abbr|XR|Extended release}} dosing: {{nowrap|1.5–2}}&nbsp;hours<ref name="Millichap: onset, peak, and duration">{{cite book | vauthors = Millichap JG | veditors = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD | year = 2010 | publisher = Springer | location = New York | isbn = 978-1-4419-1396-8 | page = 112 |edition = 2nd | chapter = Chapter 9: Medications for ADHD | quote = <br />Table 9.2 Dextroamphetamine formulations of stimulant medication<br />Dexedrine [Peak:2–3&nbsp;h] [Duration:5–6&nbsp;h]&nbsp;...<br />Adderall [Peak:2–3&nbsp;h] [Duration:5–7&nbsp;h]<br />Dexedrine spansules [Peak:7–8&nbsp;h] [Duration:12&nbsp;h]&nbsp;...<br />Adderall XR [Peak:7–8&nbsp;h] [Duration:12&nbsp;h]<br />Vyvanse [Peak:3–4&nbsp;h] [Duration:12&nbsp;h]}}</ref><ref name="XR onset-duration">{{cite journal | vauthors = Brams M, Mao AR, Doyle RL | title = Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder | journal =Postgraduate Medicine| volume = 120 | issue = 3 | pages = 69–88 | date = September 2008 | pmid = 18824827 | doi = 10.3810/pgm.2008.09.1909| s2cid = 31791162 }}</ref>
| elimination_half-life = {{nowrap|{{abbr|D-amph|dextroamphetamine}}}}: {{nowrap|9–11}}&nbsp;hours<ref name="FDA Pharmacokinetics" /><ref name="Adderall IR">{{cite web | title=Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet | website=DailyMed | publisher = Teva Pharmaceuticals USA, Inc. | date=8 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f22635fe-821d-4cde-aa12-419f8b53db81 | access-date=22 December 2019}}</ref><br />{{nowrap|{{abbr|L-amph|levoamphetamine}}}}: {{nowrap|11–14}}&nbsp;hours<ref name="FDA Pharmacokinetics" /><ref name="Adderall IR" /><br />[[pH]]-dependent: {{nowrap|7–34}}&nbsp;hours<ref name="HSDB Toxnet October 2017 Full archived record" />
| duration_of_action = {{abbr|IR|Immediate release}} dosing: {{nowrap|3–6}}&nbsp;hours<ref name="Stahl's Essential Psychopharmacology" /><ref name="Millichap: onset, peak, and duration" /><ref name="Narcolepsy guide" /><br /> {{abbr|XR|Extended release}} dosing: {{nowrap|8–12}}&nbsp;hours<ref name="Stahl's Essential Psychopharmacology" /><ref name="Millichap: onset, peak, and duration" /><ref name="Narcolepsy guide" />
| excretion = Primarily [[renal]];<br />[[pH]]-dependent {{nowrap|range: 1–75%}}<ref name="FDA Pharmacokinetics" />

<!-- Identifiers -->| IUPAC_name = <div class="center">(''RS'')-1-phenylpropan-2-amine</div>
| synonyms = α-methylphenethylamine, β-phenylisopropylamine, thyramine
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 300-62-9
| PubChem = 3007
| IUPHAR_ligand = 4804
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00182
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 13852819
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = CK833KGX7E
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07445
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 2679
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 405
| NIAID_ChemDB = 018564
| PDB_ligand = <!-- Chemical and physical data -->
| C = 9
| H = 13
| N = 1
| chirality = [[Racemic mixture]]<ref name="Proper definition" />
| density = .936
| density_notes = at 25&nbsp;°C<ref name="PubChem - amphetamine density">{{cite encyclopedia |title=Amphetamine | section=Density |url=https://pubchem.ncbi.nlm.nih.gov/compound/amphetamine |section-url=https://pubchem.ncbi.nlm.nih.gov/compound/amphetamine#section=Density |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information. PubChem Compound Database |access-date=9 November 2016 | date=5 November 2016}}</ref>
| melting_point = 146
| melting_notes = <ref name="CAS Common Chemistry - Amphetamine">{{cite encyclopedia |url=https://commonchemistry.cas.org/detail?cas_rn=300-62-9 |publisher=American Chemical Society. CAS Common Chemistry |title=Amphetamine |access-date=25 October 2022}}</ref>
| boiling_point = 203
| boiling_notes = at 760&nbsp;[[Millimeter of mercury|mmHg]]<ref name="Properties" />
| SMILES = NC(C)Cc1ccccc1
| StdInChI = 1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3
| StdInChIKey = KWTSXDURSIMDCE-UHFFFAOYSA-N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
}}

'''Amphetamine'''{{#tag:ref|''Amphetamine'' is contracted from [[Alpha and beta carbon|<u>a</u>lpha]]-[[methylphenethylamine|<u>m</u>ethyl<u>ph</u>en<u>et</u>hyl<u>amine</u>]]. Synonyms and alternate spellings include: {{nowrap|'''1-phenylpropan-2-amine'''}} ([[International Union of Pure and Applied Chemistry|IUPAC]] name), {{nowrap|'''α-methylphenethylamine'''}}, '''amfetamine''' ([[International Nonproprietary Name|International Nonproprietary Name [INN]]]), {{nowrap|'''β-phenylisopropylamine'''}}, '''thyramine''', and '''speed'''.<ref name="PubChem Header" /><ref name="Drugbank-amph" /><ref name="Acute amph toxicity" />| group = "note" }} is a [[central nervous system]] (CNS) [[stimulant]] that is used in the treatment of [[attention deficit hyperactivity disorder]] (ADHD), [[narcolepsy]], and [[obesity]]; it is also used to treat [[binge eating disorder]] in the form of its inactive [[prodrug]] [[lisdexamfetamine]]. Amphetamine was discovered as a chemical in 1887 by [[Lazăr Edeleanu]], and then as a drug in the late 1920s. It exists as two [[enantiomer]]s:{{#tag:ref|Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.<ref name="Enantiomers">{{cite book |title=IUPAC Compendium of Chemical Terminology |chapter=Enantiomer |publisher=International Union of Pure and Applied Chemistry. IUPAC Goldbook |year=2009 |doi=10.1351/goldbook.E02069 |isbn=978-0-9678550-9-7 |chapter-url=http://goldbook.iupac.org/E02069.html |archive-url=https://web.archive.org/web/20130317002318/http://goldbook.iupac.org/E02069.html |access-date=14 March 2014 |archive-date=17 March 2013 |quote=One of a pair of molecular entities which are mirror images of each other and non-superposable.}}</ref><br />Levoamphetamine and dextroamphetamine are also known as {{nowrap|L-amph}} or levamfetamine ([[International Nonproprietary Name|INN]]) and {{nowrap|D-amph}} or dexamfetamine (INN) respectively.<ref name="PubChem Header" />|group = "note"}} [[levoamphetamine]] and [[dextroamphetamine]]. ''Amphetamine'' properly refers to a specific chemical,<!-- REFS:<ref name="MeSHAmphetamine" /> --> the [[Racemic mixture|racemic]] [[free base]],<!-- REFS:<ref name="WHO INN active moiety" /><ref name="Proper definition" /> --> which is equal parts of the two enantiomers in their pure [[amine]] forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone.<!-- REFS:<ref name="Drugbank-amph" /><ref name="MeSHAmphetamine" /><ref name="Proper definition" /> --> Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an [[Performance-enhancing substance|athletic performance enhancer]] and [[Nootropic|cognitive enhancer]], and recreationally as an [[aphrodisiac]] and [[Euphoria#Euphoriant|euphoriant]]. It is a [[prescription drug]] in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.{{#tag:ref|<ref name="Amph Uses" /><ref>{{cite journal | vauthors = Rasmussen N | title = Amphetamine-Type Stimulants: The Early History of Their Medical and Non-Medical Uses | journal = International Review of Neurobiology | volume = 120 | pages = 9–25 | date = January 2015 | pmid = 26070751 | doi = 10.1016/bs.irn.2015.02.001 | publisher = Academic Press | veditors = Taba P, Lees A, Sikk K | series = The Neuropsychiatric Complications of Stimulant Abuse | hdl = 1959.4/unsworks_47518 }}</ref><ref name="Proper definition">{{cite book | vauthors = Yoshida T | veditors = Klee H | title = Amphetamine Misuse: International Perspectives on Current Trends | date = 1997 | publisher = Harwood Academic Publishers | location = Amsterdam, Netherlands | isbn = 978-90-5702-081-0 | page = [https://archive.org/details/amphetaminemisus0000unse/page/2 2] | chapter-url = https://books.google.com/books?id=gVw_wzZU4x8C&pg=PA2| chapter = Chapter 1: Use and Misuse of Amphetamines: An International Overview | quote = Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane.&nbsp;... In its broadest context, however, the term [''amphetamines''] can even embrace a large number of structurally and pharmacologically related substances. | url = https://archive.org/details/amphetaminemisus0000unse/page/2 }}</ref><ref name="Malenka_2009" /><ref name="Ergogenics" /><ref name="FDA" /><ref name="Benzedrine" /><ref name="UN Convention" /><ref name="Nonmedical" /><ref name="Libido" /><ref name="MeSHAmphetamine">{{cite web | title = Amphetamine | url = https://meshb.nlm.nih.gov/#/record/ui?name=Amphetamine | website = Medical Subject Headings | publisher = United States National Library of Medicine | access-date = 16 December 2013}}</ref><ref name="WHO INN active moiety">{{cite web | title = Guidelines on the Use of International Nonproprietary Names (INNS) for Pharmaceutical Substances | url = http://apps.who.int/medicinedocs/en/d/Jh1806e/2.4.html | archive-url = https://web.archive.org/web/20150109232455/http://apps.who.int/medicinedocs/en/d/Jh1806e/2.4.html | archive-date = 9 January 2015 | publisher = World Health Organization | access-date = 1 December 2014 | date = 1997 | quote = In principle, INNs are selected only for the active part of the molecule which is usually the base, acid or alcohol. In some cases, however, the active molecules need to be expanded for various reasons, such as formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection of INN decided to adopt a new policy for naming such molecules. In future, names for different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule.&nbsp;... The latter are called modified INNs (INNMs).}}</ref><ref name="Evekeo" /><ref name="BED rapid review" />|group="sources"}}

The first amphetamine pharmaceutical was [[History of Benzedrine|Benzedrine]], a brand which was used to treat a variety of conditions. [[#Pharmaceutical products|Pharmaceutical amphetamine]] is prescribed as racemic amphetamine, [[Adderall]],{{#tag:ref|The brand name '''Adderall''' is used throughout this article to refer to the amphetamine four-salt mixture it contains (dextroamphetamine sulfate 25%, dextroamphetamine saccharate 25%, amphetamine sulfate 25%, and amphetamine aspartate 25%). The nonproprietary name, which lists all four active constituent chemicals, is excessively lengthy.<ref name="NDCD">{{cite web | title = National Drug Code Amphetamine Search Results | url = https://www.accessdata.fda.gov/scripts/cder/ndc/results.cfm?beginrow=1&numberperpage=160&searchfield=amphetamine&searchtype=ActiveIngredient&OrderBy=ProprietaryName | website = National Drug Code Directory| publisher=United States Food and Drug Administration | access-date = 16 December 2013 | archive-url = https://web.archive.org/web/20131216080856/https://www.accessdata.fda.gov/scripts/cder/ndc/results.cfm?beginrow=1&numberperpage=160&searchfield=amphetamine&searchtype=ActiveIngredient&OrderBy=ProprietaryName | archive-date=16 December 2013 }}</ref>|name="UseOfAdderallName"| group="note"}} [[dextroamphetamine]], or the inactive [[prodrug]] [[lisdexamfetamine]]. Amphetamine increases [[monoamine neurotransmitter|monoamine]] and [[Neurotransmitter#Excitatory and inhibitory|excitatory]] [[neurotransmission]] in the brain, with its most pronounced effects targeting the [[norepinephrine]] and [[dopamine]] [[neurotransmitter system]]s.{{#tag:ref|<ref name="Amph Uses" /><ref name="Adderall IR" /><ref name="Malenka_2009" /><ref name="Benzedrine" /><ref name="Evekeo" /><ref name="Miller" /><ref name="Miller+Grandy 2016" />|group="sources"}}

At therapeutic doses, amphetamine causes emotional and cognitive effects such as [[euphoria]], change in [[libido|desire for sex]], increased [[wakefulness]], and improved [[Executive functions|cognitive control]]. It induces physical effects such as improved reaction time, fatigue resistance, [[decreased appetite]], elevated heart rate, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce [[Rhabdomyolysis|rapid muscle breakdown]]. [[Addiction]] is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in [[Stimulant psychosis#Amphetamines|psychosis]] (e.g., [[hallucination]]s, [[delusion]]s, and [[paranoia]]) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.{{#tag:ref|<ref name="Adderall IR" /><ref name="Malenka_2009" /><ref name="Ergogenics" /><ref name="FDA" /><ref name="Libido" /><ref name="Westfall" /><ref name="Cochrane" /><ref name="Amphetamine-induced psychosis" /><ref name="Stimulant Misuse" /><ref name="Long-Term Outcomes Medications" /><ref name="NHMH_3e-Addiction doses" /><ref name="Addiction risk" /><ref name="narcolepsy addiction" />|group="sources"}}

Amphetamine belongs to the [[substituted phenethylamine|phenethylamine class]]. It is also the parent compound of its own structural class, the [[substituted amphetamine]]s,{{#tag:ref|The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines,<ref name="Substituted amphetamines, FMO, and DBH" /> the "amphetamines" class does not have a standardized definition in academic literature.<ref name="Proper definition" /> One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine.<ref name="Proper definition" /> The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds.<ref name="Proper definition" /><br />Due to confusion that may arise from use of the plural form, this article will only use the terms "amphetamine" and "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for its structural class.|group="note"}} which includes prominent substances such as [[bupropion]], [[cathinone]], [[MDMA]], and [[methamphetamine]]. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring [[trace amine]] neuromodulators, specifically [[phenethylamine]] and {{nowrap|[[N-Methylphenethylamine|''N''-methylphenethylamine]]}}, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while {{nowrap|''N''-methylphenethylamine}} is a [[Structural isomer|positional isomer]] of amphetamine that differs only in the placement of the [[methyl group]].{{#tag:ref|<ref name="Trace Amines" /><ref name="EMC">{{cite web | title = Amphetamine | url = http://www.emcdda.europa.eu/publications/drug-profiles/amphetamine | website = European Monitoring Centre for Drugs and Drug Addiction | access-date = 19 October 2013}}</ref><ref name="Amphetamine - a substituted amphetamine" />|group="sources"}}

{{TOC limit|3}}

==Uses==

===Medical===
<noinclude>Amphetamine is used to treat [[attention deficit hyperactivity disorder]] (ADHD), [[narcolepsy]], [[obesity]], and, in the form of [[lisdexamfetamine]], [[binge eating disorder]].<ref name="Stahl's Essential Psychopharmacology" /><ref name="Evekeo" /><ref name="BED rapid review" /> It is sometimes prescribed {{nowrap|[[off-label]]}} for its past [[Indication (medicine)|medical indications]], particularly for [[treatment-resistant depression|depression]] and [[chronic pain]].<ref name="Stahl's Essential Psychopharmacology" /><ref name="Benzedrine sulfate"/></noinclude>
<!-- section begin:ADHD -->

====ADHD====
Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal [[Dopamine receptor|dopamine system]] development or nerve damage,<ref name="pmid22392347">{{cite journal |vauthors=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L |title=Toxicity of amphetamines: an update |journal=Archives of Toxicology|volume=86 |issue=8 |pages=1167–1231 |date=August 2012 |pmid=22392347 |doi=10.1007/s00204-012-0815-5|bibcode=2012ArTox..86.1167C |s2cid=2873101 }}</ref><ref name="AbuseAndAbnormalities">{{cite journal|vauthors=Berman S, O'Neill J, Fears S, Bartzokis G, London ED | title=Abuse of amphetamines and structural abnormalities in the brain | journal=Annals of the New York Academy of Sciences| date = October 2008 | volume= 1141 | issue=1 | pages= 195–220 | pmid=18991959 | doi=10.1196/annals.1441.031 | pmc=2769923 | bibcode=<!-- No --> }}</ref> but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth.<ref name="Neuroplasticity 1">{{cite journal |vauthors=Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K |title=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 |journal=JAMA Psychiatry|volume=70 |issue=2 |pages=185–198 |date=February 2013 |pmid=23247506 |doi=10.1001/jamapsychiatry.2013.277|doi-access=free | title-link = doi }}</ref><ref name="Neuroplasticity 2">{{cite journal |vauthors=Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J |title=Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies |journal=The Journal of Clinical Psychiatry|volume=74 |issue=9 |pages=902–917 |date=September 2013 |pmid=24107764 |doi=10.4088/JCP.12r08287 |pmc=3801446}}</ref><ref name="Neuroplasticity 3">{{cite journal | title=Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects | journal=Acta Psychiatrica Scandinavica| date=February 2012 | volume=125 | issue=2 | pages=114–126 | pmid=22118249 |vauthors=Frodl T, Skokauskas N | quote = 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| s2cid=25954331| doi-access=free | title-link = doi }}</ref> Reviews of [[magnetic resonance imaging]] (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right [[caudate nucleus]] of the [[basal ganglia]].<ref name="Neuroplasticity 1" /><ref name="Neuroplasticity 2" /><ref name="Neuroplasticity 3" />

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.<ref name="Long-Term Outcomes Medications">{{cite journal |vauthors=Huang YS, Tsai MH | title = Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge | journal =CNS Drugs| volume = 25 | issue = 7 | pages = 539–554 |date=July 2011 | pmid = 21699268 | doi = 10.2165/11589380-000000000-00000 | s2cid = 3449435 | quote = Several other studies,<sup>[97-101]</sup> including a meta-analytic review<sup>[98]</sup> and a retrospective study,<sup>[97]</sup> suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders.&nbsp;... 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.&nbsp;... 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&nbsp;years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.}}</ref><ref name="Millichap" /><ref name="Long-term 2015">{{cite journal | vauthors = Arnold LE, Hodgkins P, Caci H, Kahle J, Young S | title = Effect of treatment modality on long-term outcomes in attention-deficit/hyperactivity disorder: a systematic review | journal =PLOS ONE| volume = 10 | issue = 2 | article-number = e0116407 | date = February 2015 | pmid = 25714373 | pmc = 4340791 | doi = 10.1371/journal.pone.0116407 | quote = 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.| bibcode = <!-- No --> | doi-access = free | title-link = doi }}<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> [[Randomized controlled trial]]s of continuous stimulant therapy for the treatment of ADHD spanning 2&nbsp;years have demonstrated treatment effectiveness and safety.<ref name="Long-Term Outcomes Medications" /><ref name="Millichap" /> Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing [[quality of life]] and academic achievement, and producing improvements in a large number of functional outcomes{{#tag:ref|The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (≈55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (≈65% of obesity-related outcomes improved), self-esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved).<ref name="Long-term 2015" /><br /><br />The largest [[effect size]]s for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g., [[grade point average]], achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).<ref name="Long-term 2015" /><br /><br />Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.<ref name="Long-term 2015" /> These findings were further supported by a 2025 review of interventions for adolescents, which concluded that medications and cognitive-behavioral treatments (CBT) provide complementary benefits. Medications demonstrated strong short-term efficacy on core symptoms, while CBT contributed modest to strong, and sometimes long-lasting, improvements in functional impairments and executive skills when used as part of combination therapy.<ref>{{cite journal | vauthors = Sibley MH, Flores S, Murphy M, Basu H, Stein MA, Evans SW, Zhao X, Manzano M, van Dreel S | title = Research Review: Pharmacological and non-pharmacological treatments for adolescents with attention deficit/hyperactivity disorder - a systematic review of the literature | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | volume = 66 | issue = 1 | pages = 132–149 | date = January 2025 | pmid = 39370392 | doi = 10.1111/jcpp.14056 | quote = The main efficacy-related conclusions of this review are: (a) medications demonstrated the strongest and most consistent effects on core ADHD symptoms (especially inattention), (b) heterogeneous C/BTs demonstrated inconsistent effects on ADHD symptoms, strong consistent effects on impairment and executive function skills, and modest consistent effects on internalizing symptoms and analogue note-taking performance, (c) C/BTs demonstrated consistent maintenance effects for executive function skills and impairment up to 6 months and possibly 3 years post-treatment, (d) though comparing the efficacy of two C/BTs rarely led to significant differences, which C/BT worked best for whom could be reliably predicted from patient- and provider-level moderators&nbsp;...<br />Thus, maximal therapeutic benefit (in terms of breadth of response and maintenance of effects) might be achieved by combining medication and C/BTs, a recommendation generally reflected in current practice parameters (AACAP, 2007; AADPA, 2022; NICE, 2018; Wolraich et al., 2019). }}</ref>|group="note"}} across 9&nbsp;categories of outcomes related to academics, [[Anti-social behaviour|antisocial behavior]], driving, non-medicinal drug use, obesity, occupation, [[self-esteem]], service use (i.e., academic, occupational, health, financial, and legal services), and social function.<ref name="Long-Term Outcomes Medications" /><ref name="Long-term 2015" /> Additionally, a 2024 [[Meta-analysis|meta-analytic]] [[systematic review]] reported moderate improvements in quality of life when amphetamine treatment is used for ADHD.<ref name="2024 QOL meta-analysis">{{Cite journal |vauthors=Bellato A, Perrott NJ, Marzulli L, Parlatini V, Coghill D, Cortese S |date=30 May 2024 |title=Systematic Review and Meta-Analysis: Effects of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Quality of Life |journal=Journal of the American Academy of Child and Adolescent Psychiatry |pages=S0890–8567(24)00304–6 |doi=10.1016/j.jaac.2024.05.023 |pmid=38823477 |quote=We conducted the first systematic review and meta-analysis investigating the effects of medication for ADHD on quality of life (QoL) in parallel or crossover RCTs. Overall, we found that methylphenidate, amphetamines, and atomoxetine were significantly more efficacious than placebo in improving QoL in people with ADHD.&nbsp;...<br /> Four studies on amphetamines (950 participants with ADHD in total; 45% adults) reported relevant data for effect sizes to be computed. The meta-analysis on 14 effect sizes showed that amphetamines led to better QoL than placebo in individuals with ADHD. |doi-access=free | title-link = doi |volume=64 |issue=3 |hdl=11586/524122 |hdl-access=free }}</ref> One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5&nbsp;[[intelligence quotient|IQ]] points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.<ref name="Millichap">{{cite book | vauthors = Millichap JG | veditors = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD | year = 2010 | publisher = Springer | location = New York, US | isbn = 978-1-4419-1396-8 | pages = 121–123, 125–127 | edition = 2nd | chapter = Chapter 9: Medications for ADHD | quote = 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> Another review indicated that, based upon the longest [[Prospective cohort study|follow-up studies]] conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a [[substance use disorder]] as an adult.<ref name="Long-Term Outcomes Medications" /> 

Models of ADHD suggest that it is associated with functional impairments in some of the brain's [[neurotransmitter systems]];<ref name="Malenka_2009_03" /> these functional impairments involve impaired [[dopamine]] neurotransmission in the [[mesocorticolimbic projection]] and [[norepinephrine]] neurotransmission in the noradrenergic projections from the [[locus coeruleus]] to the [[prefrontal cortex]].<ref name="Malenka_2009_03" /> Stimulants like [[methylphenidate]] and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.<ref name="Malenka_2009" /><ref name="Malenka_2009_03">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, US | isbn = 978-0-07-148127-4 | pages = 154–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin }}</ref><ref name="cognition enhancers">{{cite journal |vauthors=Bidwell LC, McClernon FJ, Kollins SH | title = Cognitive enhancers for the treatment of ADHD | journal =Pharmacology Biochemistry and Behavior| volume = 99 | issue = 2 | pages = 262–274 |date=August 2011 | pmid = 21596055 | pmc = 3353150 | doi = 10.1016/j.pbb.2011.05.002 }}</ref> Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.<ref name="Long-term 36">{{cite journal | vauthors = Parker J, Wales G, Chalhoub N, Harpin V | title = The long-term outcomes of interventions for the management of attention-deficit hyperactivity disorder in children and adolescents: a systematic review of randomized controlled trials | journal =Psychology Research and Behavior Management| volume = 6 | pages = 87–99 | date = September 2013 | pmid = 24082796 | pmc = 3785407 | doi = 10.2147/PRBM.S49114 | quote = Only one paper<sup>53</sup> examining outcomes beyond 36 months met the review criteria.&nbsp;... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term. | doi-access = free | title-link = doi }}</ref> Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.<ref name="Millichap_3">{{cite book | vauthors = Millichap JG | veditors = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD | year = 2010 | publisher = Springer | location = New York, US | isbn = 978-1-4419-1396-8 | pages = 111–113 | edition = 2nd | chapter = Chapter 9: Medications for ADHD}}</ref><ref name="ADHD">{{cite web | title=Stimulants for Attention Deficit Hyperactivity Disorder | url=http://www.webmd.com/add-adhd/childhood-adhd/stimulants-for-attention-deficit-hyperactivity-disorder | website = WebMD | publisher = Healthwise | date = 12 April 2010 | access-date=12 November 2013 }}</ref> The [[Cochrane (organisation)|Cochrane]] reviews{{#tag:ref|Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.<ref name="pmid16052183">{{cite journal |vauthors=Scholten RJ, Clarke M, Hetherington J |title=The Cochrane Collaboration |journal=European Journal of Clinical Nutrition|volume=59 |issue=Suppl 1 |pages=S147–S149; discussion S195–S196 |date=August 2005 |pmid=16052183 |doi=10.1038/sj.ejcn.1602188|s2cid=29410060 |doi-access=free | title-link = doi }}</ref>| group = "note" }} on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse [[side effect]]s.<ref name="Cochrane Amphetamines ADHD">{{cite journal | vauthors = Castells X, Blanco-Silvente L, Cunill R | title = Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults | journal =Cochrane Database of Systematic Reviews| volume = 2018 | article-number = CD007813 | date = August 2018 | issue = 8 | pmid = 30091808 | doi = 10.1002/14651858.CD007813.pub3 | pmc = 6513464 }}</ref><ref name="pmid26844979">{{cite journal | vauthors = Punja S, Shamseer L, Hartling L, Urichuk L, Vandermeer B, Nikles J, Vohra S | title = Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents | journal =Cochrane Database of Systematic Reviews| volume = 2016 | article-number = CD009996 | date = February 2016 | issue = 2 | pmid = 26844979 | doi = 10.1002/14651858.CD009996.pub2| pmc = 10329868 }}</ref> However, a 2025 meta-analytic systematic review of 113 randomized controlled trials found that stimulant medications were the only intervention with robust short-term efficacy, and were associated with lower all-cause treatment [[discontinuation]] rates than non-stimulant medications (e.g., [[atomoxetine]]).{{#tag:ref|In contrast to the Cochrane reviews that observed higher treatment discontinuation from adverse effects alone, this figure represents '''any cause''' of discontinuation (e.g., insufficient perceived treatment benefit).<ref name="2025_113_RCTs" /> |name="all-cause discontinuation"|group="note"}}<ref name="2025_113_RCTs">{{Cite journal |vauthors=Ostinelli EG, Schulze M, Zangani C, Farhat LC, Tomlinson A, Del Giovane C, Chamberlain SR, Philipsen A, Young S, Cowen PJ, Bilbow A, Cipriani A, Cortese S |year=2025 |title=Comparative efficacy and acceptability of pharmacological, psychological, and neurostimulatory interventions for ADHD in adults: a systematic review and component network meta-analysis |journal=The Lancet. Psychiatry |volume=12 |issue=1 |pages=32–43 |doi=10.1016/S2215-0366(24)00360-2 |pmid=39701638 |quote=Our findings were based on 113 RCTs, including 14 887 participants, and indicated that stimulants were the only intervention that was supported by evidence of efficacy in the short term (ie, at timepoints closest to 12 weeks) for core symptoms of ADHD in adults (both self-reported and clinician-reported) and was associated with good acceptability (all-cause discontinuation). |doi-access=free |title-link=doi}}</ref> A Cochrane review on the treatment of ADHD in children with [[tic disorder]]s such as [[Tourette syndrome]] indicated that stimulants in general do not make [[tic]]s worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.<ref name="pmid29944175">{{cite journal | vauthors = Osland ST, Steeves TD, Pringsheim T | title = Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders | journal =Cochrane Database of Systematic Reviews| volume = 2018 | article-number = CD007990 | date = June 2018 | issue = 6 | pmid = 29944175 | pmc = 6513283 | doi = 10.1002/14651858.CD007990.pub3 }}</ref>
<!-- section end:ADHD -->
<!-- Section begin:BED -->

====Binge eating disorder====
<!-- BED content is not transcluded to Adderall and dextroamphetamine articles because unlike LDX, those formulations are not recognised their use in treating BED -->
[[Binge eating disorder]] (BED) is characterized by recurrent and persistent episodes of compulsive binge eating.<ref name="BED definition">{{cite journal | vauthors = Giel KE, Bulik CM, Fernandez-Aranda F, Hay P, Keski-Rahkonen A, Schag K, Schmidt U, Zipfel S | title = Binge eating disorder | journal = Nature Reviews. Disease Primers | volume = 8 | issue = 1 | article-number = 16 | date = March 2022 | pmid = 35301358 | pmc = 9793802 | doi = 10.1038/s41572-022-00344-y }}</ref> These episodes are often accompanied by marked distress and a feeling of loss of control over eating.<ref name="BED definition" /> The [[pathophysiology]] of BED is not fully understood, but it is believed to involve dysfunctional dopaminergic reward circuitry along the [[Cortico-basal ganglia-thalamo-cortical loop|cortico-striatal-thalamic-cortical loop]].<ref name="BED ADHD overlap">{{cite journal | vauthors = Heal DJ, Smith SL | title = Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology | journal = Journal of Psychopharmacology | volume = 36 | issue = 6 | pages = 680–703 | date = June 2022 | pmid = 34318734 | pmc = 9150143 | doi = 10.1177/02698811211032475 | quote = BED subjects have substantial decrements in their ventral striatal reward pathways and diminished ability to recruit fronto-cortical impulse-control circuits to implement dietary restraint.&nbsp;...<br /> There is not only substantial overlap between the psychopathology of BED and ADHD but also a clear association between these two disorders. Lisdexamfetamine's ability to reduce impulsivity and increase cognitive control in ADHD supports the hypothesis that efficacy in BED is dependent on treating its core obsessive, compulsive and impulsive behaviours. }}</ref><ref name="BED secondary outcomes">{{cite journal | vauthors = McElroy SL | title = Pharmacologic Treatments for Binge-Eating Disorder | journal = The Journal of Clinical Psychiatry | volume = 78 | issue = Suppl 1 | pages = 14–19 | date = 2017 | pmid = 28125174 | doi = 10.4088/JCP.sh16003su1c.03 | quote = Genetic polymorphisms associated with abnormal dopaminergic signaling have been found in individuals who exhibit binge-eating behavior, and the binge-eating episodes, which often involve the consumption of highly palatable food, further stimulate the dopaminergic system. This ongoing stimulation may contribute to progressive impairments in dopamine signaling. Lisdexamfetamine is hypothesized to reduce binge-eating behavior by normalizing dopaminergic activity.&nbsp;...<br /> After 12 weeks, both studies found significant reductions in the number of binge-eating days per week in the active treatment group compared with placebo (P < .001 for both studies; Figure 1). Lisdexamfetamine was also found to be superior to placebo on a number of secondary outcome measures including global improvement, binge-eating cessation for 4 weeks, and reduction of obsessive-compulsive binge-eating symptoms, body weight, and triglycerides. }}</ref> As of July 2024, lisdexamfetamine is the only [[Food and Drug Administration|USFDA]]- and [[Therapeutic Goods Administration|TGA]]-approved [[pharmacotherapy]] for BED.<ref name="BED rapid review">{{cite journal | vauthors = Rodan SC, Bryant E, Le A, Maloney D, Touyz S, McGregor IS, Maguire S | title = Pharmacotherapy, alternative and adjunctive therapies for eating disorders: findings from a rapid review | journal = Journal of Eating Disorders | volume = 11 | issue = 1 | article-number = 112 | date = July 2023 | pmid = 37415200 | pmc = 10327007 | doi = 10.1186/s40337-023-00833-9 | quote = LDX is commonly used in the treatment of ADHD, and is the only treatment for BED that is approved by the Food and Drug Administration (FDA) and the Therapeutic Goods Administration (TGA). LDX, like all amphetamine stimulants, has direct appetite suppressant effects that may be therapeutically useful in BED, although long-term neuroadaptations in dopaminergic and noradrenergic systems caused by LDX may also be relevant, leading to improved regulation of eating behaviours, attentional processes and goal-directed behaviours.&nbsp;...<br /> Evidently, there is a substantial volume of trials with high-quality evidence supporting the efficacy of LDX in reducing binge eating frequency in treatment of adults with moderate to severe BED at 50–70 mg/day. | doi-access = free | title-link = doi }}</ref><ref name="BED neuroplasticity">{{cite journal | vauthors = Boswell RG, Potenza MN, Grilo CM | title = The Neurobiology of Binge-eating Disorder Compared with Obesity: Implications for Differential Therapeutics | journal = Clinical Therapeutics | volume = 43 | issue = 1 | pages = 50–69 | date = January 2021 | pmid = 33257092 | pmc = 7902428 | doi = 10.1016/j.clinthera.2020.10.014 | quote = Stimulant medications may be especially effective for individuals with BED because of dual effects on reward and executive function systems. Indeed, the only FDA-approved pharmacotherapy for BED is LDX, a d-amphetamine prodrug.&nbsp;...<br /> In humans, RCTs found that LDX reduced binge eating and impulsivity/compulsivity symptoms. Notably, there is a strong correlation between compulsivity symptoms and severity/frequency of binge eating episodes observed in LDX trials. Further, in individuals with BED, changes in prefrontal brain systems associated with LDX treatment were related to treatment outcome. }}</ref> Evidence suggests that lisdexamfetamine's treatment efficacy in BED is underpinned at least in part by a [[Psychopathology|psychopathological]] overlap between BED and ADHD, with the latter conceptualized as a [[Executive functions|cognitive control]] disorder that also benefits from treatment with lisdexamfetamine.<ref name="BED ADHD overlap" /><ref name="BED secondary outcomes" />

[[File:TAAR1 organ-specific expression and function.jpg|class=skin-invert-image|thumb|right|370px|alt=Diagram of TAAR1 organ-specific expression and function|This diagram illustrates how [[TAAR1]] activation induces [[incretin]]-like effects through the release of gastrointestinal hormones and influences food intake, [[blood glucose]] levels, and [[insulin]] release.<ref name="Berry hTAAR pharmacology December 2017 review" /> TAAR1 expression in the periphery is indicated with "x".<ref name="Berry hTAAR pharmacology December 2017 review" />]]

Lisdexamfetamine's therapeutic effects for BED primarily involve direct action in the [[central nervous system]] after conversion to its pharmacologically active metabolite, dextroamphetamine.<ref name="BED neuroplasticity" /> Centrally, dextroamphetamine increases neurotransmitter activity of dopamine and norepinephrine in prefrontal cortical regions that regulate cognitive control of behavior.<ref name="BED ADHD overlap" /><ref name="BED neuroplasticity" /> Similar to its therapeutic effect in ADHD, dextroamphetamine enhances cognitive control and may reduce impulsivity in patients with BED by enhancing the cognitive processes responsible for overriding [[prepotent responses|prepotent feeding responses]] that precede binge eating episodes.<ref name="BED ADHD overlap" /><ref>{{Cite book |title=Molecular neuropharmacology: a foundation for clinical neuroscience |vauthors=Malenka RC, Nestler EJ, Hyman SE, Holtzman DM |publisher=McGraw-Hill Medical |year=2015 |isbn=978-0-07-182770-6 |edition=3rd |location=New York |chapter=Chapter 14: Higher Cognitive Function and Behavioral Control |quote=Because behavioral responses in humans are not rigidly dictated by sensory inputs and drives, behavioral responses can instead be guided in accordance with short- or long-term goals, prior experience, and the environmental context. The response to a delicious-looking dessert is different depending on whether a person is alone staring into his or her refrigerator, is at a formal dinner party attended by his or her punctilious boss, or has just formulated the goal of losing 10 lb.&nbsp;...<br /> Adaptive responses depend on the ability to inhibit automatic or prepotent responses (eg, to ravenously eat the dessert or run from the snake) given certain social or environmental contexts or chosen goals and, in those circumstances, to select more appropriate responses. In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 16), or inattention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result.}}</ref><ref name="BED systematic review">{{cite journal | vauthors = Schneider E, Higgs S, Dourish CT | title = Lisdexamfetamine and binge-eating disorder: A systematic review and meta-analysis of the preclinical and clinical data with a focus on mechanism of drug action in treating the disorder | journal = European Neuropsychopharmacology | volume = 53 | pages = 49–78 | date = December 2021 | pmid = 34461386 | doi = 10.1016/j.euroneuro.2021.08.001 | url = http://pure-oai.bham.ac.uk/ws/files/147133958/LDX_final_pure.pdf | quote = Our meta-analysis of the four RCT data sets (Guerdjikova et al., 2016; McElroy et al., 2015b; McElroy et al., 2016a) showed an overall significant effect of LDX on binge-eating symptom change.&nbsp;...<br /> BED has been described as an impulse control disorder since one of the key symptoms of the disorder is a lack of control over eating (American Psychiatric Association, 2013) and it is possible that LDX may be effective in treating BED at least in part by reducing impulsivity, compulsivity, and the repetitive nature of binge eating. There is extensive evidence that loss of impulse control in BED is a causal factor in provoking bingeing symptoms (Colles et al., 2008; Galanti et al., 2007; Giel et al., 2017; McElroy et al., 2016a; Nasser et al., 2004; Schag et al., 2013). More specifically, BED is associated with motor impulsivity and non-planning impulsivity which could initiate and maintain binge eating (Nasser et al., 2004). Neuroimaging studies using the Stroop task to measure impulse control have shown that BED patients have decreased BOLD fMRI activity in brain areas involved in self-regulation and impulse control including VMPFC, inferior frontal gyrus (IFG), and insula during performance of the task compared to lean and obese controls (Balodis et al., 2013b).&nbsp;...<br /> It is conceivable that in BED patients a low 30 mg dose of LDX could reduce food intake by suppressing appetite or enhancing satiety and higher (50 and 70 mg) doses of the drug may have a dual suppressant effect on food intake and binge-eating frequency. }}</ref> Dextroamphetamine is also a full agonist of [[trace amine-associated receptor 1]] (TAAR1), a [[G protein-coupled receptor|G-protein coupled receptor]] that regulates [[Monoamine neurotransmitter|monoaminergic systems]] in the brain;<ref name="2022 T1 LDX" /><ref name="Moore_2018">{{Cite journal |vauthors=Moore CF, Sabino V, Cottone P |date=2018 |title=Trace Amine Associated Receptor 1 (TAAR1) Modulation of Food Reward |journal=Frontiers in Pharmacology |volume=9 |article-number=129 |doi=10.3389/fphar.2018.00129 |doi-access=free |pmc=5835105 |pmid=29535626 |quote=As TAAR1 agonism has been shown to reduce various maladaptive eating behaviors, it can indeed be regarded as a very promising therapeutic target for compulsive eating behavior, even though much more research is needed at this point. Recently, Lisdexamfetamine (LDX) was approved for the treatment of BED, and has been shown to reduce binge eating behaviors as well as compulsive eating behaviors (assessed with the Yale-Brown Obsessive Compulsive Scale modified for Binge Eating; Y-BOCS-BE) (Hudson et al., 2017). Interestingly, TAAR1 is also activated by amphetamine, the active metabolite in LDX. LDX and TAAR1 agonism may, therefore, work through similar mechanisms to restore dysfunctional signaling in prefrontal areas, alleviating impaired inhibitory behaviors.}}</ref> Activation of TAAR1 may restore impaired dopaminergic signaling in the prefrontal cortex and thereby correct deficits in inhibitory control associated with binge eating behaviors.<ref name="Moore_2018" />  Beyond central nervous system mechanisms, [[Peripheral nervous system|peripheral]] actions of dextroamphetamine may also contribute to its treatment efficacy in BED. Through noradrenergic signaling pathways, dextroamphetamine triggers [[lipolysis]] in [[Adipose tissue|adipose fat]] cells, thereby prompting the release of [[triglyceride]]s into blood plasma to be utilized as a fuel substrate.<ref name="BED secondary outcomes" /><ref>{{cite journal | vauthors = Branis NM, Wittlin SD | title = Amphetamine-Like Analogues in Diabetes: Speeding towards Ketogenesis | journal = Case Reports in Endocrinology | volume = 2015 | article-number = 917869 | date = 2015 | pmid = 25960894 | pmc = 4417573 | doi = 10.1155/2015/917869 | quote = Peripheral norepinephrine concentration rises as well. As demonstrated after Dextroamphetamine administration, plasma norepinephrine can rise up to 400 pg/mL, a level comparable to that achieved during mild physical activity. Cumulative effect on norepinephrine concentration is likely when amphetamine-type medications are given in the setting of acute illness or combined with activities leading to catecholamine release, such as exercise.&nbsp;... The primary effect of norepinephrine on ketogenesis is mediated through increased substrate availability. As shown by Krentz et al., at high physiological concentrations, norepinephrine induces accelerated lipolysis and increases NEFA formation significantly. Secondly, norepinephrine stimulates ketogenesis directly at the hepatocyte level. As reported by Keller et al., norepinephrine infusion increased ketone bodies concentration to a greater degree when compared to NEFA concentration (155 ± 30 versus 57 ± 16%), suggesting direct hepatic ketogenic effect. | doi-access = free | title-link = doi }}</ref> Moreover, dextroamphetamine induces synthesis of the [[Cocaine and amphetamine regulated transcript|cocaine- and amphetamine-regulated transcript]] (CART), a peptide neurotransmitter that regulates food intake.<ref name="Prus_2018">{{Cite book |title=Drugs and the neuroscience of behavior: an introduction to psychopharmacology |vauthors=Prus AJ |date=2018 |publisher=SAGE |isbn=978-1-5063-3894-1 |edition=2nd |location=Los Angeles |pages=315–20 |chapter=Chapter 6: Psychostimulants |quote=The cocaine- and amphetamine-regulated transcript (CART) is a peptide neurotransmitter that is produced after psychostimulant administration. Acute administration of a psychostimulant drug causes the activation of the gene for CART, leading to the synthesis of the CART peptide, which is then stored in vesicles within axon terminals.&nbsp;... Psychostimulants reduce hunger through actions in the hypothalamus, a key structure for the regulation of appetite. Within this structure, enhanced dopamine release contributes to appetite suppression. CART also plays a role in hunger. In the hypothalamus, CART is activated by the appetite-suppressing hormone leptin.}}</ref> Within the [[hypothalamus]], CART interacts with [[leptin]] signaling pathways to promote appetite suppression.<ref name="Prus_2018" /> Dextroamphetamine also activates {{abbr|TAAR1|trace amine-associated receptor 1}} in peripheral organs along the [[gastrointestinal tract]] that are involved in the regulation of food intake and body weight.<ref name="Moore_2018" /><ref name="Berry hTAAR pharmacology December 2017 review">{{cite journal | vauthors = Berry MD, Gainetdinov RR, Hoener MC, Shahid M | title = Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges | journal = Pharmacology & Therapeutics | volume = 180 | pages = 161–180 | date = December 2017 | pmid = 28723415 | doi = 10.1016/j.pharmthera.2017.07.002 | doi-access = free | title-link = doi }}</ref> Together, these actions confer an [[anorexigenic]] effect that promotes [[satiety]] in response to feeding and may decrease binge eating as a secondary effect.<ref name="BED systematic review" /><ref name="Berry hTAAR pharmacology December 2017 review" /> While lisdexamfetamine's anorexigenic effects contribute to its efficacy in BED, evidence indicates that the enhancement of cognitive control is [[necessary and sufficient]] for addressing the disorder's underlying psychopathology.<ref name="BED ADHD overlap"/><ref name="Heal 2024 BED">{{Cite book |vauthors=Heal DJ, Gosden J, Smith SL |title=Pharmacological Advances in Central Nervous System Stimulants |date=2024 |chapter=Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder |chapter-url=https://pubmed.ncbi.nlm.nih.gov/38467483/ |series=Advances in Pharmacology (San Diego, Calif.) |volume=99 |pages=251–286 |doi=10.1016/bs.apha.2023.10.002 |pmid=38467483 |isbn=978-0-443-21933-7 |quote=Together, the findings indicate that LDX has independent actions to tackle the underlying psychopathology of BED to inhibit binge-eating and produce weight-loss by reducing food intake through appetite suppression or enhanced satiety.&nbsp;... Although BED is a predisposing factor for the development of obesity, it is unresponsive to appetite suppressants or anti-obesity drugs, emphasizing their different pathophysiological causes.}}</ref> This view is supported by the failure of [[anti-obesity medication]]s and other appetite suppressants to significantly reduce BED symptom severity, despite their capacity to induce weight loss.<ref name="Heal 2024 BED"/>

Medical reviews of randomized controlled trials have demonstrated that lisdexamfetamine, at doses between 50–70&nbsp;mg, is safe and effective for the treatment of moderate-to-severe BED in adults.{{#tag:ref|<ref name="BED secondary outcomes" /><ref name="BED rapid review" /><ref name="BED systematic review" /><ref name="BED neuroplasticity" /><ref name="BED review">{{cite journal | vauthors = Muratore AF, Attia E | title = Psychopharmacologic Management of Eating Disorders | journal = Current Psychiatry Reports | volume = 24 | issue = 7 | pages = 345–351 | date = July 2022 | pmid = 35576089 | pmc = 9233107 | doi = 10.1007/s11920-022-01340-5 | quote = An 11-week, double-blind RCT examined the effects of three doses of lisdexamfetamine (30 mg/day, 50 mg/day, 70 mg/day) and placebo on binge eating frequency. Results indicated that 50 mg and 70 mg doses were superior to placebo in reducing binge eating. Two follow-up 12-week RCTs confirmed the superiority of 50 and 70 mg doses to placebo in improving binge eating and secondary outcome measures, including obsessive–compulsive symptoms, body weight, and global improvement. ... Subsequent studies of lisdexamfetamine provided further support for the medication's safety and efficacy and provided additional evidence that continued use may be better than placebo in preventing relapse. While it is considered safe and effective, lisdexamfetamine's side effect profile and risk for misuse may make it inappropriate for certain patients. }}</ref>|group="sources"|name="BED efficacy"}} These reviews suggest that lisdexamfetamine is persistently effective at treating BED and is associated with significant reductions in the number of binge eating days and binge eating episodes per week.<ref name="BED efficacy" group="sources" /> Furthermore, a meta-analytic systematic review highlighted an open-label, 12-month extension safety and tolerability study that reported lisdexamfetamine remained effective at reducing the number of binge eating days for the duration of the study.<ref name="BED systematic review" /> In addition, both a review and a meta-analytic systematic review found lisdexamfetamine to be superior to placebo in several secondary outcome measures, including persistent binge eating cessation, reduction of obsessive-compulsive related binge eating symptoms, reduction of body-weight, and reduction of triglycerides.<ref name="BED secondary outcomes" /><ref name="BED systematic review" /> Lisdexamfetamine, like all pharmaceutical amphetamines, has direct appetite suppressant effects that may be therapeutically useful in both BED and its comorbidities.<ref name="BED rapid review" /><ref name="BED systematic review" /> Based on reviews of [[neuroimaging]] studies involving BED-diagnosed participants, therapeutic [[neuroplasticity]] in [[neurotransmitter#Neurotransmitter systems|dopaminergic and noradrenergic pathways]] from long-term use of lisdexamfetamine may be implicated in lasting improvements in the regulation of eating behaviors that are observed.<ref name="BED rapid review" /><ref name="BED neuroplasticity" /><ref name="BED systematic review" />
<!-- Section end:BED -->
<!-- Section begin: Narcolepsy -->

====Narcolepsy====
Narcolepsy is a chronic sleep-wake disorder that is associated with excessive daytime sleepiness, [[cataplexy]], and [[sleep paralysis]].<ref name="Autoimmune basis review">{{cite journal | vauthors = Mahlios J, De la Herrán-Arita AK, Mignot E | title = The autoimmune basis of narcolepsy | journal = Current Opinion in Neurobiology | volume = 23 | issue = 5 | pages = 767–773 | date = October 2013 | pmid = 23725858 | pmc = 3848424 | doi = 10.1016/j.conb.2013.04.013 }}</ref> Patients with narcolepsy are diagnosed as either type 1 or type 2, with only the former presenting cataplexy symptoms.<ref name="Barateau_2022">{{cite journal |vauthors=Barateau L, Pizza F, Plazzi G, Dauvilliers Y |date=August 2022 |title=Narcolepsy |journal=Journal of Sleep Research |volume=31 |issue=4 |article-number=e13631 |doi=10.1111/jsr.13631 |pmid=35624073 |hdl=11380/1280615 |quote=Narcolepsy type 1 was called "narcolepsy with cataplexy" before 2014 (AASM, 2005), but was renamed NT1 in the third and last international classification of sleep disorders (AASM, 2014).&nbsp;... A low level of Hcrt-1 in the CSF is very sensitive and specific for the diagnosis of NT1.&nbsp;...<br /> All patients with low CSF Hcrt-1 levels are considered as NT1 patients, even if they report no cataplexy (in about 10–20% of cases), and all patients with normal CSF Hcrt-1 levels (or without cataplexy when the lumbar puncture is not performed) as NT2 patients (Baumann et al., 2014).&nbsp;...<br /> In patients with NT1, the absence of Hcrt leads to the inhibition of regions that suppress REM sleep, thus allowing the activation of descending pathways inhibiting motoneurons, leading to cataplexy.}}</ref> Type 1 narcolepsy results from the loss of approximately 70,000 [[orexin]]-releasing neurons in the [[lateral hypothalamus]], leading to significantly reduced [[Cerebrospinal fluid|cerebrospinal]] orexin levels;<ref name="Narcolepsy guide">{{cite journal |vauthors=Mignot EJ |date=October 2012 |title=A practical guide to the therapy of narcolepsy and hypersomnia syndromes |journal=Neurotherapeutics |volume=9 |issue=4 |pages=739–752 |doi=10.1007/s13311-012-0150-9 |pmc=3480574 |pmid=23065655 |quote=At the pathophysiological level, it is now clear that most narcolepsy cases with cataplexy, and a minority of cases (5–30 %) without cataplexy or with atypical cataplexy-like symptoms, are caused by a lack of hypocretin (orexin) of likely an autoimmune origin. In these cases, once the disease is established, the majority of the 70,000 hypocretin-producing cells have been destroyed, and the disorder is irreversible.&nbsp;...<br /> Amphetamines are exceptionally wake-promoting, and at high doses also reduce cataplexy in narcoleptic patients, an effect best explained by its action on adrenergic and serotoninergic synapses.&nbsp;...<br /> The D-isomer is more specific for DA transmission and is a better stimulant compound. Some effects on cataplexy (especially for the L-isomer), secondary to adrenergic effects, occur at higher doses.&nbsp;...<br /> Numerous studies have shown that increased dopamine release is the main property explaining wake-promotion, although norepinephrine effects also contribute.}}</ref><ref name="Malenka_2015b">{{Cite book |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |vauthors=Malenka RC, Nestler EJ, Hyman SE, Holtzman DM |publisher=McGraw-Hill Medical |year=2015 |isbn=978-0-07-182770-6 |edition=3rd |location=New York |pages=456–457 |chapter=Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu |quote=More recently, the lateral hypothalamus was also found to play a central role in arousal. Neurons in this region contain cell bodies that produce the orexin (also called hypocretin) peptides (Chapter 6). These neurons project widely throughout the brain and are involved in sleep, arousal, feeding, reward, aspects of emotion, and learning. In fact, orexin is thought to promote feeding primarily by promoting arousal. Mutations in orexin receptors are responsible for narcolepsy in a canine model, knockout of the orexin gene produces narcolepsy in mice, and humans with narcolepsy have low or absent levels of orexin peptides in cerebrospinal fluid (Chapter 13). Lateral hypothalamus neurons have reciprocal connections with neurons that produce monoamine neurotransmitters (Chapter 6).}}</ref> this reduction is a [[Biomarker (medicine)|diagnostic biomarker]] for type 1 narcolepsy.<ref name="Barateau_2022" /> Lateral hypothalamic orexin neurons innervate every component of the [[ascending reticular activating system]] (ARAS), which includes [[Norepinephrine|noradrenergic]], [[dopamine]]rgic, [[histamine]]rgic, and [[Serotonin|serotonergic]] nuclei that promote [[wakefulness]].<ref name="Malenka_2015b" /><ref name="Malenka_2015a">{{Cite book |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |vauthors=Malenka RC, Nestler EJ, Hyman SE, Holtzman DM |publisher=McGraw-Hill Medical |year=2015 |isbn=978-0-07-182770-6 |edition=3rd |page=521 |chapter=Chapter 13: Sleep and Arousal |quote=The ARAS consists of several different circuits including the four main monoaminergic pathways discussed in Chapter 6. The norepinephrine pathway originates from the LC and related brainstem nuclei; the serotonergic neurons originate from the RN within the brainstem as well; the dopaminergic neurons originate in the ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brainstem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep, as noted earlier. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells.}}</ref>

Amphetamine's therapeutic mode of action in narcolepsy primarily involves increasing [[Monoamine neurotransmitter|monoamine]] neurotransmitter activity in the ARAS.<ref name="Narcolepsy guide" /><ref name="Amphetamine ARAS textbook">{{cite book |url=https://books.google.com/books?id=kWxWEdqvue4C&pg=PA81 |title=Sleep medicine a guide to sleep and its disorders |vauthors=Shneerson JM |date=2009 |publisher=John Wiley & Sons |isbn=978-1-4051-7851-8 |edition=2nd |page=81 |quote=All the amphetamines enhance activity at dopamine, noradrenaline and 5HT synapses. They cause presynaptic release of preformed transmitters, and also inhibit the re-uptake of dopamine and noradrenaline. These actions are most prominent in the brainstem ascending reticular activating system and the cerebral cortex.}}</ref><ref name="Narcolepsy - Amphetamine and the ARAS" /> This includes noradrenergic neurons in the [[locus coeruleus]], dopaminergic neurons in the [[ventral tegmental area]], histaminergic neurons in the [[tuberomammillary nucleus]], and serotonergic neurons in the [[dorsal raphe nucleus]].<ref name="Malenka_2015a" /><ref name="Narcolepsy - Amphetamine and the ARAS">{{cite journal |vauthors=Schwartz JR, Roth T |year=2008 |title=Neurophysiology of sleep and wakefulness: basic science and clinical implications |journal=Current Neuropharmacology |volume=6 |issue=4 |pages=367–378 |doi=10.2174/157015908787386050 |pmc=2701283 |pmid=19587857 |quote=Alertness and associated forebrain and cortical arousal are mediated by several ascending pathways with distinct neuronal components that project from the upper brain stem near the junction of the pons and the midbrain.&nbsp;...<br /> Key cell populations of the ascending arousal pathway include cholinergic, noradrenergic, serotoninergic, dopaminergic, and histaminergic neurons located in the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT), locus coeruleus, dorsal and median raphe nucleus, and tuberomammillary nucleus (TMN), respectively.&nbsp;...<br /> The mechanism of action of sympathomimetic alerting drugs (eg, dextro- and methamphetamine, methylphenidate) is direct or indirect stimulation of dopaminergic and noradrenergic nuclei, which in turn heightens the efficacy of the ventral periaqueductal grey area and locus coeruleus, both components of the secondary branch of the ascending arousal system.&nbsp;...<br />Sympathomimetic drugs have long been used to treat narcolepsy}}</ref> Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is particularly effective at promoting wakefulness because dopamine release has the greatest influence on cortical activation and cognitive arousal, relative to other monoamines.<ref name="Narcolepsy guide" /><ref>{{Cite journal |vauthors=Trotti LM, Becker LA, Friederich Murray C, Hoque R |date=2021-05-25 |title=Medications for daytime sleepiness in individuals with idiopathic hypersomnia |journal=The Cochrane Database of Systematic Reviews |volume=2021 |issue=5 |article-number=CD012714 |doi=10.1002/14651858.CD012714.pub2 |pmc=8144933 |pmid=34031871 |quote=Amphetamines both increase the release of and block the reuptake of monoaminergic neurotransmitters (i.e. dopamine, norepinephrine, and serotonin). Their effects on dopaminergic neurotransmission are particularly important for promoting wakefulness (Banerjee 2004; Gowda 2014). |doi-access=free}}</ref> In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin.<ref name="Narcolepsy guide" /> Noradrenergic and serotonergic nuclei in the ARAS are involved in the regulation of the [[Rapid eye movement sleep|REM]] sleep cycle and function as "REM-off" cells, with amphetamine's effect on norepinephrine and serotonin contributing to the suppression of REM sleep and a possible reduction of cataplexy at high doses.<ref name="Narcolepsy guide" /><ref name="Barateau_2022" /><ref name="Malenka_2015a" />

The [[American Academy of Sleep Medicine]] (AASM) 2021 [[clinical practice guideline]] conditionally recommends dextroamphetamine for the treatment of both type 1 and type 2 narcolepsy.<ref name="narcolepsy efficacy">{{cite journal | vauthors = Maski K, Trotti LM, Kotagal S, Robert Auger R, Rowley JA, Hashmi SD, Watson NF | title = Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline | journal = Journal of Clinical Sleep Medicine | volume = 17 | issue = 9 | pages = 1881–1893 | date = September 2021 | pmid = 34743789 | pmc = 8636351 | doi = 10.5664/jcsm.9328 | quote = The TF identified 1 double-blind RCT, 1 single-blind RCT, and 1 retrospective observational long-term self-reported case series assessing the efficacy of dextroamphetamine in patients with narcolepsy type 1 and narcolepsy type 2. These studies demonstrated clinically significant improvements in excessive daytime sleepiness and cataplexy. }}</ref> Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g., [[modafinil]]) and is considered a [[Therapy#Lines of therapy|third-line treatment]] option.<ref name="narcolepsy addiction">{{cite journal |vauthors=Barateau L, Lopez R, Dauvilliers Y |date=October 2016 |title=Management of Narcolepsy |journal=Current Treatment Options in Neurology |volume=18 |issue=10 |article-number=43 |doi=10.1007/s11940-016-0429-y |pmid=27549768 |quote=The usefulness of amphetamines is limited by a potential risk of abuse, and their cardiovascular adverse effects (Table 1). That is why, even though they are cheaper than other drugs, and efficient, they remain third-line therapy in narcolepsy. Three class II studies showed an improvement of EDS in that disease.&nbsp;...<br /> Despite the potential for drug abuse or tolerance using stimulants, patients with narcolepsy rarely exhibit addiction to their medication.&nbsp;...<br /> Some stimulants, such as mazindol, amphetamines, and pitolisant, may also have some anticataplectic effects.}}</ref><ref>{{cite journal | vauthors = Dauvilliers Y, Barateau L | title = Narcolepsy and Other Central Hypersomnias | journal = Continuum | volume = 23 | issue = 4, Sleep Neurology | pages = 989–1004 | date = August 2017 | pmid = 28777172 | doi = 10.1212/CON.0000000000000492 | quote = Recent clinical trials and practice guidelines have confirmed that stimulants such as modafinil, armodafinil, or sodium oxybate (as first line); methylphenidate and pitolisant (as second line [pitolisant is currently only available in Europe]); and amphetamines (as third line) are appropriate medications for excessive daytime sleepiness. }}</ref><ref>{{cite journal | vauthors = Thorpy MJ, Bogan RK | title = Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications | journal = Sleep Medicine | volume = 68 | pages = 97–109 | date = April 2020 | pmid = 32032921 | doi = 10.1016/j.sleep.2019.09.001 | quote = The first agents used to treat EDS (ie, amphetamines, methylphenidate) are now considered second- or third-line options because newer medications have been developed with improved tolerability and lower abuse potential (eg, modafinil/armodafinil, solriamfetol, pitolisant) }}</ref> Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy.<ref name="Narcolepsy guide" /><ref name="narcolepsy addiction" /><ref name="narcolepsy efficacy" /> Amphetamine appears to be most effective at improving symptoms associated with [[Excessive daytime sleepiness|hypersomnolence]], with three reviews finding clinically significant reductions in [[Somnolence|daytime sleepiness]] in patients with narcolepsy.<ref name="Narcolepsy guide" /><ref name="narcolepsy addiction" /><ref name="narcolepsy efficacy" /> Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms.<ref name="Narcolepsy guide" /><ref name="narcolepsy addiction" /><ref name="narcolepsy efficacy" /> However, the quality of evidence for these findings is low and is consequently reflected in the AASM's conditional recommendation for dextroamphetamine as a treatment option for narcolepsy.<ref name="narcolepsy efficacy" />
<!-- Section end: Narcolepsy -->
<!-- ====Obesity====
Topics to cover:

Amphetamine's MoA in the periphery:
* cover amphetamine-triggered induction of lipolysis via peripheral (nor-)adrenergic signaling in adipose fat cells which induces the release of triglycerides into blood plasma
* cover amphetamine-induced TAAR1 signaling in peripheral organs (i.e., cover "File:TAAR1 organ-specific expression and function.jpg" in the context of amphetamine's MoA for treating obesity), provided that I can find a review mentioning amphetamine+TAAR1+obesity at some point

Amphetamine's MoA in the CNS:
* indicate that every monoamine neurotransmitter is involved in energy homeostasis, specify how, and mention which DA/NE-ergic projections are involved [cite PMID 22547886 and the refs I added to the "energy homeostasis" article]
** cover the systems neurobiology of monoaminergic regulation of feeding behavior
* amphetamine-induced hypothalamic CART induction probably plays some role in the mechanism of action, but would need to find a source once its GPCR has been IDed
**quotes on CART's physiological/cognitive effects: "CART promotes physical activity and wakefulness" [PMID 22547886] and markedly inhibits hunger [pubchem amphetamine entry] (pubchem quote: "this anorectic peptide inhibits both normal and starvation-induced feeding and completely blocks the feeding response induced by neuropeptide Y and regulated by leptin in the hypothalamus")
:Note: PMID 22547886 contains material relevant to both narcolepsy and obesity as well as covers CART; doesn't mention amphetamine though

-->

===Enhancing performance===

====Cognitive performance====
In 2015, a [[systematic review]] and a [[meta-analysis]] of high quality [[clinical trial]]s found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including [[working memory]], long-term [[episodic memory]], [[inhibitory control]], and some aspects of [[Attention#Clinical model|attention]], in normal healthy adults;<ref name="Unambiguous PFC D1 A2">{{cite journal | vauthors = Spencer RC, Devilbiss DM, Berridge CW | title = The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex | journal =Biological Psychiatry| volume = 77 | issue = 11 | pages = 940–950 | date = June 2015 | pmid = 25499957 | doi = 10.1016/j.biopsych.2014.09.013 | quote = The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors.&nbsp;... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function).&nbsp;... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses. | pmc=4377121| url = https://rdw.rowan.edu/cgi/viewcontent.cgi?article=1056&context=som_facpub }}</ref><ref name="Cognitive and motivational effects">{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal =Journal of Cognitive Neuroscience| pages = 1069–1089 | date = June 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | volume=27 | issue = 6 | s2cid = 15788121 | url = https://repository.upenn.edu/neuroethics_pubs/130 | quote = Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities.&nbsp;... The results of this meta-analysis&nbsp;... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.| url-access = subscription }}</ref> these cognition-enhancing effects of amphetamine are known to be partially mediated through the [[indirect agonist|indirect activation]] of both [[dopamine receptor D1|dopamine D<sub>1</sub> receptor]] and [[Alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic receptor]] in the [[prefrontal cortex]].<ref name="Malenka_2009" /><ref name="Unambiguous PFC D1 A2" /> A systematic review from 2014 found that low doses of amphetamine also improve [[memory consolidation]], in turn leading to improved [[Recall (memory)|recall of information]].<ref name="Cognition enhancement 2014 systematic review">{{cite journal | vauthors = Bagot KS, Kaminer Y | title = Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review | journal =Addiction| volume = 109 | issue = 4 | pages = 547–557 | date = April 2014 | pmid = 24749160 | pmc = 4471173 | doi = 10.1111/add.12460 | quote = Amphetamine has been shown to improve consolidation of information (0.02&nbsp;≥&nbsp;P&nbsp;≤&nbsp;0.05), leading to improved recall.}}</ref> Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.<ref name="Malenka_2009" /><ref name="pmid11337538">{{cite journal |vauthors=Devous MD, Trivedi MH, Rush AJ |title=Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers |journal=Journal of Nuclear Medicine |volume=42 |issue=4 |pages=535–542 |date=April 2001 |pmid=11337538}}</ref> Amphetamine and other ADHD stimulants also improve [[Incentive salience|task saliency]] (motivation to perform a task) and increase [[arousal]] (wakefulness), in turn promoting goal-directed behavior.<ref name="Malenka_2009" /><ref name="Malenka NAcc">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, US | isbn = 978-0-07-148127-4 | page = 266 | edition = 2nd | chapter = Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu | quote = Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.}}</ref><ref name="Continuum">{{cite journal |vauthors=Wood S, Sage JR, Shuman T, Anagnostaras SG |title=Psychostimulants and cognition: a continuum of behavioral and cognitive activation |journal=Pharmacological Reviews|volume=66 |issue=1 |pages=193–221 |date=January 2014 |pmid=24344115 |pmc=3880463 |doi=10.1124/pr.112.007054}}</ref> Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.<ref name="Malenka_2009">{{cite book|vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, US | isbn = 978-0-07-148127-4 | pages = 318, 321 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control | quote = Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD.&nbsp;... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks&nbsp;... through indirect stimulation of dopamine and norepinephrine receptors.&nbsp;...<br />Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.}}</ref><ref name="Continuum" /><ref name="Test taking aid">{{cite web | website = JS Online | author = Twohey M | date = 26 March 2006 | title = Pills become an addictive study aid | access-date = 2 December 2007 | url = http://www.jsonline.com/story/index.aspx?id=410902 | archive-url = https://web.archive.org/web/20070815200239/http://www.jsonline.com/story/index.aspx?id=410902 | archive-date = 15 August 2007}}</ref> Based upon studies of self-reported illicit stimulant use, {{nowrap|5–35%}} of college students use [[drug diversion|diverted]] ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs.<ref name="pmid16999660">{{cite journal |vauthors=Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ | title = Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration | journal =Pharmacotherapy| volume = 26 | issue = 10 | pages = 1501–1510 |date=October 2006 | pmid = 16999660 | pmc = 1794223 | doi = 10.1592/phco.26.10.1501 }}</ref><ref name="Diversion prevalence 1">{{cite journal | vauthors = Weyandt LL, Oster DR, Marraccini ME, Gudmundsdottir BG, Munro BA, Zavras BM, Kuhar B | title = Pharmacological interventions for adolescents and adults with ADHD: stimulant and nonstimulant medications and misuse of prescription stimulants | journal =Psychology Research and Behavior Management| volume = 7 | pages = 223–249 | date = September 2014 | pmid = 25228824 | pmc = 4164338 | doi = 10.2147/PRBM.S47013 | quote = misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well.&nbsp;... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students. | doi-access = free | title-link = doi }}</ref><ref name="Diversion prevalence 2">{{cite journal | vauthors = Clemow DB, Walker DJ | title = The potential for misuse and abuse of medications in ADHD: a review | journal =Postgraduate Medicine| volume = 126 | issue = 5 | pages = 64–81 | date = September 2014 | pmid = 25295651 | doi = 10.3810/pgm.2014.09.2801 | s2cid = 207580823 | quote = Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.}}</ref> However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.<ref name="Malenka_2009" /><ref name="Continuum" />

====Physical performance====
<!-- Do not change this section header to "Physical"; there is already a "Physical" heading located under the "Side effects" section, so changing the heading here will affect section linking. -->
Amphetamine is used by some athletes for its psychological and [[ergogenic aid|athletic performance-enhancing effects]], such as increased endurance and alertness;<ref name="Ergogenics">{{cite journal |vauthors=Liddle DG, Connor DJ | title = Nutritional supplements and ergogenic AIDS | journal =Primary Care: Clinics in Office Practice| volume = 40 | issue = 2 | pages = 487–505 |date=June 2013 | pmid = 23668655 | doi = 10.1016/j.pop.2013.02.009 |quote= Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training&nbsp;...<br />Physiologic and performance effects<br />{{•}}Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation<br />{{•}}Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40<br />{{•}}Improved reaction time<br />{{•}}Increased muscle strength and delayed muscle fatigue<br />{{•}}Increased acceleration<br />{{•}}Increased alertness and attention to task}}</ref><ref name="Westfall">{{cite book |title=Goodman & Gilman's Pharmacological Basis of Therapeutics |vauthors=Westfall DP, Westfall TC |publisher=McGraw-Hill |year=2010 |isbn=978-0-07-162442-8 |veditors=Brunton LL, Chabner BA, Knollmann BC |edition=12th |location=New York, US |section=Miscellaneous Sympathomimetic Agonists |quote=Dextrorotatory substitution on the α-carbon generally results in a more potent compound. d-Amphetamine is more potent than l-amphetamine in central but not peripheral activity.&nbsp;... In eliciting CNS excitatory effects, the d-isomer (dextroamphetamine) is three to four times more potent than the l-isomer.}}</ref> however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.<ref name="NCAA">{{cite web |date=January 2012 | vauthors = Bracken NM | title=National Study of Substance Use Trends Among NCAA College Student-Athletes | url=http://www.ncaapublications.com/productdownloads/SAHS09.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://www.ncaapublications.com/productdownloads/SAHS09.pdf |archive-date=9 October 2022 |url-status=live | website=NCAA Publications | publisher = National Collegiate Athletic Association | access-date=8 October 2013}}</ref><ref name="WADA & AD regulation">{{cite journal | author = Docherty JR | title = Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) | journal =British Journal of Pharmacology| volume = 154 | issue = 3 | pages = 606–622 | date = June 2008 | pmid = 18500382 | pmc = 2439527 | doi = 10.1038/bjp.2008.124}}</ref> In healthy people at oral therapeutic doses, amphetamine has been shown to increase [[physical strength|muscle strength]],<!-- Refs:"Ergogenics" & "Ergogenics2" --> acceleration,<!-- Refs:"Ergogenics" & "Ergogenics2" --> athletic performance in [[anaerobic exercise|anaerobic conditions]],<!-- Refs:"Ergogenics" & "Ergogenics2" --> and [[endurance]] (i.e., it delays the onset of [[fatigue (medical)|fatigue]]),<!-- Refs:"Ergogenics" & "Ergogenics2" & "Roelands_2013" --> while improving [[mental chronometry|reaction time]].<ref name="Ergogenics" /><ref name="Ergogenics2" /><ref name="Roelands_2013" /> Amphetamine improves endurance and reaction time primarily through [[Reuptake inhibitor|reuptake inhibition]] and [[Releasing agent|release]] of dopamine in the central nervous system.<ref name="Ergogenics2" /><ref name="Roelands_2013">{{cite journal |vauthors=Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R | title = Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing | journal =Sports Medicine| volume = 43 | issue = 5 | pages = 301–311 |date=May 2013 | pmid = 23456493 | doi = 10.1007/s40279-013-0030-4 | s2cid = 30392999 | quote = In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo.&nbsp;... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is 'off-limits' in a normal (placebo) situation.}}</ref><ref name="Amph-DA reaction time">{{cite journal |vauthors=Parker KL, Lamichhane D, Caetano MS, Narayanan NS | title = Executive dysfunction in Parkinson's disease and timing deficits | journal =Frontiers in Integrative Neuroscience| volume = 7 | page = 75 | date = October 2013 | pmid = 24198770 | pmc = 3813949 | doi = 10.3389/fnint.2013.00075 | quote = Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing. | doi-access = free | title-link = doi }}</ref> Amphetamine and other dopaminergic drugs also increase power output at fixed [[rating of perceived exertion|levels of perceived exertion]] by overriding a "safety switch", allowing the [[Human body temperature|core temperature limit]] to increase in order to access a reserve capacity that is normally off-limits.<ref name="Roelands_2013" /><ref name="Central mechanisms affecting exertion">{{cite journal | vauthors = Rattray B, Argus C, Martin K, Northey J, Driller M | title = Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance? | journal =Frontiers in Physiology| volume = 6 | page = 79 | date = March 2015 | pmid = 25852568 | pmc = 4362407 | doi = 10.3389/fphys.2015.00079 | quote = Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009).&nbsp;... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)| doi-access = free | title-link = doi }}</ref><ref name="Monoamine+drug effects on exercise - fatigue and heat">{{cite journal | vauthors = Roelands B, De Pauw K, Meeusen R | title = Neurophysiological effects of exercise in the heat | journal =Scandinavian Journal of Medicine & Science in Sports| volume = 25 |issue=Suppl 1 | pages = 65–78 | date = June 2015 | pmid = 25943657 | doi = 10.1111/sms.12350 | s2cid = 22782401 | quote = This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the "safety switch" or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.| doi-access = free | title-link = doi }}</ref> At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;<ref name="Ergogenics" /><ref name="Ergogenics2" /> however, at much higher doses, amphetamine can induce effects that severely impair performance, such as [[rhabdomyolysis|rapid muscle breakdown]] and [[hyperthermia|elevated body temperature]].<ref name="FDA">{{cite web | title=Adderall XR- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate capsule, extended release | website=DailyMed | publisher = Shire US Inc. | date=17 July 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aff45863-ffe1-4d4f-8acf-c7081512a6c0 | access-date=22 December 2019}}</ref><ref name="Ergogenics2">{{cite journal |author =Parr JW |title=Attention-deficit hyperactivity disorder and the athlete: new advances and understanding |journal=Clinics in Sports Medicine|volume=30 |issue=3 |pages=591–610 |date=July 2011 |pmid=21658550 |doi=10.1016/j.csm.2011.03.007 |quote=In 1980, Chandler and Blair<sup>47</sup> showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.}}</ref>

===Recreational===
Amphetamine, specifically the more dopaminergic [[dextrorotatory]] enantiomer ([[dextroamphetamine]]), is also used recreationally as a euphoriant and aphrodisiac, and like other [[amphetamines]]; is used as a [[club drug]] for its energetic and euphoric high. Dextroamphetamine (d-amphetamine) is considered to have a high potential for misuse in a [[recreational drug use|recreational manner]] since individuals typically report feeling [[euphoria|euphoric]], more alert, and more energetic after taking the drug.<ref>{{cite web|url=http://www.drugabuse.gov/drugs-abuse/commonly-abused-drugs/commonly-abused-prescription-drugs-chart |title=Commonly Abused Prescription Drugs Chart |publisher=National Institute on Drug Abuse|access-date=7 May 2012}}</ref><ref>{{cite web |url=http://www.drugabuse.gov/publications/infofacts/stimulant-adhd-medications-methylphenidate-amphetamines |title=Stimulant ADHD Medications – Methylphenidate and Amphetamines |publisher=National Institute on Drug Abuse |access-date=7 May 2012 |archive-date=2 May 2012 |archive-url=https://web.archive.org/web/20120502072325/http://www.drugabuse.gov/publications/infofacts/stimulant-adhd-medications-methylphenidate-amphetamines }}</ref><ref name="NIDA ADHD stimulants" /> A notable part of the 1960s [[mod subculture]] in the UK was recreational amphetamine use, which was used to fuel all-night dances at clubs like Manchester's [[Twisted Wheel Club|Twisted Wheel]]. Newspaper reports described dancers emerging from clubs at 5 a.m. with dilated pupils.<ref name="mixing the medicine">{{cite journal | vauthors = Wilson A |title=Mixing the Medicine: The Unintended Consequence of Amphetamine Control on the Northern Soul Scene |year=2008 |journal=The Internet Journal of Criminology |ssrn=1339332 |url=http://www.internetjournalofcriminology.com/Wilson%20-%20Mixing%20the%20Medicine.pdf |archive-url=https://web.archive.org/web/20110713045851/http://www.internetjournalofcriminology.com/Wilson%20-%20Mixing%20the%20Medicine.pdf|archive-date=13 July 2011 }}</ref> Mods used the drug for [[stimulation]] and [[alertness]], which they viewed as different from the [[Substance intoxication|intoxication]] caused by alcohol and other drugs.<ref name="mixing the medicine" /> Dr. Andrew Wilson argues that for a significant minority, "amphetamines symbolised the smart, on-the-ball, cool image" and that they sought "stimulation not intoxication [...] greater awareness, not escape" and "[[confidence]] and articulacy" rather than the "[[Alcohol intoxication|drunken]] rowdiness of previous generations."<ref name="mixing the medicine" /> Dextroamphetamine's [[dopaminergic]] (rewarding) properties affect the [[mesocorticolimbic circuit]]; a group of neural structures responsible for [[incentive salience]] (i.e., "wanting"; desire or craving for a reward and motivation), [[positive reinforcement]] and [[Valence (psychology)|positively-valenced]] emotions, particularly ones involving [[pleasure]].<ref name=Schultz>{{cite journal | vauthors = Schultz W | year = 2015 | title = Neuronal reward and decision signals: from theories to data | journal = Physiological Reviews | volume = 95 | issue = 3 | pages = 853–951 | pmid = 26109341 | pmc = 4491543 | doi=10.1152/physrev.00023.2014 | quote = Rewards in operant conditioning are positive reinforcers.&nbsp;... Operant behavior gives a good definition for rewards. Anything that makes an individual come back for more is a positive reinforcer and therefore a reward. Although it provides a good definition, positive reinforcement is only one of several reward functions.&nbsp;... Rewards are attractive. They are motivating and make us exert an effort.&nbsp;... Rewards induce approach behavior, also called appetitive or preparatory behavior, sexual behavior, and consummatory behavior.&nbsp;... Thus any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward.&nbsp;... Rewarding stimuli, objects, events, situations, and activities consist of several major components. First, rewards have basic sensory components (visual, auditory, somatosensory, gustatory, and olfactory)&nbsp;... Second, rewards are salient and thus elicit attention, which are manifested as orienting responses. The salience of rewards derives from three principal factors, namely, their physical intensity and impact (physical salience), their novelty and surprise (novelty/surprise salience), and their general motivational impact shared with punishers (motivational salience). A separate form not included in this scheme, incentive salience, primarily addresses dopamine function in addiction and refers only to approach behavior (as opposed to learning)&nbsp;... Third, rewards have a value component that determines the positively motivating effects of rewards and is not contained in, nor explained by, the sensory and attentional components. This component reflects behavioral preferences and thus is subjective and only partially determined by physical parameters. Only this component constitutes what we understand as a reward. It mediates the specific behavioral reinforcing, approach generating, and emotional effects of rewards that are crucial for the organism's survival and reproduction, whereas all other components are only supportive of these functions.&nbsp;... Rewards can also be intrinsic to behavior. They contrast with extrinsic rewards that provide motivation for behavior and constitute the essence of operant behavior in laboratory tests. Intrinsic rewards are activities that are pleasurable on their own and are undertaken for their own sake, without being the means for getting extrinsic rewards.&nbsp;... Intrinsic rewards are genuine rewards in their own right, as they induce learning, approach, and pleasure, like perfectioning, playing, and enjoying the piano. Although they can serve to condition higher order rewards, they are not conditioned, higher order rewards, as attaining their reward properties does not require pairing with an unconditioned reward.&nbsp;... These emotions are also called liking (for pleasure) and wanting (for desire) in addiction research and strongly support the learning and approach generating functions of reward.}}</ref> Large recreational doses of dextroamphetamine may produce [[#Overdose|symptoms of dextroamphetamine overdose]].<ref name="NIDA ADHD stimulants" /> Recreational users sometimes open dexedrine capsules and crush the contents in order to insufflate (snort) it or subsequently dissolve it in water and inject it.<ref name="NIDA ADHD stimulants">{{cite web|title=National Institute on Drug Abuse. 2009. Stimulant ADHD Medications – Methylphenidate and Amphetamines|url=https://nida.nih.gov/publications/research-reports/misuse-prescription-drugs/overview|archive-url=https://web.archive.org/web/20220127060519/https://nida.nih.gov/publications/research-reports/misuse-prescription-drugs/overview|archive-date=27 January 2022|publisher=National Institute on Drug Abuse|access-date=27 February 2013}}</ref> Immediate-release formulations have higher potential for abuse via insufflation (snorting) or intravenous injection due to a more favorable pharmacokinetic profile and easy crushability (especially tablets).<ref name="CADDRA_2018">{{cite book |title=Canadian ADHD Practice Guidelines |date=2018 |publisher=Canadian ADHD Resource Alliance |page=67 |edition=Fourth |url=https://www.caddra.ca/wp-content/uploads/CADDRA-Guidelines-4th-Edition_-Feb2018.pdf |access-date=2 May 2023 |archive-date=2 May 2023 |archive-url=https://web.archive.org/web/20230502204112/https://www.caddra.ca/wp-content/uploads/CADDRA-Guidelines-4th-Edition_-Feb2018.pdf }}</ref><ref name="Bright2008">{{cite journal | vauthors = Bright GM | title = Abuse of medications employed for the treatment of ADHD: results from a large-scale community survey | journal = Medscape Journal of Medicine | volume = 10 | issue = 5 | page = 111 | date = May 2008 | pmid = 18596945 | pmc = 2438483 }}</ref> Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.<ref name="NIDA ADHD stimulants" /> Chronic overuse of dextroamphetamine can lead to severe [[drug dependence]], resulting in withdrawal symptoms when drug use stops.<ref name="NIDA ADHD stimulants" />

==Contraindications==
<noinclude>{{See also|Amphetamine#Drug interactions}}</noinclude>
According to the [[International Programme on Chemical Safety]] (IPCS) and the U.S. [[United States Food and Drug Administration|Food and Drug Administration]] (FDA),{{#tag:ref|The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA. USFDA contraindications are not necessarily intended to limit medical practice but limit claims by pharmaceutical companies.<ref name="pmid8545689">{{cite journal | vauthors = Kessler S | title = Drug therapy in attention-deficit hyperactivity disorder | journal =Southern Medical Journal| volume = 89 | issue = 1 | pages = 33–38 | date = January 1996 | pmid = 8545689 |quote = 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| s2cid = 12798818 }}</ref>|group="note"}} amphetamine is [[contraindicated]] in people with a history of [[drug abuse]],{{#tag:ref|According to one review, amphetamine can be prescribed to individuals with a history of abuse provided that appropriate medication controls are employed, such as requiring daily pick-ups of the medication from the prescribing physician.<ref name="Amph Uses" />|group="note"}} [[cardiovascular disease]], severe [[Irritability|agitation]], or severe anxiety.<ref name="Evekeo">{{cite web | title=Evekeo- amphetamine sulfate tablet | website=DailyMed | publisher=Arbor Pharmaceuticals, LLC | date=14 August 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f469fb38-0380-4621-9db3-a4f429126156 | access-date=22 December 2019}}</ref><ref name="FDA"/><ref name="International" /> It is also contraindicated in individuals with advanced [[arteriosclerosis]] (hardening of the arteries), [[glaucoma]] (increased eye pressure), [[hyperthyroidism]] (excessive production of thyroid hormone), or moderate to severe [[hypertension]].<ref name="Evekeo" /><ref name="FDA" /><ref name="International"/> These agencies indicate that people who have experienced [[hypersensitivity|allergic reactions]] to other stimulants or who are taking [[monoamine oxidase inhibitor]]s (MAOIs) should not take amphetamine,<ref name="Evekeo" /><ref name="FDA" /><ref name="International" /> although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.<ref name="Review MAOI-amph">{{cite journal | vauthors = Feinberg SS | title = Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication | journal =The Journal of Clinical Psychiatry| volume = 65 | issue = 11 | pages = 1520–1524 | date = November 2004 | pmid = 15554766 | doi=10.4088/jcp.v65n1113}}</ref><ref name="Primary MAOI-amph">{{cite journal | vauthors = Stewart JW, Deliyannides DA, McGrath PJ | title = How treatable is refractory depression? | journal =Journal of Affective Disorders| volume = 167 | pages = 148–152 | date = June 2014 | pmid = 24972362 | doi = 10.1016/j.jad.2014.05.047}}</ref> These agencies also state that anyone with [[anorexia nervosa]], [[bipolar disorder]], depression, hypertension, liver or kidney problems, [[mania]], [[psychosis]], [[Raynaud's phenomenon]], [[seizure]]s, [[thyroid]] problems, [[tic]]s, or [[Tourette syndrome]] should monitor their symptoms while taking amphetamine.<ref name="FDA" /><ref name="International" /> Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human [[Teratology|teratogen]]), but amphetamine abuse does pose risks to the fetus.<ref name="International" /> Amphetamine has also been shown to pass into breast milk, so the IPCS and the FDA advise mothers to avoid breastfeeding when using it.<ref name="FDA" /><ref name="International" /> Due to the potential for reversible growth impairments,{{#tag:ref|In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.<ref name="Long-Term Outcomes Medications" /><ref name="Millichap" /><ref name="pmid18295156" /> The average reduction in final adult height from 3&nbsp;years of continuous stimulant therapy is 2&nbsp;cm.<ref name="pmid18295156" />|group="note"}} the FDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.<ref name="FDA" />

==Adverse effects==
<noinclude>The [[adverse effect|adverse side effect]]s of amphetamine are many and varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of adverse effects.<ref name="FDA" /><ref name="Westfall" /> Amphetamine products such as [[Adderall]], Dexedrine, and their generic equivalents are currently approved by the U.S. FDA for long-term therapeutic use.<ref name="NDCD" /><ref name="FDA" /> [[Recreational drug use#Stimulants|Recreational use]] of amphetamine generally involves much larger doses, which have a greater risk of serious adverse drug effects than dosages used for therapeutic purposes.<ref name="Westfall" /></noinclude>

===Physical===
[[Cardiovascular]] side effects can include [[hypertension]] or [[hypotension]] from a [[vasovagal response]], [[Raynaud's phenomenon]] (reduced blood flow to the hands and feet), and [[tachycardia]] (increased heart rate).<ref name="FDA" /><ref name="Westfall" /><ref name="pmid18295156">{{cite journal | author = Vitiello B | title = Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function | journal =Child and Adolescent Psychiatric Clinics of North America| volume = 17 | issue = 2 | pages = 459–474 |date=April 2008 | pmid = 18295156 | pmc = 2408826 | doi = 10.1016/j.chc.2007.11.010 }}</ref> Sexual side effects in males may include [[erectile dysfunction]], frequent erections, or [[priapism|prolonged erections]].<ref name="FDA" /> Gastrointestinal side effects may include [[abdominal pain]], [[constipation]], [[diarrhea]], and [[nausea]].<ref name="Stahl's Essential Psychopharmacology" /><ref name="FDA" /><ref name="Dyanavel">{{cite web |title=Dyanavel XR- amphetamine suspension, extended release |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a8a7eb93-4192-4826-bbf1-82c06634f553 |website=DailyMed |publisher= Tris Pharma, Inc. |access-date=22 December 2019 |date=6 February 2019 |quote=DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1&nbsp;... The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6 to 12 years) were: epistaxis, allergic rhinitis and upper abdominal pain.&nbsp;... <br />DOSAGE FORMS AND STRENGTHS<br />Extended-release oral suspension contains 2.5 mg amphetamine base equivalents per mL.}}</ref> Other potential physical side effects include [[Anorexia (symptom)|appetite loss]], [[blurred vision]], [[xerostomia|dry mouth]], [[bruxism|excessive grinding of the teeth]], nosebleed, profuse sweating, [[rhinitis medicamentosa]] (drug-induced nasal congestion), reduced [[seizure threshold]], [[tics]] (a type of movement disorder), and [[weight loss]].{{#tag:ref|<ref name="Stahl's Essential Psychopharmacology" /><ref name="FDA" /><ref name="Westfall" /><ref name="pmid18295156" /><ref name="Dyanavel" /><ref name="rhinitis">{{cite journal | vauthors = Ramey JT, Bailen E, Lockey RF | title = Rhinitis medicamentosa | journal =Journal of Investigational Allergology & Clinical Immunology| volume = 16 | issue = 3 | pages = 148–155 | year = 2006 | pmid = 16784007 | access-date = 29 April 2015 | url = https://www.jiaci.org/issues/vol16issue03/1.pdf | quote = Table 2. Decongestants Causing Rhinitis Medicamentosa<br /> – Nasal decongestants:<br />&nbsp;– Sympathomimetic:<br />&nbsp;&nbsp; • Amphetamine}}</ref>|group="sources"}} Dangerous physical side effects are rare at typical pharmaceutical doses.<ref name="Westfall" />

Amphetamine stimulates the [[Respiratory center|medullary respiratory centers]], producing faster and deeper breaths.<ref name="Westfall"/> In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.<ref name="Westfall" /> Amphetamine also induces [[Muscle contraction|contraction]] in the urinary [[Detrusor muscle|bladder sphincter]], the muscle which controls urination, which can result in difficulty urinating.<ref name="Westfall" /> This effect can be useful in treating [[enuresis|bed wetting]] and [[urinary incontinence|loss of bladder control]].<ref name="Westfall" /> The effects of amphetamine on the gastrointestinal tract are unpredictable.<ref name="Westfall" /> If intestinal activity is high, amphetamine may reduce [[gastrointestinal motility]] (the rate at which content moves through the digestive system);<ref name="Westfall" /> however, amphetamine may increase motility when the [[smooth muscle tissue|smooth muscle]] of the tract is relaxed.<ref name="Westfall" /> Amphetamine also has a slight [[analgesic]] effect and can enhance the pain relieving effects of [[opioid]]s.<ref name="Stahl's Essential Psychopharmacology">{{cite book | vauthors=Stahl SM | title=Prescriber's Guide: Stahl's Essential Psychopharmacology | date=March 2017 | publisher=Cambridge University Press | location=Cambridge, United Kingdom | isbn=978-1-108-22874-9 | pages=45–51 | edition=6th | chapter-url=https://books.google.com/books?id=9hssDwAAQBAJ&pg=PA45 | chapter=Amphetamine (D,L) | access-date=5 August 2017 }}</ref><ref name="Westfall" />

FDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events ([[sudden cardiac death|sudden death]], [[myocardial infarction|heart attack]], and [[stroke]]) and the medical use of amphetamine or other ADHD stimulants.{{#tag:ref|<ref name="FDA - cardiovascular effects in young individuals">{{cite web | title=FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults | date=1 November 2011 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-medications-used-treat-attention | website=United States Food and Drug Administration | access-date=24 December 2019 | archive-url=https://web.archive.org/web/20190825032123/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-medications-used-treat-attention | archive-date=25 August 2019 }}</ref><ref name="pmid22043968">{{cite journal |vauthors=Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA | title = ADHD drugs and serious cardiovascular events in children and young adults | journal =New England Journal of Medicine| volume = 365 | issue = 20 | pages = 1896–1904 |date=November 2011 | pmid = 22043968 | doi = 10.1056/NEJMoa1110212 | pmc=4943074}}</ref><ref name="FDA - cardiovascular effects in adults">{{cite web | title=FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults | date=12 December 2011 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-medications-used-treat-attention-0 | website=United States Food and Drug Administration | access-date=24 December 2013 | archive-url=https://web.archive.org/web/20191214114954/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-medications-used-treat-attention-0 | archive-date=14 December 2019 }}</ref><ref name="pmid22161946">{{cite journal |vauthors=Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA, Selby JV | title = ADHD medications and risk of serious cardiovascular events in young and middle-aged adults |date=December 2011 | journal =JAMA| volume = 306 | issue = 24 | pages = 2673–2683 | pmid = 22161946 | pmc = 3350308 | doi = 10.1001/jama.2011.1830 }}</ref>|group="sources"}} These findings were subsequently corroborated by a 2022 meta-analysis that sampled nearly four million participants, which found no association between therapeutic use of amphetamine and the development of [[cardiovascular disease]] in any age group.<ref>{{Cite journal |vauthors=Zhang L, Yao H, Li L, Du Rietz E, Andell P, Garcia-Argibay M, D'Onofrio BM, Cortese S, Larsson H, Chang Z |date=2022-11-01 |title=Risk of Cardiovascular Diseases Associated With Medications Used in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis |journal=JAMA Network Open |volume=5 |issue=11 |pages=e2243597 |doi=10.1001/jamanetworkopen.2022.43597 |pmc=9685490 |pmid=36416824 |quote=This systematic review and meta-analysis based on 19 observational studies with more than 3.9 million participants suggested that there was no statistically significant association between ADHD medications and the risk of cardiovascular events among children and adolescents, young and middle-aged adults, or older adults. |doi-access=free}}</ref> However, amphetamine pharmaceuticals are [[contraindicated]] in individuals with preexisting cardiovascular disease.{{#tag:ref|<ref name="FDA" /><ref name="International">{{cite web |vauthors=Heedes G, Ailakis J | title=Amphetamine (PIM 934) | url=http://www.inchem.org/documents/pims/pharm/pim934.htm | website=INCHEM | publisher=International Programme on Chemical Safety | access-date=24 June 2014 }}</ref><ref name="FDA - cardiovascular effects in young individuals" /><ref name="FDA - cardiovascular effects in adults" />|group="sources"}}

===Psychological===
At normal therapeutic doses, the most common psychological side effects of amphetamine include increased [[alertness]], apprehension, [[mental concentration|concentration]], initiative, [[self-confidence]] and sociability, mood swings ([[euphoria|elated mood]] followed by mildly [[dysphoria|depressed mood]]), [[insomnia]] or [[wakefulness]], and decreased sense of fatigue.<ref name="FDA" /><ref name="Westfall" /> Less common side effects include [[anxiety (mood)|anxiety]], change in [[libido]], [[grandiosity]], [[irritability]], repetitive or [[Fixation (psychology)|obsessive]] behaviors, and restlessness;{{#tag:ref|<ref name="Libido">{{cite journal | author = Montgomery KA | title = Sexual desire disorders | journal =Psychiatry | volume = 5 | issue = 6 | pages = 50–55 |date=June 2008 | pmid = 19727285 | pmc = 2695750}}</ref><ref name="FDA" /><ref name="Westfall" /><ref name="Merck_Manual_Amphetamines">{{cite web | url = http://www.merckmanuals.com/professional/special_subjects/drug_use_and_dependence/amphetamines.html | author = O'Connor PG | title = Amphetamines | website = Merck Manual for Health Care Professionals | publisher = Merck |date=February 2012 | access-date = 8 May 2012 }}</ref>|group="sources"}} these effects depend on the user's personality and current mental state.<ref name="Westfall" /> [[Amphetamine psychosis]] (e.g., [[delusion]]s and [[paranoia]]) can occur in heavy users.<ref name="FDA" /><ref name="Cochrane">{{cite journal | veditors = Shoptaw SJ, Ali R |vauthors=Shoptaw SJ, Kao U, Ling W | title = Treatment for amphetamine psychosis | journal =Cochrane Database of Systematic Reviews| issue = 1 | article-number = CD003026 | date = January 2009 |volume=2009 | pmid = 19160215 | doi = 10.1002/14651858.CD003026.pub3 |pmc=7004251 | quote=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.<br />psychotic symptoms of individuals with amphetamine psychosis may be due exclusively to heavy use of the drug or heavy use of the drug may exacerbate an underlying vulnerability to schizophrenia.}}</ref><ref name="Amphetamine-induced psychosis">{{cite journal | vauthors = Bramness JG, Gundersen ØH, Guterstam J, Rognli EB, Konstenius M, Løberg EM, Medhus S, Tanum L, Franck J | title = Amphetamine-induced psychosis—a separate diagnostic entity or primary psychosis triggered in the vulnerable? | journal =BMC Psychiatry| volume = 12 | article-number = 221 | date = December 2012 | pmid = 23216941 | pmc = 3554477 | doi = 10.1186/1471-244X-12-221 | quote = In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine&nbsp;... Secondly, psychosis has been viewed as an adverse event, although rare, in children with ADHD who have been treated with amphetamine | doi-access = free | title-link = doi }}</ref> Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.<ref name="FDA" /><ref name="Amphetamine-induced psychosis" /><ref name="Stimulant Misuse">{{cite web | author = Greydanus D | title=Stimulant Misuse: Strategies to Manage a Growing Problem | type=Review Article | url=http://www.acha.org/prof_dev/ADHD_docs/ADHD_PDprogram_Article2.pdf | archive-url=https://web.archive.org/web/20131103155156/http://www.acha.org/prof_dev/ADHD_docs/ADHD_PDprogram_Article2.pdf | website=American College Health Association | publisher=ACHA Professional Development Program | access-date=2 November 2013 | archive-date=3 November 2013 | page=20}}</ref> According to the FDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.<ref name="FDA" />

Amphetamine has also been shown to produce a [[conditioned place preference]] in humans taking therapeutic doses,<ref name="Cochrane Amphetamines ADHD" /><ref name="Human CPP">{{cite journal | vauthors = Childs E, de Wit H | title = Amphetamine-induced place preference in humans | journal =Biological Psychiatry| volume = 65 | issue = 10 | pages = 900–904 | date = May 2009 | pmid = 19111278 | pmc = 2693956 | doi = 10.1016/j.biopsych.2008.11.016 | quote = 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> meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.<ref name="Human CPP" /><ref name="Addiction glossary" />

===Reinforcement disorders===

====Addiction====
{{Addiction glossary|collapse=y|width=610px}}
{{Transcription factor glossary|collapse=y|width=610px}}
{{Psychostimulant addiction|align=right|header=[[Signaling cascade]] in the [[nucleus accumbens]] that results in amphetamine addiction}}
[[Addiction]] is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;<ref name="NHMH_3e-Addiction doses">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE, Holtzman DM | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2015 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-182770-6 | edition = 3rd | chapter = Chapter 16: Reinforcement and Addictive Disorders | quote= 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">{{cite journal | vauthors = Kollins SH | title = A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders | journal =Current Medical Research and Opinion| volume = 24 | issue = 5 | pages = 1345–1357 | date = May 2008 | pmid = 18384709 | doi = 10.1185/030079908X280707 | s2cid = 71267668 | quote = 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="narcolepsy addiction" /> in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing [[substance use disorder]]s as an adult.<ref name="Long-Term Outcomes Medications" /> {{if pagename | Lisdexamfetamine= Compared to other amphetamine pharmaceuticals, lisdexamfetamine may have a lower liability for abuse as a recreational drug.<ref name="LDX abuse">{{cite journal | vauthors = Coghill DR, Caballero B, Sorooshian S, Civil R | title = A systematic review of the safety of lisdexamfetamine dimesylate | journal =CNS Drugs| volume = 28 | issue = 6 | pages = 497–511 | date = June 2014 | pmid = 24788672 | pmc = 4057639 | doi = 10.1007/s40263-014-0166-2 | quote = The prodrug formulation of LDX may also lead to reduced abuse potential of LDX compared with immediate-release d-AMP. }}</ref>| other=}} Pathological overactivation of the [[mesolimbic pathway]], a [[dopamine pathway]] that connects the [[ventral tegmental area]] to the [[nucleus accumbens]], plays a central role in amphetamine addiction.<ref name="Amphetamine KEGG – ΔFosB">{{cite web | title=Amphetamine – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05031 | website=KEGG Pathway | access-date=31 October 2014 | author=Kanehisa Laboratories | date=10 October 2014}}</ref><ref name="Magnesium" /> Individuals who frequently [[Self-administration|self-administer]] high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of [[accumbal]] [[ΔFosB]], a "molecular switch" and "master control protein" for addiction.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /><ref name="Nestler" /> Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression.<ref name="What the ΔFosB?">{{cite journal | author = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal =The American Journal of Drug and Alcohol Abuse| volume = 40 | issue = 6 | pages = 428–437 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | s2cid = 19157711 | quote = 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" /> While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction.<ref name="Running vs addiction" /><ref name="Exercise, addiction prevention, and ΔFosB">{{cite journal | vauthors = Zhou Y, Zhao M, Zhou C, Li R | title = Sex differences in drug addiction and response to exercise intervention: From human to animal studies | journal =Frontiers in Neuroendocrinology| date = July 2015 | pmid = 26182835 | doi = 10.1016/j.yfrne.2015.07.001 | volume=40 | pages=24–41 | quote = 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;... The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.| pmc = 4712120 }}</ref> Exercise therapy improves [[wikt:clinical|clinical]] treatment outcomes and may be used as an [[adjunct therapy]] with behavioral therapies for addiction.<ref name="Running vs addiction" /><ref name="Exercise Rev 3" /><ref name="Exercise therapy" group="sources" />

====Biomolecular mechanisms====
Chronic use of amphetamine at excessive doses causes alterations in [[gene expression]] in the [[mesocorticolimbic projection]], which arise through [[transcriptional]] and [[epigenetic]] mechanisms.<ref name="Nestler" /><ref name="Nestler, Hyman, and Malenka 2">{{cite journal |vauthors=Hyman SE, Malenka RC, Nestler EJ |title=Neural mechanisms of addiction: the role of reward-related learning and memory |journal=Annual Review of Neuroscience|volume=29 |pages=565–598 |date=July 2006 |pmid=16776597 |doi=10.1146/annurev.neuro.29.051605.113009|s2cid=15139406 }}</ref><ref name="Addiction genetics" /> The most important [[transcription factor]]s{{#tag:ref|Transcription factors are proteins that increase or decrease the [[gene expression|expression]] of specific genes.<ref name="NHM-Transcription factor">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, US | isbn = 978-0-07-148127-4 | page = 94 | edition = 2nd | chapter = Chapter 4: Signal Transduction in the Brain | quote= <!-- All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug. -->}}</ref>|group="note"}} that produce these alterations are ''Delta FBJ murine osteosarcoma viral oncogene homolog B'' ([[ΔFosB]]), ''[[Cyclic adenosine monophosphate|cAMP]] response element binding protein'' ([[cAMP response element binding protein|CREB]]), and ''nuclear factor-kappa B'' ([[NF-κB]]).<ref name="Nestler" /> ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB [[overexpression]] (i.e., an abnormally high level of gene expression which produces a pronounced gene-related [[phenotype]]) in the [[D1-type]] [[medium spiny neuron]]s in the [[nucleus accumbens]] is [[necessary and sufficient]]{{#tag:ref|In simpler terms, this ''necessary and sufficient'' relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.|group="note"}} for many of the neural adaptations and regulates multiple behavioral effects (e.g., [[reward sensitization]] and escalating drug [[self-administration]]) involved in addiction.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /><ref name="Nestler" /> Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /> It has been implicated in addictions to [[alcoholism|alcohol]], [[cannabinoid]]s, [[cocaine]], [[methylphenidate]], [[nicotine]], [[opioid]]s, [[phencyclidine]], [[propofol]], and [[substituted amphetamines]], among others.{{#tag:ref|<ref name="What the ΔFosB?" /><!--Preceding review covers ΔFosB in propofol addiction --><ref name="Natural and drug addictions" /><ref name="Nestler" /><ref name="Alcoholism ΔFosB">{{cite web | title=Alcoholism – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 | website=KEGG Pathway | access-date=31 October 2014 | author=Kanehisa Laboratories | date=29 October 2014}}</ref><ref name="MPH ΔFosB">{{cite journal | vauthors = Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P | title = Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens | journal =Proceedings of the National Academy of Sciences| volume = 106 | issue = 8 | pages = 2915–2920 | date = February 2009 | pmid = 19202072 | pmc = 2650365 | doi = 10.1073/pnas.0813179106 | quote = <!-- Despite decades of clinical use of methylphenidate for ADHD, concerns have been raised that long-term treatment of children with this medication may result in subsequent drug abuse and addiction. However, meta analysis of available data suggests that treatment of ADHD with stimulant drugs may have a significant protective effect, reducing the risk for addictive substance use (36, 37). Studies with juvenile rats have also indicated that repeated exposure to methylphenidate does not necessarily lead to enhanced drug-seeking behavior in adulthood (38). However, the recent increase of methylphenidate use as a cognitive enhancer by the general public has again raised concerns because of its potential for abuse and addiction (3, 6–10). Thus, although oral administration of clinical doses of methylphenidate is not associated with euphoria or with abuse problems, nontherapeutic use of high doses or i.v. administration may lead to addiction (39, 40). --> | bibcode = 2009PNAS..106.2915K| doi-access = free | title-link = doi }}</ref>|group="sources"}}

[[ΔJunD]], a transcription factor, and [[EHMT2|G9a]], a [[histone methyltransferase]] enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.<ref name="Cellular basis" /><ref name="Nestler" /><ref name="Nestler 2014 epigenetics">{{cite journal | vauthors = Nestler EJ | title = Epigenetic mechanisms of drug addiction | journal =Neuropharmacology| volume = 76 | issue = Pt B | pages = 259–268 | date = January 2014 | pmid = 23643695 | pmc = 3766384 | doi = 10.1016/j.neuropharm.2013.04.004 | quote = <!-- Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors.&nbsp;... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).<br />G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a).&nbsp;... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. -->}}</ref> Sufficiently overexpressing ΔJunD in the nucleus accumbens with [[viral vector]]s can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).<ref name="Nestler" /> Similarly, accumbal G9a hyperexpression results in markedly increased [[histone]] 3 [[lysine]] [[residue (biochemistry)|residue]] 9 [[Epigenetic methylation|dimethylation]] ([[H3K9me2]]) and blocks the induction of ΔFosB-mediated [[neuroplasticity|neural]] and [[behavioral plasticity]] by chronic drug use,{{#tag:ref|<ref name="Nestler" /><ref name="G9a reverses ΔFosB plasticity">{{cite journal | vauthors = Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T | title = Epigenetic regulation in drug addiction | journal = Annals of Agricultural and Environmental Medicine | volume = 19 | issue = 3 | pages = 491–496 | year = 2012 | pmid = 23020045 | url = http://www.aaem.pl/Epigenetic-regulation-in-drug-addiction,71809,0,2.html }}</ref><ref name="HDACi-induced G9a+H3K9me2 primary source">{{cite journal | vauthors = Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ | title = Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation | journal = Nature Neuroscience | volume = 16 | issue = 4 | pages = 434–440 | date = April 2013 | pmid = 23475113 | pmc = 3609040 | doi = 10.1038/nn.3354 }}</ref><ref name="A feat of epigenetic engineering">{{cite journal | vauthors = Whalley K | title = Psychiatric disorders: a feat of epigenetic engineering | journal = Nature Reviews. Neuroscience | volume = 15 | issue = 12 | pages = 768–769 | date = December 2014 | pmid = 25409693 | doi = 10.1038/nrn3869 | s2cid = 11513288 | doi-access = free | title-link = doi }}</ref>|group="sources"}} which occurs via [[H3K9me2]]-mediated [[gene repression|repression]] of [[transcription factor]]s for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., [[CDK5]]).<ref name="Nestler" /><ref name="Nestler 2014 epigenetics" /><ref name="G9a reverses ΔFosB plasticity" /> ΔFosB also plays an important role in regulating behavioral responses to [[natural reward]]s, such as palatable food, sex, and exercise.<ref name="Natural and drug addictions" /><ref name="Nestler" /><ref name="ΔFosB reward">{{cite journal |vauthors=Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M | title = Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms | journal = Journal of Psychoactive Drugs | volume = 44 | issue = 1 | pages = 38–55 | date = March 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112| quote = It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus.&nbsp;... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance.&nbsp;... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.}}</ref> Since both natural rewards and addictive drugs [[inducible gene|induce the expression]] of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.<ref name="Natural and drug addictions" /><ref name="Nestler">{{cite journal |vauthors=Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal =Nature Reviews Neuroscience| volume = 12 | issue = 11 | pages = 623–637 |date=November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB has been linked directly to several addiction-related behaviors&nbsp;... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure<sup>14,22–24</sup>. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.&nbsp;... ΔFosB serves as one of the master control proteins governing this structural plasticity.}}</ref> Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced [[sexual addiction]]s, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.<ref name="Natural and drug addictions" /><ref name="Amph-Sex X-sensitization through D1 signaling"><!-- Supplemental primary source -->{{cite journal |vauthors=Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM | title = Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator | journal =The Journal of Neuroscience | volume = 33 | issue = 8 | pages = 3434–3442 |date=February 2013 | pmid = 23426671 | pmc = 3865508 | doi = 10.1523/JNEUROSCI.4881-12.2013}}</ref><ref name="Amph-Sex X-sensitization through NMDA signaling"><!-- Supplemental primary source -->{{cite journal | vauthors = Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM | title = Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats | journal =Neuropharmacology| volume = 101 | pages = 154–164 | date = February 2016 | pmid = 26391065 | doi = 10.1016/j.neuropharm.2015.09.023| s2cid = 25317397 }}</ref> These sexual addictions are associated with a [[dopamine dysregulation syndrome]] which occurs in some patients taking [[dopaminergic#Supplements and drugs|dopaminergic drugs]].<ref name="Natural and drug addictions" /><ref name="ΔFosB reward" />

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

=====Pharmacological treatments=====
<!-- warning! This section is transcluded to other articles (like Adderall), and as such must not invoke reference tags from elsewhere in this article -->
{{Further|Addiction#Research}}
{{As of|December 2019|post=,}} there is no effective [[pharmacotherapy]] for amphetamine addiction.<ref name="NHMH_3e-Physical dependence + psychostimulant addiction treatment">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE, Holtzman DM | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2015 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-182770-6 | edition = 3rd | chapter = Chapter 16: Reinforcement and Addictive Disorders | quote = Pharmacologic treatment for psychostimulant addiction is generally unsatisfactory. As previously discussed, cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria, anhedonia, and an intense desire to reinitiate drug use.}}</ref><ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" /><ref name="pmid24716825">{{cite journal | vauthors = Stoops WW, Rush CR | title = Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research | journal =Expert Review of Clinical Pharmacology| volume = 7 | issue = 3 | pages = 363–374 | date = May 2014 | pmid = 24716825 | doi = 10.1586/17512433.2014.909283 | quote = Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved. | pmc = 4017926 }}</ref> Reviews from 2015 and 2016 indicated that [[TAAR1]]-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;<ref name="Miller+Grandy 2016" /><ref name="TAAR1 addiction 2015" /> however, {{As of|February 2016|lc=y|post=,}} the only compounds which are known to function as TAAR1-selective agonists are [[experimental drug]]s.<ref name="Miller+Grandy 2016">{{cite journal | vauthors = Grandy DK, Miller GM, Li JX | title = "TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference | journal =Drug and Alcohol Dependence| volume = 159 | pages = 9–16 | date = February 2016 | pmid = 26644139 | doi = 10.1016/j.drugalcdep.2015.11.014 | quote = When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.| pmc = 4724540 }}</ref><ref name="TAAR1 addiction 2015">{{cite journal | vauthors = Jing L, Li JX | title = Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction | journal =European Journal of Pharmacology| volume = 761 | pages = 345–352 | date = August 2015 | pmid = 26092759 | doi = 10.1016/j.ejphar.2015.06.019 | quote = Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction. | pmc=4532615}}</ref> Amphetamine addiction is largely mediated through increased activation of [[dopamine receptor]]s and {{nowrap|[[wikt:colocalize|co-localized]]}} [[NMDA receptor]]s{{#tag:ref|NMDA receptors are voltage-dependent [[ligand-gated ion channels]] that requires simultaneous binding of glutamate and a co-agonist ({{nowrap|[[D-serine|{{smallcaps all|D}}-serine]]}} or [[glycine]]) to open the ion channel.<ref name="NHM-NMDA">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, US | isbn = 978-0-07-148127-4 | pages = 124–125 | edition = 2nd | chapter = Chapter 5: Excitatory and Inhibitory Amino Acids | quote = <!-- At membrane potentials more negative than approximately −50 mV, the Mg<sup>2+</sup> in the extracellular fluid of the brain virtually abolishes ion flux through NMDA receptor channels, even in the presence of glutamate.&nbsp;... The NMDA receptor is unique among all neurotransmitter receptors in that its activation requires the simultaneous binding of two different agonists. In addition to the binding of glutamate at the conventional agonist-binding site, the binding of glycine appears to be required for receptor activation. Because neither of these agonists alone can open this ion channel, glutamate and glycine are referred to as coagonists of the NMDA receptor. The physiologic significance of the glycine binding site is unclear because the normal extracellular concentration of glycine is believed to be saturating. However, recent evidence suggests that D-serine may be the endogenous agonist for this site. -->}}</ref>|group="note"}} in the nucleus accumbens;<ref name="Magnesium" /> [[magnesium|magnesium ions]] inhibit NMDA receptors by blocking the receptor [[calcium channel]].<ref name="Magnesium" /><ref name="NHM-NMDA" /> One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.<ref name="Magnesium" /> [[Dietary supplement|Supplemental magnesium]]{{#tag:ref|The review indicated that [[magnesium aspartate|magnesium {{nowrap|L-aspartate}}]] and [[magnesium chloride]] produce significant changes in addictive behavior;<ref name="Magnesium" /> other forms of magnesium were not mentioned.|group="note"}} treatment has been shown to reduce amphetamine [[self-administration]] (i.e., doses given to oneself) in humans, but it is not an effective [[monotherapy]] for amphetamine addiction.<ref name="Magnesium">{{cite journal |author =Nechifor M |title=Magnesium in drug dependences |journal=Magnesium Research|volume=21 |issue=1 |pages=5–15 |date=March 2008 |pmid=18557129 |doi=10.1684/mrh.2008.0124|doi-broken-date=9 July 2025 |url=https://www.jle.com/10.1684/mrh.2008.0124}}</ref>

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

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

Additionally, research on the [[neurobiological effects of physical exercise]] suggests that daily aerobic exercise, especially endurance exercise (e.g., [[marathon running]]), prevents the development of drug addiction and is an effective [[adjunct therapy]] (i.e., a supplemental treatment) for amphetamine addiction.{{#tag:ref|<ref name="Natural and drug addictions" /><ref name="Running vs addiction" /><ref name="Exercise, addiction prevention, and ΔFosB" /><ref name="Exercise Rev 3" /><ref name="Addiction review 2016" />|group="sources"|name="Exercise therapy"}} Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.<ref name="Running vs addiction">{{cite journal |vauthors=Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA | title = Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis | journal =Neuroscience & Biobehavioral Reviews| volume = 37 | issue = 8 | pages = 1622–1644 |date=September 2013 | pmid = 23806439 | pmc = 3788047 | doi = 10.1016/j.neubiorev.2013.06.011 | quote = These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug.&nbsp;... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes&nbsp;... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.}}</ref><ref name="Exercise Rev 3">{{cite journal | vauthors = Linke SE, Ussher M | title = Exercise-based treatments for substance use disorders: evidence, theory, and practicality | journal =The American Journal of Drug and Alcohol Abuse| volume = 41 | issue = 1 | pages = 7–15 | date = January 2015 | pmid = 25397661 | doi = 10.3109/00952990.2014.976708 | quote = The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published.&nbsp;... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects. | pmc=4831948}}</ref><ref name="Addiction review 2016">{{cite journal | vauthors = Carroll ME, Smethells JR | title = Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments | journal =Frontiers in Psychiatry| volume = 6 | page = 175 | date = February 2016 | pmid = 26903885 | pmc = 4745113 | doi = 10.3389/fpsyt.2015.00175 | quote = Physical Exercise<br />There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction&nbsp;... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse.&nbsp;... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis.&nbsp;... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.| doi-access = free | title-link = doi }}</ref> In particular, [[aerobic exercise]] decreases psychostimulant self-administration, reduces the [[reinstatement]] (i.e., relapse) of drug-seeking, and induces increased [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]] (DRD2) density in the [[striatum]].<ref name="Natural and drug addictions" /><ref name="Addiction review 2016" /> This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.<ref name="Natural and drug addictions">{{cite journal | author = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal =Neuropharmacology| volume = 61 | issue = 7 | pages = 1109–1122 | date = December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005).&nbsp;... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008). }}</ref> One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or {{nowrap|[[c-Fos]]}} [[immunoreactivity]] in the striatum or other parts of the [[reward system]].<ref name="Exercise, addiction prevention, and ΔFosB" />
{{FOSB addiction table|Table title=Summary of addiction-related plasticity}}

====Dependence and withdrawal====
[[Drug tolerance]] develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect.<ref name="Cochrane 2013 treatments">{{cite journal | vauthors = Perez-Mana C, Castells X, Torrens M, Capella D, Farre M | title = Efficacy of psychostimulant drugs for amphetamine abuse or dependence | journal =Cochrane Database of Systematic Reviews| volume = 2013 | issue = 9 | article-number = CD009695 | date = September 2013 | pmid = 23996457 | doi = 10.1002/14651858.CD009695.pub2 | pmc = 11521360 }}</ref><ref>{{cite web| title = Amphetamines: Drug Use and Abuse | website = Merck Manual Home Edition | publisher = Merck | url = http://www.merckmanuals.com/home/special_subjects/drug_use_and_abuse/amphetamines.html | access-date = 28 February 2007 | archive-url = https://web.archive.org/web/20070217053619/http://www.merck.com/mmhe/sec07/ch108/ch108g.html |date=February 2003 | archive-date = 17 February 2007}}</ref>
According to a Cochrane 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">{{cite journal |vauthors=Shoptaw SJ, Kao U, Heinzerling K, Ling W | title = Treatment for amphetamine withdrawal | journal =Cochrane Database of Systematic Reviews| issue = 2 | article-number = CD003021 | date = April 2009 | volume = 2009 | pmid = 19370579 | doi = 10.1002/14651858.CD003021.pub2 | veditors = Shoptaw SJ | quote = 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&nbsp;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;... | pmc = 7138250}}</ref> This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for {{nowrap|3–4}}&nbsp;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" />

According to a 2025 review, the discontinuation of amphetamine at therapeutic doses does not typically result in withdrawal symptoms.<ref name="2025_Leaver">{{Cite journal | vauthors = Leaver L |date=2025-06-03 |title=Medical management of ADHD in adults: part 2 |journal=Drug and Therapeutics Bulletin |volume=63 |issue=6 |pages=85–93 |doi=10.1136/dtb.2025.000019 |pmid=40461172 |quote=Tolerance to stimulants is rare (<3%) at least after the initial dose titration period. If there are repeated requests for increasing doses, this might suggest non- medical use, or that treatment goals may not reflect what ADHD medication can achieve. Drug 'holidays' are not necessary to avoid the risk of tolerance (but may be helpful to assess or mitigate adverse effects, or to establish continuing need for treatment).&nbsp;...<br /> There are many SPCs for different stimulants mention the possibility of withdrawal symptoms. In practice, many patients experience periods without medication but do not suffer withdrawal symptoms. Discontinuation may unmask symptoms of ADHD, but small trials of discontinuing therapeutic doses of methylphenidate and lisdexamfetamine have not found withdrawal symptoms.&nbsp;... Premenstrual increase in stimulant dose may be helpful. |doi-access=free}}</ref> Discontinuation may unmask or cause a rebound of ADHD symptoms due to the cessation of treatment-related drug effects.<ref name="2025_Leaver" /> In cases where mild withdrawal symptoms do occur, they can be avoided by tapering the dose.<ref name="Stahl's Essential Psychopharmacology" /> Unlike amphetamine abuse, where drug tolerance necessitates escalating doses to achieve the same effect, tolerance to clinically relevant doses of amphetamine plateaus after the initial titration period, and "drug holidays" (i.e., temporary treatment discontinuation) are not required to prevent the development of tolerance.<ref name="2025_Leaver" />

==Overdose==
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.<ref name="Stahl's Essential Psychopharmacology" /><ref name="International" /><ref name="Amphetamine toxidrome">{{cite journal |vauthors=Spiller HA, Hays HL, Aleguas A | title = Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management | journal =CNS Drugs| volume = 27| issue = 7| pages = 531–543|date=June 2013 | pmid = 23757186 | doi = 10.1007/s40263-013-0084-8 | s2cid = 40931380 |quote=Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.| doi-access = free | title-link = doi }}</ref> The severity of overdose symptoms increases with dosage and decreases with [[drug tolerance]] to amphetamine.<ref name="Westfall" /><ref name="International" /> Tolerant individuals have been known to take as much as 5&nbsp;grams of amphetamine in a day, which is roughly 100&nbsp;times the maximum daily therapeutic dose.<ref name="International" /> Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and [[coma]].<ref name="FDA" /><ref name="Westfall" /> In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "[[amphetamine use disorder]]" resulted in an estimated 3,788&nbsp;deaths worldwide ({{nowrap|3,425–4,145}}&nbsp;deaths, [[95% confidence interval|95%&nbsp;confidence]]).{{#tag:ref|The 95%&nbsp;confidence interval indicates that there is a 95%&nbsp;probability that the true number of deaths lies between 3,425 and 4,145.|group="note"}}<ref name=GDB2013>{{cite journal | vauthors = ((GBD 2013 Mortality and Causes of Death Collaborators)) | title = Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 | journal =The Lancet| volume = 385 | issue = 9963 | pages = 117–171 | date = January 2015 | pmid = 25530442 | pmc = 4340604 | doi = 10.1016/S0140-6736(14)61682-2 | hdl = 11655/15525 | doi-access = free | title-link = doi }}</ref>

{| class="wikitable center" style="margin: 1em auto;"
|+ Overdose symptoms by system
! scope="col" style="text-align:center"| System
! scope="col" style="width: 40%;"| Minor or moderate overdose<ref name="FDA" /><ref name="Westfall" /><ref name="International" />
! scope="col" style="width: 50%;"| Severe overdose{{#tag:ref|<ref name="Acute amph toxicity">{{cite journal |vauthors=Greene SL, Kerr F, Braitberg G | title = Review article: amphetamines and related drugs of abuse | journal =Emergency Medicine Australasia| volume = 20 | issue = 5 | pages = 391–402 | date = October 2008 | pmid = 18973636 | doi = 10.1111/j.1742-6723.2008.01114.x | s2cid = 20755466 }}</ref><ref name="FDA" /><ref name="Westfall" /><ref name="Amphetamine toxidrome" /><ref name="Albertson_2011">{{cite book|veditors=Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AH | title = Poisoning & Drug Overdose | author = Albertson TE| year = 2011 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-166833-0 | chapter = Amphetamines | pages = 77–79 | edition = 6th }}</ref>| group = "sources"}}
|-
! scope="row"| [[Cardiovascular system|Cardiovascular]]
|
* [[Cardiac dysrhythmia|Abnormal heartbeat]]
* [[Hypertension|High]] or [[Hypotension|low blood pressure]]
|
* [[Cardiogenic shock]] (heart not pumping enough blood)
* [[Cerebral hemorrhage]] (bleeding in the brain)
* [[Circulatory collapse]] (partial or complete failure of the [[circulatory system]])
|-
! scope="row"| [[Central nervous system|Central nervous<br />system]]
|
* Confusion
* [[Hyperreflexia|Abnormally fast reflexes]]
* Severe agitation
* [[Tremor]] (involuntary muscle twitching)
|
* [[Stimulant psychosis#Substituted amphetamines|Acute amphetamine psychosis]] (e.g., [[delusion]]s and [[paranoia]])
* [[Stereotypy|Compulsive and repetitive movement]]
* [[Serotonin syndrome]] (excessive serotonergic nerve activity)
* [[Sympathomimetic toxidrome]] (excessive adrenergic nerve activity)
|-
! scope="row"| [[Musculoskeletal system|Musculoskeletal]]
|
* [[Myalgia|Muscle pain]]
|
* [[Rhabdomyolysis]] (rapid muscle breakdown)
|-
! scope="row"| [[Respiratory system|Respiratory]]
|
* Rapid breathing
|
* [[Pulmonary edema]] (fluid accumulation in the lungs)
* [[Pulmonary hypertension]] (high blood pressure in the [[Pulmonary artery|arteries of the lung]])
* [[Respiratory alkalosis]] (reduced blood [[carbon dioxide|CO<sub>2</sub>]])
|-
! scope="row"| [[Urogenital system|Urinary]]
|
* [[Dysuria|Painful urination]]
* [[Urinary retention]] (inability to urinate)
|
* [[Anuria|No urine production]]
* [[Kidney failure]]
|-
! scope="row"| Other
|
* [[Hyperthermia|Elevated body temperature]]
* [[Mydriasis]] (dilated pupils)
|
* [[Hyperkalemia|Elevated]] or [[Hypokalemia|low blood potassium]]
* [[Hyperpyrexia]] (extremely elevated [[core body temperature]])
* [[Metabolic acidosis]] (excessively acidic bodily fluids)
|}

===Toxicity===
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">{{cite journal| vauthors = Advokat C| title=Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD | journal=Journal of Attention Disorders| date = July 2007 | volume= 11 | issue= 1 | pages= 8–16 | pmid=17606768 | doi=10.1177/1087054706295605| s2cid=7582744 }}</ref><ref name="Amph-induced hyperthermia and neurotoxicity review" /> There is no evidence that amphetamine is directly neurotoxic in humans.<ref>{{cite web | title=Amphetamine | url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+300-62-9 | website=United States National Library of Medicine&nbsp;– Toxicology Data Network | publisher=Hazardous Substances Data Bank | access-date=2 October 2017 | archive-url=https://web.archive.org/web/20171002194327/https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/cgi-bin/sis/search2/f?.%2Ftemp%2F~mdjW95%3A1%3AFULL | archive-date=2 October 2017 | quote=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">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, US | isbn = 978-0-07-148127-4 | page = 370 | edition = 2nd | chapter = Chapter 15: Reinforcement and addictive disorders | quote = 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"/><ref name="Amph-induced hyperthermia and neurotoxicity review" /><ref name="Autoxidation1">{{cite journal |vauthors=Sulzer D, Zecca L | title = Intraneuronal dopamine-quinone synthesis: a review | journal =Neurotoxicity Research| volume = 1 | issue = 3 | pages = 181–195 |date=February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289 | s2cid = 21892355 }}</ref><ref name="Autoxidation2">{{cite journal |vauthors=Miyazaki I, Asanuma M | title = Dopaminergic neuron-specific oxidative stress caused by dopamine itself | journal =Acta Medica Okayama| volume = 62 | issue = 3 | pages = 141–150 |date=June 2008 | pmid = 18596830| url = http://ousar.lib.okayama-u.ac.jp/files/public/3/30980/20160528022138672578/fulltext.pdf | doi=10.18926/AMO/30942}}</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">{{cite journal | vauthors = Bowyer JF, Hanig JP | title = Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity | journal =Temperature| volume = 1 | issue = 3 | pages = 172–182 | date = November 2014 | pmid = 27626044 | pmc = 5008711 | doi = 10.4161/23328940.2014.982049 | quote = Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40&nbsp;°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production.&nbsp;... 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" />

===Psychosis===
{{See also|Stimulant psychosis}}
An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.<ref name="Cochrane" /><ref name="Amphetamine-induced psychosis"/> A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about {{nowrap|5–15%}} of users fail to recover completely.<ref name="Cochrane"/><ref name="Hofmann">{{cite book | author = Hofmann FG | title = A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects | publisher = Oxford University Press | isbn = 978-0-19-503057-0 | location = New York, US | year = 1983 | page = [https://archive.org/details/handbookondrugal0002hofm/page/329 329] | edition = 2nd | url = https://archive.org/details/handbookondrugal0002hofm/page/329 }}</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 rarely arises from therapeutic use.<ref name="FDA" /><ref name="Amphetamine-induced psychosis" /><ref name="Stimulant Misuse" />

==Drug interactions{{anchor|Interactions}}==
{{See also|Amphetamine#Contraindications|Amphetamine#Pharmacokinetics}}
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" /> [[enzyme inhibitor|Inhibitors of enzyme]]s 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"/> 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" /> therefore, concurrent use of both is dangerous.<ref name="FDA" /> 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" /> Amphetamine may also decrease the effects of [[antihypertensives]] and [[antipsychotic]]s due to its effects on blood pressure and dopamine respectively.<ref name="FDA" /> [[Zinc supplementation]] may reduce the [[minimum effective dose]] of amphetamine when it is used for the treatment of ADHD.{{#tag:ref|The human [[dopamine transporter]] (hDAT) contains a [[affinity (pharmacology)|high-affinity]], extracellular, and [[Allosteric modulator|allosteric]] [[zinc|Zn<sup>2+</sup>]] (zinc ion) [[binding site]] which, upon zinc binding, inhibits dopamine [[reuptake]], inhibits amphetamine-induced hDAT internalization, and amplifies amphetamine-induced [[neurotransmitter efflux|dopamine efflux]].<ref name="Allosteric Zn2+ regulation of hDAT 2019 Review">{{cite journal | vauthors = Hasenhuetl PS, Bhat S, Freissmuth M, Sandtner W | title = Functional Selectivity and Partial Efficacy at the Monoamine Transporters: A Unified Model of Allosteric Modulation and Amphetamine-Induced Substrate Release | journal = Molecular Pharmacology | volume = 95 | issue = 3 | pages = 303–312 | date = March 2019 | pmid = 30567955 | doi = 10.1124/mol.118.114793 | s2cid = 58557130 | quote = Although the monoamine transport cycle has been resolved in considerable detail, kinetic knowledge on the molecular actions of synthetic allosteric modulators is still scarce. Fortunately, the DAT catalytic cycle is allosterically modulated by an endogenous ligand (namely, Zn<sup>2+</sup>; Norregaard et al., 1998). It is worth consulting Zn<sup>2+</sup> as an instructive example, because its action on the DAT catalytic cycle has been deciphered to a large extent&nbsp;... Zn+ binding stabilizes the outward-facing conformation of DAT&nbsp;... This potentiates both the forward-transport mode (i.e., DA uptake; Li et al., 2015) and the substrate-exchange mode (i.e., amphetamine-induced DA release; Meinild et al., 2004; Li et al., 2015). Importantly, the potentiating effect on substrate uptake is only evident when internal Na<sup>+</sup> concentrations are low&nbsp;... If internal Na<sup>+</sup> concentrations rise during the experiment, the substrate-exchange mode dominates and the net effect of Zn<sup>2+</sup> on uptake is inhibitory. Conversely, Zn<sup>2+</sup> accelerates amphetamine-induced substrate release via DAT.&nbsp;... t is important to emphasize that Zn<sup>2+</sup> has been shown to reduce dopamine uptake under conditions that favor intracellular Na<sup>+</sup> accumulation<br />—Fig. 3. Functional selectivity by conformational selection. | doi-access = free | title-link = doi }}</ref><ref name="Zinc binding sites + ADHD review">{{cite journal | vauthors = Krause J | title = SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder | journal =Expert Review of Neurotherapeutics| volume = 8 | issue = 4 | pages = 611–625 | date = April 2008 | pmid = 18416663 | doi = 10.1586/14737175.8.4.611 | s2cid = 24589993 | quote = 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="Primary 2002 amph-zinc study">{{cite journal | vauthors = Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH | title = The role of zinc ions in reverse transport mediated by monoamine transporters | journal =Journal of Biological Chemistry| volume = 277 | issue = 24 | pages = 21505–21513 | date = June 2002 | pmid = 11940571 | doi = 10.1074/jbc.M112265200 | s2cid = 10521850 | quote = The human dopamine transporter (hDAT) contains an endogenous high affinity Zn<sup>2+</sup> binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396).&nbsp;... Although Zn<sup>2+</sup> inhibited uptake, Zn<sup>2+</sup> 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 Zn<sup>2+</sup> to the superfusion buffer (Fig. 2 A, open squares).&nbsp;... The concentrations of Zn<sup>2+</sup> 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.&nbsp;... Thus, when Zn<sup>2+</sup> is co-released with glutamate, it may greatly augment the efflux of dopamine.| doi-access = free | title-link = doi }}</ref><ref name="pmid16684900">{{cite journal | vauthors = Kahlig KM, Lute BJ, Wei Y, Loland CJ, Gether U, Javitch JA, Galli A | title = Regulation of dopamine transporter trafficking by intracellular amphetamine | journal =Molecular Pharmacology| volume = 70 | issue = 2 | pages = 542–548 | date = August 2006 | pmid = 16684900 | doi = 10.1124/mol.106.023952 | s2cid = 10317113 | quote = Coadministration of Zn(2+) and AMPH consistently reduced WT-hDAT trafficking}}</ref> The human [[serotonin transporter]] and [[norepinephrine transporter]] do not contain zinc binding sites.<ref name="Primary 2002 amph-zinc study" />|name="zinc"|group="note"}}<ref name="Zinc and PEA">{{cite journal |vauthors=Scassellati C, Bonvicini C, Faraone SV, Gennarelli M | title = Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses | journal =Journal of the American Academy of Child & Adolescent Psychiatry| volume = 51 | issue = 10 | pages = 1003–1019.e20 | date = October 2012 | pmid = 23021477 | doi = 10.1016/j.jaac.2012.08.015 | quote = 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% reduction in amphetamine optimal dose with 30&nbsp;mg per day of zinc.<sup>110</sup>}}</ref> [[Norepinephrine reuptake inhibitor]]s (NRIs) like [[atomoxetine]] prevent [[norepinephrine]] release induced by amphetamines and have been found to reduce the [[stimulant]], [[euphoriant]], and [[sympathomimetic]] effects of [[dextroamphetamine]] in humans.<ref name="TreuerGauMéndez2013">{{cite journal | vauthors = Treuer T, Gau SS, Méndez L, Montgomery W, Monk JA, Altin M, Wu S, Lin CC, Dueñas HJ | title = A systematic review of combination therapy with stimulants and atomoxetine for attention-deficit/hyperactivity disorder, including patient characteristics, treatment strategies, effectiveness, and tolerability | journal = J Child Adolesc Psychopharmacol | volume = 23 | issue = 3 | pages = 179–193 | date = April 2013 | pmid = 23560600 | pmc = 3696926 | doi = 10.1089/cap.2012.0093 | url = }}</ref><ref name="HealSmithFindling2012">{{cite book | vauthors = Heal DJ, Smith SL, Findling RL | title = Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment | chapter = ADHD: current and future therapeutics | series = Current Topics in Behavioral Neurosciences | volume = 9 | pages = 361–390 | date = 2012 | pmid = 21487953 | doi = 10.1007/7854_2011_125 | isbn = 978-3-642-24611-1 | chapter-url = | quote = Adjunctive therapy with DL-methylphenidate in atomoxetine partial responders has been successful (Wilens et al. 2009), but this also increases the rates of insomnia, irritability and loss of appetite (Hammerness et al. 2009). This combination therapy has not included amphetamine because blockade of NET by atomoxetine prevents entry of amphetamine into presynaptic noradrenergic terminals (Sofuoglu et al. 2009). }}</ref><ref name="SofuogluPolingHill2009">{{cite journal | vauthors = Sofuoglu M, Poling J, Hill K, Kosten T | title = Atomoxetine attenuates dextroamphetamine effects in humans | journal = Am J Drug Alcohol Abuse | volume = 35 | issue = 6 | pages = 412–416 | date = 2009 | pmid = 20014909 | pmc = 2796580 | doi = 10.3109/00952990903383961 | url = }}</ref>

In general, there is no significant interaction when consuming amphetamine with food, but the [[pH]] of gastrointestinal content and urine affects the [[Absorption (pharmacokinetics)|absorption]] and [[excretion]] of amphetamine, respectively.<ref name="FDA" /> Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.<ref name="FDA" /> Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as [[proton pump inhibitor]]s and [[H2 antagonist|H<sub>2</sub> antihistamines]], which increase gastrointestinal pH (i.e., make it less acidic).<ref name="FDA" />

==Pharmacology==

===Pharmacodynamics===
{{For|a simpler and less technical explanation of amphetamine's mechanism of action|Adderall#Mechanism of action}}
{{Amphetamine pharmacodynamics}}
Amphetamine exerts its behavioral effects by altering the use of [[monoamines]] as neuronal signals in the brain, primarily in [[catecholamine]] neurons in the reward and executive function pathways of the brain.<ref name="Miller" /><ref name="cognition enhancers" /> The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine because of its effects on [[monoamine transporter]]s.<ref name="Miller" /><ref name="cognition enhancers" /><ref name="E Weihe" /> The [[reinforcement|reinforcing]] and [[motivational salience]]-promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the [[mesolimbic pathway]].<ref name="Malenka_2009" /> The [[euphoric]] and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the [[striatum]].<ref name="Amph Uses" />

Amphetamine potentiates monoaminergic neurotransmission primarily by entering [[axon terminal]]s either through active transport by monoamine transporters ({{nowrap|[[Dopamine transporter|DAT]], [[Norepinephrine|NET]], and [[Serotonin transporter|SERT]]}}) or by passive diffusion across [[neuronal membrane]]s.<ref name="Stahl2021">{{Cite book |title=Stahl's essential psychopharmacology: neuroscientific basis and practical applications |vauthors=Stahl SM |publisher=Cambridge University Press |year=2021 |isbn=978-1-108-97529-2 |edition=5th |location=Cambridge |pages=471–73 |quote=Unlike methylphenidate and reuptake blocking drugs used for depression, amphetamine is a competitive inhibitor and pseudosubstrate for NETs and DATs (Figure 11-32, top left), binding at the same site that the monoamines bind to the transporters, thus inhibiting NE and DA reuptake. At the doses of amphetamine used for the treatment of ADHD, the clinical differences between the actions of amphetamine versus methylphenidate can be relatively small. However, at the high doses of amphetamine used by stimulant addicts, additional pharmacological actions of amphetamine are triggered.&nbsp;...<br /> Once there in sufficient quantities, such as occurs at doses taken for abuse, amphetamine is also a competitive inhibitor of the vesicular transporter (VMAT2) for both DA and NE. Once amphetamine hitch-hikes another ride into synaptic vesicles, it displaces DA there, causing a flood of DA release. As DA accumulates in the cytoplasm of the presynaptic neuron, it causes the DATs to reverse directions, spilling intracellular DA into the synapse, and also opening presynaptic channels to further release DA in a flood into the synapse. These pharmacological actions of high-dose amphetamine are not linked to therapeutic action in ADHD but to reinforcement, reward, and euphoria in amphetamine abuse. &nbsp;...<br /> The D-isomer of amphetamine is more potent than the L-isomer for DAT binding, but D- and L- amphetamine isomers are more equally potent in their actions on NET binding. Thus, D-amphetamine preparations will have relatively more action on DATs at lower therapeutic doses utilized for the treatment of ADHD.}}</ref><ref name="handbook2022_DAT">{{Cite book |title=Handbook of Substance Misuse and Addictions |vauthors=Tendilla-Beltran H, Arroyo-García LE, Flores G |publisher=Springer International Publishing |year=2022 |isbn=978-3-030-92391-4 |veditors=Patel VB, Preedy VR |location=Cham |pages=2176–2177 |chapter=Chapter 102: Amphetamine and the Biology of Neuronal Morphology |doi=10.1007/978-3-030-92392-1_115 |quote=At low concentrations, amphetamines (extracellular) and dopamine (intracellular) are interchanged as described by the exchange diffusion model&nbsp;... Amphetamines can also increase dopaminergic transmission by channel-like transport which involves second-messenger signaling. Amphetamines increase PKC activity, which increase DAT N-terminus domain phosphorylation, and consequently DAT activity, which, because of the amphetamines, will release dopamine from the presynaptic terminal.&nbsp; PKC and CaMKIIα-mediated reverse transport have also been demonstrated in NET&nbsp;...<br /> Also, amphetamines can indirectly enhance monoaminergic neurotransmission through the stimulation of trace amine-associated receptor 1 (TAAR1) (Underhill et al. 2021). TAAR1 is an intracellular G protein-coupled receptor (GPCR), which has activity that promotes the endocytosis of both DAT and the excitatory amino acid transporter 3 (EAAT3). DAT endocytosis, together with the aforementioned mechanisms, contributes to the enhancement of the dopaminergic neurotransmission.&nbsp;... <br /> It is important to note that amphetamines also stimulate protein kinase A (PKA) activity, which in turn inhibits RhoA activity and consequently reduces DAT internalization.}}</ref> The uptake of amphetamine through these transporters competitively [[Reuptake inhibitor|inhibits the reuptake]] of monoamine neurotransmitters from the [[synaptic cleft]], thereby elevating their synaptic concentrations.<ref name="Stahl2021" /><ref name="Caye_2019" /> Once inside the neuronal [[cytosol]], amphetamine initiates intracellular [[Biochemical cascade|signaling cascades]] involving [[Protein kinase|protein kinases]], including [[protein kinase C]] (PKC) and [[Ca2+/calmodulin-dependent protein kinase II alpha|Ca²⁺/calmodulin-dependent protein kinase II alpha]] (CaMKIIα), leading to the [[phosphorylation]] of specific monoamine transporters and modification of their activity.<ref name="handbook2022_DAT" /><ref name="Caye_2019" /> PKC-mediated phosphorylation can either reverse transporter function to facilitate neurotransmitter efflux into the synaptic cleft or induce [[Endocytosis|transporter internalization]], resulting in non-competitive inhibition of neurotransmitter reuptake.<ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review">{{cite journal |vauthors=Bermingham DP, Blakely RD |date=October 2016 |title=Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters |journal=Pharmacol. Rev. |volume=68 |issue=4 |pages=888–953 |doi=10.1124/pr.115.012260 |pmc=5050440 |pmid=27591044 |quote=<!--RhoA signaling--> The Amara laboratory recently provided evidence that AMPH triggered DAT endocytosis is clathrin-independent and requires the small GTPase Rho (Wheeler et al., 2015)...<!--CAMKII signaling--> Whereas little support for CaMKII regulation of DA uptake exists, substantial evidence supports a role for the kinase in DAT-dependent DA efflux triggered by AMPH... Importantly, AMPH treatment of DAT transfected cells produced a rise in intracellular Ca2+ that could be blocked by thapsigargin or cocaine, supporting a model whereby AMPH is first transported into cells where it can then produce release of endoplasmic reticulum Ca2+ stores. Subsequently, AMPH was shown to activate CaMKII in DAT transfected cells (Wei et al., 2007).&nbsp;... At present, information is lacking as to the site(s) that support CaMKII phosphorylation of DAT in vivo ... The current model... DAT by phosphorylating one or more Ser residues in the transporter N terminus. This phosphorylation is then thought to facilitate conformational changes that place the transporter in a "DA efflux-willing" conformation.}}</ref> In contrast, CaMKIIα-mediated transporter phosphorylation selectively reverses DAT and NET to confer dopamine and norepinephrine efflux respectively, but unlike PKC does not terminate transporter function through internalization.<ref name="handbook2022_DAT" /><ref name="2020_Reith">{{cite journal |vauthors=Reith ME, Gnegy ME |date=2020 |title=Molecular Mechanisms of Amphetamines |journal=Handbook of Experimental Pharmacology |volume=258 |pages=265–297 |doi=10.1007/164_2019_251 |pmid=31286212 |isbn=978-3-030-33678-3 |quote=At lower doses, amphetamine preferentially releases a newly synthesized pool of DA. Administration of the tyrosine hydroxylase inhibitor α-methyl-para-tyrosine (AMPT) simultaneously with amphetamine blocks the DA-releasing effect of amphetamine (Smith 1963; Weissman et al. 1966; Chiueh and Moore 1975; Butcher et al. 1988).&nbsp;...<br /> Undoubtedly vesicles contribute strongly to the maximal DA released by amphetamine, although VMAT2 is not absolutely required for amphetamine to release DA from nerve terminals (Pifl et al. 1995; Fon et al. 1997; Wang et al. 1997; Patel et al. 2003).&nbsp;...<br /> However, the study in rat PC12 cells and hDAT-HEK293 cells demonstrated some involvement of extracellular Ca2+ (effect of nisoxetine or removal of extracellular Ca2+) and as well as of Ca2+ stores in the endoplasmic reticulum (blockade by thapsigargin) (Gnegy et al. 2004).&nbsp;...<br /> The increase in intracellular Ca2+ stimulated by amphetamine activates two major modulators of amphetamine action: protein kinase C (PKC) and Ca2+ and calmodulin-stimulated protein kinase II (CaMKII).}}</ref>

Amphetamine has been identified as a [[full agonist]] of [[TAAR1|trace amine-associated receptor 1]] (TAAR1), a {{nowrap|[[Gs alpha subunit|G<sub>s</sub>-coupled]]}} and [[G12/G13 alpha subunits|G<sub>13</sub>-coupled]] [[G protein-coupled receptor]] (GPCR) discovered in 2001, which is important for regulation of brain monoamines.<ref name="Miller" /><ref name="handbook2022_TAAR1" /> Several reviews have linked amphetamine's agonism at TAAR1 to modulation of monoamine transporter function and subsequent neurotransmitter efflux and reuptake inhibition at monoaminergic synapses.{{#tag:ref|<ref name="Caye_2019">{{Cite journal |vauthors=Caye A, Swanson JM, Coghill D, Rohde LA |year=2019 |title=Treatment strategies for ADHD: an evidence-based guide to select optimal treatment |journal=Molecular Psychiatry |volume=24 |issue=3 |pages=390–408 |doi=10.1038/s41380-018-0116-3 |issn=1476-5578 |pmid=29955166 |quote=Amphetamines have at least three mechanisms of action: (1) they are transported by the monoamine transporters DAT and NET, thus competing with those neurotransmitters and decreasing their reuptake in the synapse; (2) They also cause trace amine-associated receptor 1 (TAAR1) to phosphorylate DAT. The phosphorylated DAT is either internalized into the presynaptic neuron and ceases transport or inverses the efflux of dopamine; (3) they enter the presynaptic monoamine vesicle and cause efflux of neurotransmitters off the vesicle, which in turn augments the efflux towards the synapse. These mechanisms are more studied and established for dopamine neurotransmission, but are thought to occur similarly for norepinephrine.}}</ref><ref name="Miller" /><ref name="handbook2022_DAT" /><ref name="2022 T1 LDX">{{Cite journal |vauthors=Quintero J, Gutiérrez-Casares JR, Álamo C |date=11 August 2022 |title=Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review |journal=Neurology and Therapy |volume=11 |issue=4 |pages=1489–1517 |doi=10.1007/s40120-022-00392-2 |issn= |pmc=9588136 |pmid=35951288 |quote=The active form of the drug has a central nervous system stimulating activity by the primary inhibition of DAT, NET, trace amine-associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (SLC18A2), among other targets, therefore regulating the reuptake and release of catecholamines (primarily NE and DA) on the synaptic cleft.&nbsp;...<br /> LDX can also promote the increase of DA in the synaptic cleft by activating protein TAAR1, which produces the efflux of monoamine NTs, mainly DA, from storage sites on presynaptic neurons. TAAR1 activation leads to intracellular cAMP signalling that results in PKA and PKC phosphorylation and activation. This PKC activation decreases DAT1, NET1 and SERT cell surface expression, intensifying the direct blockage of monoamine transporters by LDX and improving the neurotransmission imbalance in ADHD. |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Garey JD, Lusskin SI, Scialli AR |year=2020 |title=Teratogen update: Amphetamines |journal=Birth Defects Research |volume=112 |issue=15 |pages=1171–1182 |doi=10.1002/bdr2.1774 |pmid=32755038 |quote=According to a systematic review of the literature on CNS actions of amphetamine by Faraone (2018), the primary pharmacologic effect of amphetamine is to increase central dopamine and norepinephrine activity. The trace amine-associated receptor 1 (TAAR1) is a G-coupled receptor expressed in the monoaminergic regions of the brain (Lam et al., 2018). When activated by appropriate ligands including methamphetamine, dopaminergic function is modulated (Miner, Elmore, Baumann, Phillips, & Janowsky, 2017).&nbsp;...<br /> It has long been assumed that amphetamines are indirectly acting sympathomimetic amines, with responses being due to the release of norepinephrine from sympathetic neurons (Broadley, 2010). With the discovery of TAAR in blood vessels and evidence that amphetamine binds to these receptors, it has been suggested that the vasoconstrictor effect may be due in part to this additional mechanism (Broadley, Fehler, Ford, & Kidd, 2013).}}</ref><ref name="TAAR1_cAMP2025">{{Cite journal |vauthors=Dalvi S, Bhatt LK |year=2025 |title=Trace amine-associated receptor 1 (TAAR1): an emerging therapeutic target for neurodegenerative, neurodevelopmental, and neurotraumatic disorders |journal=Naunyn-Schmiedeberg's Archives of Pharmacology |volume=398 |issue=5 |pages=5057–5075 |doi=10.1007/s00210-024-03757-6 |pmid=39738834 |quote=The mechanism of efflux of monoamines in the synapse is due to the activation of TAAR1 by TAs or drugs belonging to the amphetamine class which increases the level of cAMP (cyclic adenosine monophosphate) followed by an increase in the level of PKA (protein kinase A) and PKC (protein kinase C) phosphorylation. This reverses the monoamine transport by reversing the direction of monoamine transporters.}}</ref>|group="sources"|name="TAAR1 phosphorylation"}} Activation of {{abbr|TAAR1|trace amine-associated receptor 1}} increases {{abbrlink|cAMP|cyclic adenosine monophosphate}} production via [[adenylyl cyclase]] activation, which triggers [[protein kinase A]] (PKA)- and PKC-mediated transporter phosphorylation.<ref name="Miller" /><ref name="2022 T1 LDX" /><ref name="pmid114599292">{{cite journal |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 |date=July 2001 |title=Trace amines: identification of a family of mammalian G protein-coupled receptors |journal=Proceedings of the National Academy of Sciences |volume=98 |issue=16 |pages=8966–8971 |bibcode=2001PNAS...98.8966B |doi=10.1073/pnas.151105198 |pmc=55357 |pmid=11459929 |doi-access=free |title-link=doi}}</ref> Monoamine [[autoreceptors]] (e.g., [[D2sh|D<sub>2</sub> short]], [[Alpha-2 adrenergic receptor|presynaptic α<sub>2</sub>]], and [[5-HT1A#Autoreceptors|presynaptic 5-HT<sub>1A</sub>]]) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.<ref name="Miller" /><ref name="Miller+Grandy 2016" /><ref name="handbook2022_TAAR1">{{Cite book |title=Handbook of Substance Misuse and Addictions |vauthors=Liu J |publisher=Springer International Publishing |year=2022 |isbn=978-3-030-92391-4 |veditors=Patel VB, Preedy VR |location=Cham |pages=560–565 |chapter=Chapter 28: Trace Amine-Associated Receptor 1 and Its Links to Addictions |doi=10.1007/978-3-030-92392-1_32 |quote=The study further showed that amphetamine (AMPH) activated TAAR1 by interacting with G13 and GS α-subunits to increase RhoA and PKA activity, respectively (Underhill et al. 2021).&nbsp;...<br />  Using microdialysis showed that TAAR1 knockout mice showed higher AMPH-triggered dopamine, norepinephrine, and serotonin levels in the striatum (Lindemann et al. 2008; Wolinsky et al. 2007). As mentioned above, the psychostimulants amphetamines are TAAR1 agonists. These studies may suggest that amphetamines activate TAAR1 in WT animals to attenuate the behavioral responses to amphetamines.}}</ref> Notably, amphetamine and [[trace amine]]s possess high binding affinities for TAAR1, but not for monoamine autoreceptors.<ref name="Miller" /><ref name="Miller+Grandy 2016" /> Although TAAR1 is implicated in amphetamine-induced transporter phosphorylation, the [[Magnitude (mathematics)|magnitude]] of TAAR1-mediated monoamine release in humans remains unclear.<ref name="TAAR1 phosphorylation" group="sources" /><ref name="handbook2022_TAAR1" /> Findings from studies using TAAR1 [[gene knockout]] models suggest that, despite facilitating [[reverse transport]] through {{nowrap|G<sub>s</sub>-coupled}} receptor-mediated {{abbr|cAMP|cyclic adenosine monophosphate}} signaling, TAAR1 may paradoxically attenuate amphetamine's psychostimulant effects by opening [[G protein-coupled inwardly rectifying potassium channels]] through a G<sub>s</sub>-independent pathway, an action that reduces [[neuronal firing]].<ref>{{Cite journal |vauthors=Rutigliano G, Accorroni A, Zucchi R |date=2017 |title=The Case for TAAR1 as a Modulator of Central Nervous System Function |journal=Frontiers in Pharmacology |volume=8 |article-number=987 |doi=10.3389/fphar.2017.00987 |issn=1663-9812 |pmc=5767590 |pmid=29375386 |quote=Gs-mediated cAMP production was initially considered as the hallmark of TAAR1 activation, but we have now evidence that TAAR1 can also activate inward rectifying potassium channels and the β-arrestin 2 pathway, probably by Gs-independent pathways. |doi-access=free}}</ref><ref name="Miller" /><ref name="handbook2022_TAAR1" />

Amphetamine is also a substrate for the vesicular monoamine transporters [[VMAT1]] and [[Vesicular monoamine transporter 2|VMAT2]].<ref name="Amphetamine VMAT2 pH gradient">{{cite journal | vauthors = Sulzer D, Cragg SJ, Rice ME | title = Striatal dopamine neurotransmission: regulation of release and uptake | journal =Basal Ganglia| volume = 6 | issue = 3 | pages = 123–148 | date = August 2016 | pmid = 27141430 | pmc = 4850498 | doi = 10.1016/j.baga.2016.02.001 | quote = Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle.&nbsp;... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.}}</ref><ref name="VMAT2ADHD2">{{Cite journal |vauthors=Warlick Iv H, Tocci D, Prashar S, Boldt E, Khalil A, Arora S, Matthews T, Wahid T, Fernandez R, Ram D, Leon L, Arain A, Rey J, Davis K |year=2024 |title=Role of vesicular monoamine transporter-2 for treating attention deficit hyperactivity disorder: a review |journal=Psychopharmacology |volume=241 |issue=11 |pages=2191–2203 |doi=10.1007/s00213-024-06686-7 |pmid=39302436 |quote=Current psychopharmacology research shows that at high doses (non-therapeutic ranges), VMAT-2 can be "inhibited" by amphetamines, causing VMAT-2 vesicles to release the classical monoamines DA and NE into the axoplasm; however, this model is no longer broadly accepted. For instance, Stahl (2014) reported that VMAT-2 is not affected by amphetamines at therapeutic doses but is affected at higher doses.}}</ref> Under normal conditions, VMAT2 transports cytosolic monoamines into synaptic vesicles for storage and later [[Exocytosis|exocytotic]] release. When amphetamine accumulates in the presynaptic terminal, it collapses the vesicular pH gradient and releases vesicular monoamines into the neuronal cytosol.<ref name="Amphetamine VMAT2 pH gradient" /><ref name="VMAT2ADHD2"/> These displaced monoamines expand the cytosolic pool available for reverse transport, thereby increasing the capacity for monoamine efflux beyond that achieved by amphetamine-mediated transporter phosphorylation alone.<ref name="Caye_2019" /><ref name="2020_Reith" /><ref name="VMAT2ADHD2"/> Although VMAT2 is recognized as a major target in amphetamine-induced monoamine release at higher doses, some reviews have challenged its relevance at therapeutic doses.<ref name="Stahl2021" /><ref name="VMAT2ADHD2"/><ref name="Gowda_2014">{{Cite journal |vauthors=Gowda CR, Lundt LP |year=2014 |title=Mechanism of action of narcolepsy medications |journal=CNS Spectrums |volume=19 |pages= 25–34|doi=10.1017/S1092852914000583 |pmid=25403789 |quote=Once inside the cell, and at higher doses, amphetamines compete with dopamine and norepinephrine for transport into vesicles, displacing these molecules by acting as a substrate for the vesicular monamine transporter 2 (VMAT2). This leads to an increased concentration of cytoplasmic dopamine and norepinephrine.&nbsp;... At even higher concentrations, amphetamines can inhibit monoamine oxidase enzymes, preventing degradation of catecholamines.}}</ref>

In addition to [[Membrane transport protein|membrane]] and [[vesicular monoamine transporter]]s, amphetamine also inhibits [[SLC1A1]], [[SLC22A3]], and [[SLC22A5]].{{#tag:ref|<ref name="E Weihe" /><ref name="EAAT3">{{cite journal |vauthors=Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG | title = Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons | journal =Neuron| volume = 83 | issue = 2 | pages = 404–416 | date = July 2014 | pmid = 25033183 | pmc = 4159050 | doi = 10.1016/j.neuron.2014.05.043 | quote = 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">{{cite web|title=SLC18 family of vesicular amine transporters|url=http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=193|website=IUPHAR database|publisher=International Union of Basic and Clinical Pharmacology|access-date=13 November 2015}}</ref><ref name="SLC1A1">{{cite web | title=SLC1A1 solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 [ Homo sapiens (human) ] | url=https://www.ncbi.nlm.nih.gov/gene/6505 | website=NCBI Gene | publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | access-date=11 November 2014 | quote = 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">{{cite journal |vauthors=Zhu HJ, Appel DI, Gründemann D, Markowitz JS | title = Interaction of organic cation transporter 3 (SLC22A3) and amphetamine | journal =Journal of Neurochemistry| volume = 114 | issue = 1 | pages = 142–149 |date=July 2010 | pmid = 20402963 | pmc = 3775896 | doi = 10.1111/j.1471-4159.2010.06738.x}}</ref><ref name="SLC22A5">{{cite journal |vauthors=Rytting E, Audus KL | s2cid = 31465243 | title = Novel organic cation transporter 2-mediated carnitine uptake in placental choriocarcinoma (BeWo) cells | journal =Journal of Pharmacology and Experimental Therapeutics| volume = 312 | issue = 1 | pages = 192–198 |date=January 2005 | pmid = 15316089 | doi = 10.1124/jpet.104.072363}}</ref><ref name="pmid13677912">{{cite journal |vauthors=Inazu M, Takeda H, Matsumiya T | title = [The role of glial monoamine transporters in the central nervous system] | language = ja | journal =Nihon Shinkei Seishin Yakurigaku Zasshi | volume = 23 | issue = 4 | pages = 171–178 |date=August 2003 | pmid = 13677912}}</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="Drugbank-amph" /><ref name="CART NAcc">{{cite journal |vauthors=Vicentic A, Jones DC | title = The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction | journal =Journal of Pharmacology and Experimental Therapeutics| volume = 320 | issue = 2 | pages = 499–506 |date=February 2007 | pmid = 16840648 | doi = 10.1124/jpet.105.091512 | s2cid = 14212763 | quote = 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> a [[neuropeptide]] involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival ''[[in vitro]]''.<ref name="Drugbank-amph" /><ref name="CART functions">{{cite journal |vauthors=Zhang M, Han L, Xu Y | title = Roles of cocaine- and amphetamine-regulated transcript in the central nervous system | journal =Clinical and Experimental Pharmacology and Physiology| volume = 39 | issue = 6 | pages = 586–592 |date=June 2012 | pmid = 22077697 | doi = 10.1111/j.1440-1681.2011.05642.x | s2cid = 25134612 | quote = 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.&nbsp;... 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">{{cite journal |vauthors=Rogge G, Jones D, Hubert GW, Lin Y, Kuhar MJ |title=CART peptides: regulators of body weight, reward and other functions |journal=Nature Reviews Neuroscience |volume=9 |issue=10 |pages=747–758 |date=October 2008 |pmid=18802445 |pmc=4418456 |doi=10.1038/nrn2493 |quote=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<sub>i</sub>/G<sub>o</sub>-coupled]]}} {{abbr|GPCR|G protein-coupled receptor}}.<ref name="CART" /><ref name="pmid21855138">{{cite journal |vauthors=Lin Y, Hall RA, Kuhar MJ |title=CART peptide stimulation of G protein-mediated signaling in differentiated PC12 cells: identification of PACAP 6–38 as a CART receptor antagonist |journal=Neuropeptides |volume=45 |issue=5 |pages=351–358 |date=October 2011 |pmid=21855138 |pmc=3170513 |doi=10.1016/j.npep.2011.07.006}}</ref> Amphetamine also inhibits [[monoamine oxidase]]s at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines.<ref name="Gowda_2014" /><ref name="PubChem Header">{{cite encyclopedia |title=Amphetamine |section-url=https://pubchem.ncbi.nlm.nih.gov/compound/3007 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information. PubChem Compound Database |access-date=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 |publisher=Technische Universität Braunschweig. BRENDA |access-date=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 low [[micromolar]] affinity.<ref name="5HT1A secondary2">{{cite encyclopedia |title=Amphetamine |publisher=University of Alberta T3DB |url=http://www.t3db.ca/toxins/T3D2706 |access-date=24 February 2015 |section=Targets}}</ref><ref name="5HT1A Primary">{{cite journal |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 |date=March 1998 |title=Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications |journal=NIDA Research Monograph |volume=178 |pages=440–466 |pmid=9686407}}</ref>

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">{{cite journal | vauthors = Miller GM |title=The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal =Journal of Neurochemistry |volume=116 |issue=2 |pages=164–176 |date=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">{{cite journal |vauthors=Eiden LE, Weihe E |title=VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal =Annals of the New York Academy of Sciences| volume = 1216 |issue = 1 | pages = 86–98 | date=January 2011 | pmid = 21272013 | pmc=4183197 | doi = 10.1111/j.1749-6632.2010.05906.x | quote = 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).&nbsp;... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.| bibcode = <!-- No --> }}</ref> [[histamine]],<ref name="E Weihe" /> [[cocaine and amphetamine regulated transcript|CART peptides]],<ref name="Drugbank-amph" /><ref name="CART NAcc" /> [[endogenous opioid]]s,<ref name="Amphetamine-induced endogenous opioid release review">{{cite journal | vauthors = Finnema SJ, Scheinin M, Shahid M, Lehto J, Borroni E, Bang-Andersen B, Sallinen J, Wong E, Farde L, Halldin C, Grimwood S | title = Application of cross-species PET imaging to assess neurotransmitter release in brain | journal =Psychopharmacology| volume = 232 | issue = 21–22 | pages = 4129–4157 | date = November 2015 | pmid = 25921033 | pmc = 4600473 | doi = 10.1007/s00213-015-3938-6 | quote = More recently, Colasanti and colleagues reported that a pharmacologically induced elevation in endogenous opioid release reduced [<sup>11</sup>C]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 [<sup>11</sup>C]carfentanil injection, reduced BPND values by 2–10%. The results were confirmed in another group of subjects (Mick et al. 2014). However, Guterstam and colleagues observed no change in [<sup>11</sup>C]carfentanil binding when d-amphetamine, 0.3&nbsp;mg/kg, was administered intravenously directly before injection of [<sup>11</sup>C]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">{{cite journal | vauthors = Loseth GE, Ellingsen DM, Leknes S | title = State-dependent μ-opioid modulation of social motivation | journal =Frontiers in Behavioral Neuroscience| volume = 8 | page = 430 | date = December 2014 | pmid = 25565999 | pmc = 4264475 | doi = 10.3389/fnbeh.2014.00430 | quote = 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). | doi-access = free | title-link = doi }}</ref><ref name="Opioids cited primary source">{{cite journal | 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 | title = Endogenous opioid release in the human brain reward system induced by acute amphetamine administration | journal =Biological Psychiatry| volume = 72 | issue = 5 | pages = 371–377 | date = September 2012 | pmid = 22386378 | doi = 10.1016/j.biopsych.2012.01.027| s2cid = 18555036 }}</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 affects 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 secondary2"/>|group="sources"}} Amphetamine also activates seven human [[carbonic anhydrase]] enzymes, several of which are expressed in the human brain.<ref name="Amphetamine-induced activation of 7 hCA isoforms" />

Dextroamphetamine displays higher binding affinity for DAT than levoamphetamine, whereas both [[enantiomer]]s share comparable affinity at NET;<ref name="Stahl2021" /> 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="Stahl2021" /><ref name="Westfall" /> Dextroamphetamine is also a more potent agonist of {{abbr|TAAR1|trace amine-associated receptor 1}} than levoamphetamine.<ref name="D-meth ADHD">{{cite journal |vauthors=Moszczynska A, Callan SP |date=September 2017 |title=Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=362 |issue=3 |pages=474–488 |doi=10.1124/jpet.116.238501 |pmc=11047030 |pmid=28630283 |quote=In rodents, d-enantiomers of both amphetamines produced greater central stimulant effects than l-METH due to a higher potency to release DA. Interestingly, Easton et al. (2007) found that areas mediating pleasurable effects in the rat brain differ for each amphetamine isomer. In addition, d-amphetamine is a more potent agonist of the TAAR1 receptor (which regulates DAergic neurotransmission) than l-amphetamine.}}</ref><ref name="TAAR1 stereoselective">{{cite journal |vauthors=Lewin AH, Miller GM, Gilmour B |date=December 2011 |title=Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class |journal=Bioorganic & Medicinal Chemistry |volume=19 |issue=23 |pages=7044–7048 |doi=10.1016/j.bmc.2011.10.007 |pmc=3236098 |pmid=22037049}}</ref>

====Dopamine====
In certain brain regions, amphetamine increases the concentration of dopamine in the [[synaptic cleft]] by modulating {{abbr|DAT|dopamine transporter}} through several overlapping processes.<ref name="2020_Reith" /><ref name="handbook2022_DAT"/><ref name="2022 T1 LDX" /> Amphetamine can enter the [[presynaptic neuron]] either through {{abbr|DAT|dopamine transporter}} or, to a lesser extent, by diffusing across the neuronal membrane directly.<ref name="Miller" /><ref name="handbook2022_DAT" /> As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.<ref name="Stahl2021" /><ref name="Caye_2019" /> Upon entering the presynaptic neuron, amphetamine provokes the release of [[Ca²⁺]] from [[endoplasmic reticulum]] stores, an effect that raises intracellular calcium to levels sufficient for downstream kinase-dependent signalling.<ref name="Kinase-dependent transporter regulation review" /><ref name="2020_Reith" /> In parallel, amphetamine also increases intracellular {{abbrlink|cAMP|cyclic adenosine monophosphate}}, which activates [[protein kinase A]] (PKA) and [[protein kinase C]] (PKC), whilst elevated intracellular Ca²⁺ activates PKC alone.<ref name="TAAR1_cAMP2025" /><ref name="handbook2022_DAT" /><ref name="2022 T1 LDX" /> Phosphorylation of DAT by either kinase induces transporter [[Endocytosis|internalization]] ({{nowrap|non-competitive}} reuptake inhibition), but {{nowrap|PKC-mediated}} phosphorylation alone induces the [[Reverse transport|reversal of dopamine transport]] through DAT (i.e., dopamine [[wiktionary:efflux|efflux]]).<ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review" />

{{abbr|TAAR1|trace amine associated receptor 1}} has been identified as a [[biomolecular target]] of amphetamine that initiates some of amphetamine's kinase-dependent signaling cascades.<ref name="TAAR1_cAMP2025" /><ref name="handbook2022_DAT" /><ref name="2022 T1 LDX" /> When {{abbr|TAAR1|trace amine associated receptor 1}} signals via Gs-coupled receptors, intracellular {{abbr|cAMP|cyclic adenosine monophosphate}} increases through [[adenylyl cyclase]] activation and activates PKA and PKC, in turn phosphorylating {{abbr|DAT|dopamine transporter}}.<ref name="2022 T1 LDX" /><ref name="TAAR1_cAMP2025" /> {{abbr|TAAR1|trace amine associated receptor 1}} also couples [[G12/G13 alpha subunits|G-protein alpha subunit G<sub>13</sub>]];<ref name="Underhill_2021">{{Cite journal |vauthors=Underhill SM, Hullihen PD, Chen J, Fenollar-Ferrer C, Rizzo MA, Ingram SL, Amara SG |year=2021 |title=Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains |journal=Molecular Psychiatry |language=en |volume=26 |issue=4 |pages=1208–1223 |doi=10.1038/s41380-019-0469-2 |pmc=7038576 |pmid=31399635 |quote=These studies strongly implicate the TAAR1 as the intracellular target of AMPH that initiates the trafficking effects of AMPH on DAT and EAAT3 (Fig. 6). We report here that the cytoplasmic activation of the TAAR1 receptor by intracellular AMPHs leads to activation of both PKA and RhoA signaling pathways. PKA activation occurs through coupling of the receptor to GS-subunits resulting in a signal that propagates in intracellular compartments throughout the cell, whereas RhoA activation occurs through TAAR1 coupling to G13 subunits more preferentially localized near the ER. |doi-access=free}}</ref> when triggered by amphetamine, this pathway activates [[Transforming protein RhoA|Ras homolog A]] (RhoA) and its downstream effector, [[Rho-associated coiled-coil kinase]] (ROCK), an effect that internalizes both {{abbr|DAT|dopamine transporter}} and the neuronal [[Glutamate (neurotransmitter)|glutamate]] transporter [[Excitatory amino acid transporter 3|EAAT3]].{{#tag:ref|Mesolimbic dopamine neurons co-express the glutamate transporter EAAT3 alongside DAT, permitting amphetamine-induced EAAT3 internalization to influence glutamatergic signaling in the [[mesolimbic pathway]].<ref name="EAAT3" /><ref name="handbook2022_DAT" />|name="mesolimbic EAAT3"|group="note"}}<ref name="Amphetamine signaling through ROCKs">{{cite journal |vauthors=Saunders C, Galli A |date=December 2015 |title=Insights in how amphetamine ROCKs (Rho-associated containing kinase) membrane protein trafficking |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=112 |issue=51 |pages=15538–15539 |bibcode=2015PNAS..11215538S |doi=10.1073/pnas.1520960112 |pmc=4697384 |pmid=26607447 |quote=In this elegant and thorough study (7), Amara and her collaborators identify multiple novel targets for intracellular AMPH. They demonstrate that cytoplasmic AMPH stimulates a secondary pathway of cAMP production, which leads to Rho inactivation by PKA-dependent phosphorylation.&nbsp;... ROCK inhibition blocks the effects of AMPH pretreatment on DA uptake, supporting previous studies suggesting a role for ROCK in AMPH's behavioral effects... These results further support the idea that direct activation of cytoplasmic signaling cascades by AMPH might contribute to the behavioral effects of acute AMPH exposure. |doi-access=free}}</ref><ref name="handbook2022_DAT" /> Transporter internalization via {{abbr|TAAR1|trace amine associated receptor 1}}'s G<sub>13</sub>-coupled pathway is transient because G<sub>s</sub>-cAMP-PKA signaling functionally inhibits RhoA's downstream activity;<ref name="Underhill_2021" /><ref name="Amph RhoA+ROCK signaling to DAT - primary" /> once intracellular {{abbr|cAMP|cyclic adenosine monophosphate}} sufficiently accumulates, PKA is activated and phosphorylates RhoA, thereby terminating ROCK-mediated transporter internalization.<ref name="Amphetamine signaling through ROCKs" /><ref name="handbook2022_DAT" /> In addition to presynaptic actions that regulate DAT, {{abbr|TAAR1|trace amine associated receptor 1}} activation exerts a [[somatodendritic]] inhibitory influence on dopamine output by reducing the firing rate of [[midbrain]] dopamine neurons via [[G protein-coupled inwardly-rectifying potassium channel|G protein-coupled inwardly-rectifying potassium channels]], an effect that can attenuate amphetamine's psychostimulant response.<ref name="handbook2022_TAAR1" /><ref name="GIRK">{{cite journal |vauthors=Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB |date=July 2011 |title=Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons |journal=Frontiers in Systems Neuroscience |volume=5 |page=56 |doi=10.3389/fnsys.2011.00056 |pmc=3131148 |pmid=21772817 |quote=Three important new aspects of TAs action have recently emerged: (a) 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. |doi-access=free |title-link=doi}}</ref><ref name="Genatlas TAAR1">{{cite web |date=28 January 2012 |title=TAAR1 |url=http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=TAAR1 |access-date=29 May 2014 |website=GenAtlas |publisher=University of Paris |quote={{•}} tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)}}</ref> 

Amphetamine's effect on intracellular calcium is associated with DAT phosphorylation through [[Ca2+/calmodulin-dependent protein kinase II alpha|Ca²⁺/calmodulin-dependent protein kinase II alpha]] (CAMKIIα), in turn producing dopamine efflux.<ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review" /><ref name="DAT regulation review">{{cite journal |vauthors=Vaughan RA, Foster JD | title = Mechanisms of dopamine transporter regulation in normal and disease states | journal =Trends in Pharmacological Sciences| volume = 34 | issue = 9 | pages = 489–496 | date = September 2013 | pmid = 23968642 | pmc = 3831354 | doi = 10.1016/j.tips.2013.07.005 | quote = 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> Because conventional PKC [[isoforms]] can be activated by Ca²⁺ and [[diacylglycerol]], elevated intracellular calcium can promote PKC-dependent DAT phosphorylation independent of TAAR1.<ref name="2020_Reith" />
{| class="wikitable" style="text-align: center;"
|+ Effects of amphetamine on [[membrane transport protein]]s in dopamine neurons{{#tag:ref|Amphetamine interacts with its receptor protein target(s), TAAR1 and an as-yet-unidentified biomolecular target, which initiates signaling cascades that generate second messengers and activate protein kinases.<ref name="Caye_2019" /> The activated kinases then phosphorylate their respective transporter(s), which in turn causes a conformational change in transporter protein, thereby altering its function and affecting dopaminergic/glutamatergic neurotransmission at dopaminergic synapses.<ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review" />|name="DAT table"|group="note"}}
! [[Biological target]] of amphetamine
! Initial effector / [[G-protein]]
! [[Signal transduction|Second messenger(s)]]
! Secondary effector<br />[[protein kinase]]
! [[Phosphorylated]] transporter
! Effect on transporter function
! Effect on neurotransmission
! <small>Sources</small>
|-
| Unidentified
| Unidentified intracellular [[Effector (biology)|effector]]
| [[Inositol trisphosphate|IP₃]]-mediated intracellular [[Ca²⁺]] release
| {{abbrlink|CAMKIIα|Calcium/calmodulin-dependent protein kinase II alpha}}
| {{abbrlink|DAT|Dopamine transporter}}
| [[Reverse transport]] of [[dopamine]]
| Dopamine efflux into synaptic cleft
| <ref name="2020_Reith" /><ref name="Kinase-dependent transporter regulation review" />
|-
| {{abbrlink|TAAR1|Trace amine-associated receptor 1}}
| [[G12/G13 alpha subunits|G<sub>13</sub>]]
| [[Transforming protein RhoA|RhoA–GTP]]
| [[Rho-associated protein kinase|ROCK]]<sup>†</sup>
| DAT
| Transporter [[Endocytosis|internalization]]
| Dopamine [[Reuptake inhibitor|reuptake inhibition]]
| <ref name="handbook2022_DAT" /><ref name="Amph RhoA+ROCK signaling to DAT - primary">{{cite journal | vauthors = Wheeler DS, Underhill SM, Stolz DB, Murdoch GH, Thiels E, Romero G, Amara SG | title = Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 112 | issue = 51 | pages = E7138–E7147 | date = December 2015 | pmid = 26553986 | pmc = 4697400 | doi = 10.1073/pnas.1511670112 | doi-access = free | bibcode = 2015PNAS..112E7138W | quote = These observations support the existence of an unanticipated intracellular target that mediates the effects of AMPH on RhoA and cAMP signaling and suggest new pathways to target to disrupt AMPH action.&nbsp;... Using a ROCK inhibitor, Y27632, blocked the effects of AMPH pretreatment on dopamine uptake... The activation of intracellular signaling pathways by AMPH and the Rho-mediated internalization of DAT are also observed in nonneural cell lines... Cytoplasmic cAMP appears to integrate both intracellular signals through GTPase activation and extracellular signals from GPCR-coupled pathways... Thus, modulation of the Rho activation/inactivation sequence provides a mechanism by which drugs and endogenous neurotransmitters can influence the response of dopamine neurons to AMPH.}}</ref><ref name="Amphetamine signaling through ROCKs" />
|-
| {{abbrlink|TAAR1|Trace amine-associated receptor 1}}
| G<sub>13</sub>
| RhoA–GTP
| [[Rho-associated protein kinase|ROCK]]<sup>†</sup>
| {{abbrlink|EAAT3|Excitatory amino acid transporter 3}}
| Transporter internalization
| [[Glutamate]] reuptake inhibition
| <ref name="handbook2022_DAT" /><ref name="handbook2022_TAAR1" /><ref name="Amphetamine signaling through ROCKs" />
|-
| {{abbrlink|TAAR1|Trace amine-associated receptor 1}}
| [[Gs alpha subunit|G<sub>s</sub>]]
| ↑ {{abbrlink|cAMP|cyclic adenosine monophosphate}}
| {{abbrlink|PKA|Protein kinase A}}
| DAT
| Transporter internalization
| Dopamine reuptake inhibition
| <ref name="Miller" /><ref name="handbook2022_DAT" /><ref name="2022 T1 LDX" />
|-
| {{abbrlink|TAAR1|Trace amine-associated receptor 1}}
| G<sub>s</sub>
| ↑ {{abbr|cAMP|cyclic adenosine monophosphate}}
| {{abbrlink|PKC|Protein kinase C}}
| DAT
| Reverse transport of dopamine<br />Transporter internalization
| Dopamine efflux into synaptic cleft<br />Dopamine reuptake inhibition
| <ref name="Miller" /><ref name="2022 T1 LDX" /><ref name="TAAR1_cAMP2025" />
|-
| Unidentified
| Unidentified intracellular effector
| [[Ip3/dag pathway|IP₃/DAG pathway]]<sup>‡</sup>
| {{abbrlink|PKC|Protein kinase C}}
| DAT
| Reverse transport of dopamine<br />Transporter internalization
| Dopamine efflux into synaptic cleft<br />Dopamine reuptake inhibition
| <ref name="2020_Reith" /><ref name="Kinase-dependent transporter regulation review" />
|-
| colspan="7" | †ROCK-mediated transporter internalization is transient due to the inactivation of [[RhoA]] (which activates ROCK) by PKA.
‡IP₃ binds to its receptors on the [[endoplasmic reticulum]] to release intracellular Ca²⁺ stores, and together with [[diacylglycerol]] activates conventional PKC [[isoforms]]. 
| <ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review" /><ref name="Amphetamine signaling through ROCKs" />
|}

Amphetamine is also a substrate for the presynaptic [[vesicular monoamine transporter]], {{abbr|VMAT2|vesicular monoamine transporter 2}}.<ref name="Amphetamine VMAT2 pH gradient" /> Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in a dose-dependent release of dopamine molecules from [[synaptic vesicle]]s into the cytosol via dopamine efflux through VMAT2.<ref name="Amphetamine VMAT2 pH gradient" /><ref name="VMAT2ADHD2"/> Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at {{abbr|DAT|dopamine transporter}}.<ref name="Caye_2019" /><ref name="Amphetamine VMAT2 pH gradient" /><ref name="VMAT2ADHD2" />

====Norepinephrine====
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of [[epinephrine]]. Amphetamine is believed to affect norepinephrine analogously to dopamine.<ref name="handbook2022_DAT" /><ref name="2020_Reith" /><ref name="2022 T1 LDX" /> In other words, amphetamine induces competitive {{abbr|NET|norepinephrine transporter}} reuptake inhibition, non-competitive reuptake inhibition and efflux at phosphorylated NET via PKC activation, CAMKIIα-mediated NET efflux without internalization, and norepinephrine release from {{abbr|VMAT2|vesicular monoamine transporter 2}}.<ref name="handbook2022_DAT" /><ref name="2020_Reith" /><ref name="2022 T1 LDX" />

====Serotonin====
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.<ref name="Miller" /> Amphetamine affects serotonin via {{abbr|VMAT2|vesicular monoamine transporter 2}} and is thought to phosphorylate {{abbr|SERT|serotonin transporter}} via a PKC-dependent signaling cascade.<ref name="2022 T1 LDX" /> Like dopamine, amphetamine has low, micromolar affinity at the human [[5-HT1A receptor]].<ref name="5HT1A secondary2"/><ref name="5HT1A Primary" />

====Other neurotransmitters, peptides, hormones, and enzymes====
{| class="wikitable sortable" style="margin-left: 8px; float:right; text-align:center"
|+ Human [[carbonic anhydrase]]<br />activation potency
! [[Enzyme]]
! K<sub>A</sub> ({{abbrlink|nM|nanomolar}})
! class="unsortable" | <small>Sources</small>
|-
| [[Carbonic anhydrase 4|hCA4]] || 94 ||<ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
| [[Carbonic anhydrase 5A, mitochondrial|hCA5A]] || 810 ||<ref name="Amphetamine-induced activation of 7 hCA isoforms">{{cite journal | vauthors = Angeli A, Vaiano F, Mari F, Bertol E, Supuran CT | title = Psychoactive substances belonging to the amphetamine class potently activate brain carbonic anhydrase isoforms VA, VB, VII, and XII | journal = Journal of Enzyme Inhibition and Medicinal Chemistry | volume = 32 | issue = 1 | pages = 1253–1259 | date = December 2017 | pmid = 28936885 | pmc = 6009978 | doi = 10.1080/14756366.2017.1375485 | quote = Here, we report the first such study, showing that amphetamine, methamphetamine, phentermine, mephentermine, and chlorphenteramine, potently activate several CA isoforms, some of which are highly abundant in the brain, where they play important functions connected to cognition and memory, among others26,27.&nbsp;... We investigated psychotropic amines based on the phenethylamine scaffold, such as amphetamine 5, methamphetamine 6, phentermine 7, mephentermine 8, and the structurally diverse chlorphenteramine 9, for their activating effects on 11 CA isoforms of human origin&nbsp;... The widespread hCA I and II, the secreted hCA VI, as well as the cytosolic hCA XIII and membrane-bound hCA IX and XIV were poorly activated by these amines, whereas the extracellular hCA IV, the mitochondrial enzymes hCA VA/VB, the cytosolic hCA VII, and the transmembrane isoform hCA XII were potently activated. Some of these enzymes (hCA VII, VA, VB, XII) are abundant in the brain, raising the possibility that some of the cognitive effects of such psychoactive substances might be related to the activation of these enzymes.&nbsp;... CAAs started to be considered only recently for possible pharmacologic applications in memory/cognition therapy27. This work may bring new lights on the intricate relationship between CA activation by this type of compounds and the multitude of pharmacologic actions that they can elicit.<br /> —Table 1: CA activation of isoforms hCA I, II, IV, VII, and XIII [5: amphetamine]<br /> —Table 2: CA activation of isoforms hCA VA, VB, VI, IX, XII, and XIV [5: amphetamine]}}</ref><ref name="IUPHAR Amphetamine">{{cite web | title=Amphetamine: Biological activity | url=https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=4804 | website=IUPHAR/BPS Guide to Pharmacology | publisher=International Union of Basic and Clinical Pharmacology | access-date=31 December 2019}}</ref>
|-
| [[Carbonic anhydrase 5B, mitochondrial|hCA5B]] || 2560 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
| [[Carbonic anhydrase 7|hCA7]] || 910 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" /><ref name="IUPHAR Amphetamine" />
|-
| [[Carbonic anhydrase 12|hCA12]] || 640 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
| [[Carbonic anhydrase 13|hCA13]] || 24100 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
| [[Carbonic anhydrase 14|hCA14]] || 9150 || <ref name="Amphetamine-induced activation of 7 hCA isoforms" />
|-
|}
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" /> This internalization is mediated by [[RhoA]] activation and its downstream effector [[Rho-associated coiled-coil kinase|ROCK]].<ref name="handbook2022_DAT" /><ref name="EAAT3 review">{{cite journal | vauthors = Bjørn-Yoshimoto WE, Underhill SM | title = The importance of the excitatory amino acid transporter 3 (EAAT3) | journal = Neurochem. Int. | volume = 98 | issue = | pages = 4–18 | date = September 2016 | pmid = 27233497 | pmc = 4969196 | doi = 10.1016/j.neuint.2016.05.007 | quote = Recently, it was reported that amphetamine decreases the surface expression of EAAT3 (Underhill et al., 2014).&nbsp;...<br />RhoA is a downstream target of intracellular amphetamine. Both mechanisms of RhoA activation lead to a rapid decrease the surface expression of EAAT3. }}</ref> 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">{{cite book | vauthors = Gunne LM | title=Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence | date=2013 | publisher=Springer | location=Berlin, Germany; Heidelberg, Germany | isbn=978-3-642-66709-1 | pages=247–260 | access-date=4 December 2015 | chapter=Effects of Amphetamines in Humans | chapter-url=https://books.google.com/books?id=gb_uCAAAQBAJ&pg=PA247}}</ref><ref name="Primary: Human HPA axis">{{cite journal | vauthors = Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L, Brasic J, Wand GS | title = Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine | journal =Neuropsychopharmacology| volume = 30 | issue = 4 | pages = 821–832 | date = April 2005 | pmid = 15702139 | doi = 10.1038/sj.npp.1300667 | s2cid = 12302237 | quote = 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| doi-access = free | title-link = doi }}</ref><!--
Amphetamine has no direct effect on [[acetylcholine]] neurotransmission, but several studies have noted that acetylcholine release increases after its use.<ref name="Acetylcholine">{{cite journal |vauthors=Hutson PH, Tarazi FI, Madhoo M, Slawecki C, Patkar AA | title = Preclinical pharmacology of amphetamine: implications for the treatment of neuropsychiatric disorders | journal =Pharmacol Ther| volume = 143 | issue = 3 | pages = 253–264 | date = September 2014 | pmid = 24657455 | doi = 10.1016/j.pharmthera.2014.03.005}}</ref> In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream effect.<ref name="Acetylcholine" /> -->

In December 2017, the first study assessing the interaction between amphetamine and human [[carbonic anhydrase]] enzymes was published;<ref name="Amphetamine-induced activation of 7 hCA isoforms" /> of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the [[human brain]], with low nanomolar through low micromolar activating effects.<ref name="Amphetamine-induced activation of 7 hCA isoforms" /> Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects;<ref name="Carbonic anhydrase modulators 2019 Review" /> but, based upon the clinical use of [[carbonic anhydrase inhibitor]]s, carbonic anhydrase activation in other tissues may be associated with adverse effects, such as [[ocular]] activation exacerbating [[glaucoma]].<ref name="Carbonic anhydrase modulators 2019 Review">{{cite journal | vauthors = Bozdag M, Altamimi AA, Vullo D, Supuran CT, Carta F | title = State of the Art on Carbonic Anhydrase Modulators for Biomedical Purposes | journal = Current Medicinal Chemistry | volume = 26 | issue = 15 | pages = 2558–2573 | date = 2019 | pmid = 29932025 | doi = 10.2174/0929867325666180622120625 | s2cid = 49345601 | quote = CARBONIC ANHYDRASE INHIBITORS (CAIs). The design and development of CAIs represent the most prolific area within the CA research field. Since the introduction of CAIs in the clinical use in the 40', they still are the first choice for the treatment of edema [9], altitude sickness [9], glaucoma [7] and epilepsy [31].&nbsp;... CARBONIC ANHYDRASE ACTIVATORS (CAAs)&nbsp;... The emerging class of CAAs has recently gained attraction as the enhancement of the kinetic properties in hCAs expressed in the CNS were proved in animal models to be beneficial for the treatment of both cognitive and memory impairments. Thus, CAAs have enormous potentiality in medicinal chemistry to be developed for the treatment of symptoms associated to aging, trauma or deterioration of the CNS tissues.}}</ref>

==== Sex-dependent differences ====


[[Clinical research]] indicates that the pharmacological effects of amphetamine may vary depending on [[sex]] and [[menstrual cycle]] phase, possibly due to fluctuations in [[female sex hormones]].{{#tag:ref|<ref name="Findeis_2025">{{Cite journal |vauthors=Findeis H, Strauß M |date=2025-03-20 |title=The effects of psychostimulants in menstruating women with ADHD - A gender health gap in ADHD treatment? |journal=Progress in Neuro-Psychopharmacology & Biological Psychiatry |volume=137 |article-number=111261 |doi=10.1016/j.pnpbp.2025.111261 |pmid=39837362 |quote=Justice and de Wit (1999) were the first to assess the subjective and behavioural effects of psychostimulants (15 mg orally d-amphetamine) at two hormonally distinct phases of the menstrual cycle in healthy menstruating women (without ADHD). The test subjects stated that they felt a significantly greater effect of D-amphetamine during the follicular phase. There was a positive correlation between the effectiveness of D-amphetamine and the oestrogen concentration: the greater the oestrogen concentration was, the greater the effectiveness of D-amphetamine. This correlation did not exist in the luteal phase, when both oestrogen and progesterone are elevated.&nbsp;... These findings suggest that there is a cycle-dependent efficacy of psychostimulants in menstruating women |doi-access=free}}</ref><ref name="Rapoport_2025">{{Cite journal |vauthors=Rapoport IL, Groenman AP |year=2025 |title=A Review of Sex and Gender Factors in Stimulant Treatment for ADHD: Knowledge Gaps and Future Directions |journal=Journal of Attention Disorders |volume=29 |issue=8 |pages=602–616 |doi=10.1177/10870547251315601 |pmc=12064863 |pmid=39878255 |quote=Evidence suggests that amphetamines interact with estrogens, as higher estrogen levels in female individuals are associated with increased subjective effects.&nbsp;... In a recent case study (N = 9), stimulant dosage was increased in the premenstrual week, and all participants reported improved mood, energy, and/or ADHD symptoms (De Jong et al., 2023).}}</ref><ref name="Kok_2020">{{Cite journal |vauthors=Kok FM, Groen Y, Fuermaier AB, Tucha O |date=2020 |title=The female side of pharmacotherapy for ADHD-A systematic literature review |journal=PLOS ONE |volume=15 |issue=9 |article-number=e0239257 |doi=10.1371/journal.pone.0239257 |pmc=7500607 |pmid=32946507 |quote=Although studies specifically focusing on sex differences in efficacy or effectiveness of ADHD pharmacotherapy are scarce, recent studies show females may respond differently than males.&nbsp;...<br />One explanation for the findings of less favourable outcomes in girls and women using dexAMP compared to their male counterparts could be the influence of hormones, in particular as one of the samples included adolescents. Levels of estrogen and progesterone fluctuate among the menstrual cycle and differently influence the effect of stimulant drugs at different points of the month in adolescent and adult females.&nbsp;... After all, evidence exists that amphetamines in particular, unlike other substances, interact markedly with female sex hormones. |doi-access=free|bibcode=2020PLoSO..1539257K }}</ref><ref name="Amphetamine - menstrual cycle">{{cite journal |vauthors=Van Voorhees EE, Mitchell JT, McClernon FJ, Beckham JC, Kollins SH |date=May 2012 |title=Sex, ADHD symptoms, and smoking outcomes: an integrative model |journal=Med. Hypotheses |volume=78 |issue=5 |pages=585–593 |doi=10.1016/j.mehy.2012.01.034 |pmc=3321070 |pmid=22341778 |quote=research with cocaine and amphetamine in humans has found that the women report greater positive subjective effects of both substances during the follicular than the luteal phase of the menstrual cycle [129]. Moreover, men report greater positive subjective effects of stimulants compared to women who are in the luteal phase, though these gender differences disappear during the follicular phase [104, 130, 131]. Some [130, 131] but not all [132] research has found plasma or salivary estrogen levels to be associated positively with subjective response to amphetamine, and one study found that exogenously administered estrogen enhanced the discriminative stimulus effects of low doses of amphetamine [106].}}</ref><ref name="Franconi_2007">{{Cite journal |vauthors=Franconi F, Brunelleschi S, Steardo L, Cuomo V |year=2007 |title=Gender differences in drug responses |journal=Pharmacological Research |volume=55 |issue=2 |pages=81–95 |doi=10.1016/j.phrs.2006.11.001 |pmid=17129734 |quote=However, in humans a marked sex difference in striatal dopamine response to amphetamine has been reported with women exhibiting lower neurotransmitter release [115]. Differently from preclinical investigations, human studies have shown that women in the luteal phase of menstrual cycle display reduced subjective responses to amphetamine and cocaine compared to men.&nbsp;... At moment, it is possible to assume that differences between women and men in striatal dopamine release may serve as possible mechanism underlying the observed GDs in consequences of stimulant use.}}</ref>|group="sources"|name="menstrual cycle"}} In [[menstruating]] individuals, subjective and behavioral responses to amphetamine are heightened during the [[follicular phase]] (i.e., when [[estrogen]] levels are higher), and reduced during the [[luteal phase]] (i.e., when [[progesterone]] is elevated).<ref name="Findeis_2025" /><ref name="Rapoport_2025" /><ref name="Amphetamine - menstrual cycle" /> Reviews of human studies have also noted that men typically report stronger positive subjective responses to amphetamine compared to women tested during the luteal phase, whereas these sex differences are absent when women are tested during the follicular phase;<ref name="menstrual cycle" group="sources" /> subjective responses to amphetamine appear to correlate positively with [[Blood plasma|plasma]] or [[Saliva|salivary]] estrogen concentrations.<ref name="Findeis_2025" /><ref name="Amphetamine - menstrual cycle" /> Moreover, [[neuroimaging]] studies have reported significant sex differences in the neural response to amphetamine in humans, including differences in dopamine release within the [[striatum]] and other brain regions.<ref name="Franconi_2007" /><ref name="Gillies_2012" />

Preclinical studies have also produced findings of sex-dependent differences in drug response to amphetamine.<ref name="Gillies_2012">{{Cite journal |vauthors=Gillies GE, Virdee K, McArthur S, Dalley JW |date=2014-12-12 |title=Sex-dependent diversity in ventral tegmental dopaminergic neurons and developmental programing: A molecular, cellular and behavioral analysis |journal=Neuroscience |volume=282 |pages=69–85 |doi=10.1016/j.neuroscience.2014.05.033 |pmc=4245713 |pmid=24943715 |quote=Significant sex differences were also found when correlating changes in cognition and affect with DA release in striatal and extra-striatal regions after amphetamine administration (Riccardi et al., 2011).&nbsp;...<br />Far greater extracellular levels of DA are found in female rats compared with males treated with the indirectly acting DA receptor agonists, amphetamine (Fig. 1) (Virdee et al., 2013) or cocaine (Walker et al., 2006), which both target DAT in the DA nerve terminals. Baseline (control) levels of DA efflux were similar in males and females (A), whereas amphetamine-stimulated DA efflux was almost fourfold greater in females compared with male rats.&nbsp;...<br />Animal studies confirm and extend the human studies and provide empirical support for the view that gonadal factors may be acting on a sexually differentiated mesolimbic dopaminergic circuitry.&nbsp;... For example, in female rats basal and amphetamine-stimulated concentrations of DA in the striatum (especially the NAc), as well as behavioral responses to amphetamine (locomotor activity and stereotypy), are positively correlated with endogenous estradiol levels as they fluctuate over the estrous cycle. |doi-access=free}}</ref><ref name="Dafny_2006">{{Cite journal |vauthors=Dafny N, Yang PB |date=2006-02-15 |title=The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects |journal=Brain Research Bulletin |volume=68 |issue=6 |pages=393–405 |doi=10.1016/j.brainresbull.2005.10.005 |pmid=16459193 |quote=Adult female rats showing more severe symptoms of drug side effects, such as withdrawal symptoms, express a more rapid and robust behavioral response to acute cocaine and amphetamine and usually display a greater and more rapid behavioral sensitivity to chronic exposure to these drugs compared to their male counterparts [17,18,20,23,24,59,88,176]. This sexual dimorphism was only observed in adult rats, suggesting that gonadal hormones secreted in adulthood might modulate the responsiveness to psychostimulants.}}</ref> In contrast to human studies, adult female [[Rat|rats]] exhibit markedly greater dopamine release in the [[nucleus accumbens]] and more pronounced behavioral effects from amphetamine administration relative to males, effects that may be modulated by fluctuating [[estradiol]] levels across the [[estrous cycle]] or more broadly by adult [[gonadal hormones]].<ref name="Franconi_2007" /><ref name="Gillies_2012" /><ref name="Dafny_2006" />

Some evidence suggests that amphetamine interacts more strongly with female sex hormones than other psychostimulants such as [[methylphenidate]], which may result in relatively greater variability in drug response across the menstrual cycle.<ref name="Findeis_2025" /><ref name="Kok_2020" /> Although preliminary observational evidence suggests potential benefit from adjusting amphetamine doses according to menstrual cycle phases, [[randomized controlled trial]]s have not evaluated this practice.<ref name="Findeis_2025" /><ref name="Rapoport_2025" /><ref name="2025_Leaver" />


===Pharmacokinetics===
The oral [[bioavailability]] of amphetamine varies with gastrointestinal pH;<ref name="FDA" /> it is well [[Absorption (pharmacology)|absorbed]] from the gut, and bioavailability is typically 90%.<ref name="Antunes_2022">{{cite book | vauthors = Antunes M, Marques H, Rosado T, Soares S, Gonçalves J, Barroso M, Gallardo E, Simão AY | veditors = Patel VB, Preedy VR | chapter = Amphetamine in Biological Specimens: Impact and Implications for Public Health | title = Handbook of Substance Misuse and Addictions | pages = 2003–2027 (2006) | date = 2022 | doi = 10.1007/978-3-030-92392-1_104 | publisher = Springer International Publishing | publication-place = Cham | isbn = 978-3-030-92391-4 | chapter-url = https://www.researchgate.net/publication/358977284 | quote = Amphetamine is usually consumed via inhalation or orally, either in the form of a racemic mixture (levoamphetamine and dextroamphetamine) or dextroamphetamine alone (Childress et al. 2019). In general, all amphetamines have high bioavailability when consumed orally, and in the specific case of amphetamine, 90% of the consumed dose is absorbed in the gastrointestinal tract, with no significant differences in the rate and extent of absorption between the two enantiomers (Carvalho et al. 2012; Childress et al. 2019). The onset of action occurs approximately 30 to 45 minutes after consumption, depending on the ingested dose and on the degree of purity or on the concomitant consumption of certain foods (European Monitoring Centre for Drugs and Drug Addiction 2021a; Steingard et al. 2019). It is described that those substances that promote acidification of the gastrointestinal tract cause a decrease in amphetamine absorption, while gastrointestinal alkalinization may be related to an increase in the compound's absorption (Markowitz and Patrick 2017). }}</ref> Amphetamine is a weak base with a [[Acid dissociation constant|p''K''<sub>a</sub>]] of 9.9;<ref name="FDA Pharmacokinetics" /> 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" /> 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|20%}} of amphetamine circulating in the bloodstream is bound to [[plasma protein]]s.<ref name="Drugbank-amph">{{cite DrugBank|drug=Amphetamine|id=DB00182}}</ref> Following absorption, amphetamine readily [[Distribution (pharmacology)|distributes]] into most tissues in the body, with high concentrations occurring in [[cerebrospinal fluid]] and [[human brain|brain]] tissue.<ref name="HSDB Toxnet October 2017 Full archived record">{{cite encyclopedia |title=Amphetamine |section=Metabolism/Pharmacokinetics |url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+300-62-9 |publisher=Hazardous Substances Data Bank. United States National Library of Medicine&nbsp;– Toxicology Data Network |access-date=2 October 2017 |archive-url=https://web.archive.org/web/20171002194327/https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/cgi-bin/sis/search2/f?.%2Ftemp%2F~mdjW95%3A1%3AFULL |archive-date=2 October 2017 |quote=Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34&nbsp;hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine).&nbsp;... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3&nbsp;hours following oral administration.&nbsp;... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine}}</ref>

The [[Biological half-life|half-lives]] 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" /> Highly acidic urine will reduce the enantiomer half-lives to 7&nbsp;hours;<ref name="HSDB Toxnet October 2017 Full archived record" /> highly alkaline urine will increase the half-lives up to 34&nbsp;hours.<ref name="HSDB Toxnet October 2017 Full archived record" /> The immediate-release and extended release variants of salts of both isomers reach [[Cmax (pharmacology)|peak plasma concentrations]] at 3&nbsp;hours and 7&nbsp;hours post-dose respectively.<ref name="FDA Pharmacokinetics" /> Amphetamine is [[Elimination (pharmacology)|eliminated]] via the [[kidney]]s, 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 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.<ref name="FDA Pharmacokinetics" /> Following oral administration, amphetamine appears in urine within 3&nbsp;hours.<ref name="HSDB Toxnet October 2017 Full archived record" /> Roughly 90% of ingested amphetamine is eliminated 3&nbsp;days after the last oral dose.<ref name="HSDB Toxnet October 2017 Full archived record" />{{if pagename|Adderall=|Dextroamphetamine=|other=&nbsp;

Lisdexamfetamine is a [[prodrug]] of dextroamphetamine.<ref name="pmid27021968" /><ref name=USVyvanselabel /> It is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract.<ref name=USVyvanselabel>{{cite web | title=Vyvanse- lisdexamfetamine dimesylate capsule Vyvanse- lisdexamfetamine dimesylate tablet, chewable | website=DailyMed | publisher = Shire US Inc. | date=30 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad | access-date=22 December 2019}}</ref> Following absorption into the blood stream, lisdexamfetamine is completely converted by [[red blood cell]]s to dextroamphetamine and the [[amino acid]] [[lysine|<small>L</small>-lysine]] by [[hydrolysis]] via undetermined [[aminopeptidase]] [[enzyme]]s.<ref name=USVyvanselabel/><ref name="pmid27021968" /><ref name="pmid28936175">{{cite journal | vauthors = Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME | title = Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects | journal = Front Pharmacol | volume = 8 | issue = | article-number = 617 | date = 2017 | pmid = 28936175 | pmc = 5594082 | doi = 10.3389/fphar.2017.00617 | quote = Inactive lisdexamfetamine is completely (>98%) converted to its active metabolite D-amphetamine in the circulation (Pennick, 2010; Sharman and Pennick, 2014). When lisdexamfetamine is misused intranasally or intravenously, the pharmacokinetics are similar to oral use (Jasinski and Krishnan, 2009b; Ermer et al., 2011), and the subjective effects are not enhanced by parenteral administration in contrast to D-amphetamine (Lile et al., 2011) thus reducing the risk of parenteral misuse of lisdexamfetamine compared with D-amphetamine. Intravenous lisdexamfetamine use also produced significantly lower increases in "drug liking" and "stimulant effects" compared with D-amphetamine in intravenous substance users (Jasinski and Krishnan, 2009a).| doi-access = free | title-link = doi }}</ref> This is the [[rate-limiting step]] in the [[bioactivation]] of lisdexamfetamine.<ref name="pmid27021968" /> The elimination half-life of lisdexamfetamine is generally less than 1&nbsp;hour.<ref name=USVyvanselabel /><ref name="pmid27021968" /> Due to the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release dextroamphetamine.<ref name="pmid27021968">{{cite journal | vauthors = Ermer JC, Pennick M, Frick G | title = Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy | journal = Clinical Drug Investigation | volume = 36 | issue = 5 | pages = 341–356 | date = May 2016 | pmid = 27021968 | pmc = 4823324 | doi = 10.1007/s40261-015-0354-y }}</ref><ref name="pmid28936175" /> Presumably due to its rate-limited activation by red blood cells, [[intravenous administration]] of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine.<ref name="pmid27021968" /> The pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally, [[intranasal administration|intranasally]], or intravenously.<ref name="pmid27021968" /><ref name="pmid28936175" /> Hence, in contrast to dextroamphetamine, [[parenteral administration|parenteral]] use does not enhance the subjective effects of lisdexamfetamine.<ref name="pmid27021968" /><ref name="pmid28936175" /> Because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential.<ref name="pmid27021968" /><ref name="pmid28936175" />
}}

[[CYP2D6]], [[dopamine β-hydroxylase]] (DBH), [[flavin-containing monooxygenase 3]] (FMO3), [[butyrate-CoA ligase]] (XM-ligase), and [[glycine N-acyltransferase|glycine ''N''-acyltransferase]] (GLYAT) are the enzymes known to [[Drug metabolism|metabolize]] amphetamine or its metabolites in humans.<ref 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="Metabolites" /> Among these metabolites, the active [[sympathomimetics]] are {{nowrap|4-hydroxyamphetamine}},<ref>{{cite encyclopedia |title=p-Hydroxyamphetamine. PubChem Compound Database|section-url=https://pubchem.ncbi.nlm.nih.gov/compound/3651 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | access-date=15 October 2013 |section=Compound Summary}}</ref> {{nowrap|4-hydroxynorephedrine}},<ref>{{cite encyclopedia |title=p-Hydroxynorephedrine. PubChem Compound Database |section-url=https://pubchem.ncbi.nlm.nih.gov/compound/11099 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information |access-date=15 October 2013 |section=Compound Summary}}</ref> and norephedrine.<ref>{{cite encyclopedia |title=Phenylpropanolamine. PubChem Compound Database |section-url=https://pubchem.ncbi.nlm.nih.gov/compound/26934 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information |access-date=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">{{cite encyclopedia |title=Amphetamine. Pubchem Compound Database |section-url=https://pubchem.ncbi.nlm.nih.gov/compound/3007 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information |access-date=12 October 2013 |section=Pharmacology and Biochemistry}}</ref> The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:
{{Amphetamine pharmacokinetics|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 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]], which is then metabolized by {{abbr|GLYAT|glycine ''N''-acyltransferase}} into hippuric acid.<ref name="Glycine conjugation review" />}}
{{clear}}

===Pharmacomicrobiomics===

The [[human metagenome]] (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals.<ref name="Pharmacomicrobiomics">{{cite journal | vauthors = ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK | title = Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics | journal =Omics | volume = 18 | issue = 7 | pages = 402–414 | date = July 2014 | pmid = 24785449 | pmc = 4086029 | doi = 10.1089/omi.2014.0018 | quote = The hundred trillion microbes and viruses residing in every human body, which outnumber human cells and contribute at least 100 times more genes than those encoded on the human genome (Ley et al., 2006), offer an immense accessory pool for inter-individual genetic variation that has been underestimated and largely unexplored (Savage, 1977; Medini et al., 2008; Minot et al., 2011; Wylie et al., 2012).&nbsp;... Meanwhile, a wealth of literature has long been available about the biotransformation of xenobiotics, notably by gut bacteria (reviewed in Sousa et al., 2008; Rizkallah et al., 2010; Johnson et al., 2012; Haiser and Turnbaugh, 2013). This valuable information is predominantly about drug metabolism by unknown human-associated microbes; however, only a few cases of inter-individual microbiome variations have been documented [e.g., digoxin (Mathan et al., 1989) and acetaminophen (Clayton et al., 2009)].}}</ref><ref name="Human microbiome">{{cite journal | vauthors = Cho I, Blaser MJ | title = The human microbiome: at the interface of health and disease | journal =Nature Reviews Genetics| volume = 13 | issue = 4 | pages = 260–270 | date = March 2012 | pmid = 22411464 | doi = 10.1038/nrg3182 | quote=The composition of the microbiome varies by anatomical site (Figure 1). The primary determinant of community composition is anatomical location: interpersonal variation is substantial<sup>23,24</sup> and is higher than the temporal variability seen at most sites in a single individual<sup>25</sup>.&nbsp;... How does the microbiome affect the pharmacology of medications? Can we "micro-type" people to improve pharmacokinetics and/or reduce toxicity? Can we manipulate the microbiome to improve pharmacokinetic stability?| pmc = 3418802 }}</ref> Since the total number of microbial and viral cells in the human body (over 100&nbsp;trillion) greatly outnumbers human cells (tens of trillions),{{#tag:ref|There is substantial variation in microbiome composition and microbial concentrations by anatomical site.<ref name="Pharmacomicrobiomics" /><ref name="Human microbiome" /> Fluid from the human colon&nbsp;– which contains the highest concentration of microbes of any anatomical site&nbsp;– contains approximately one trillion (10^12) bacterial cells/ml.<ref name="Pharmacomicrobiomics" />|group="note"}}<ref name="Pharmacomicrobiomics" /><ref name="Gut feeling">{{cite journal | vauthors = Hutter T, Gimbert C, Bouchard F, Lapointe FJ | title = Being human is a gut feeling | journal =Microbiome| volume = 3 | article-number = 9 | pmid = 25774294 | doi = 10.1186/s40168-015-0076-7 | pmc = 4359430 | quote=Some metagenomic studies have suggested that less than 10% of the cells that comprise our bodies are Homo sapiens cells. The remaining 90% are bacterial cells. The description of this so-called human microbiome is of great interest and importance for several reasons. For one, it helps us redefine what a biological individual is. We suggest that a human individual is now best described as a super-individual in which a large number of different species (including Homo sapiens) coexist.| year = 2015 | doi-access = free | title-link = doi }}</ref> there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the [[human microbiome]], [[drug metabolism]] by microbial enzymes modifying the drug's [[pharmacokinetic]] profile, and microbial drug metabolism affecting a drug's clinical efficacy and [[toxicity]] profile.<ref name="Pharmacomicrobiomics" /><ref name="Human microbiome" /><ref name="Microbial amphetamine metabolism - E. coli" /> The field that studies these interactions is known as [[pharmacomicrobiomics]].<ref name="Pharmacomicrobiomics" />

Similar to most [[biomolecule]]s and other [[oral administration|orally administered]] [[xenobiotic]]s (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by [[human gastrointestinal microbiota]] (primarily bacteria) prior to absorption into the [[blood stream]].<ref name="Microbial amphetamine metabolism - E. coli" /> The first amphetamine-metabolizing microbial enzyme, [[primary amine oxidase|tyramine oxidase]] from a strain of [[Escherichia coli|''E. coli'']] commonly found in the human gut, was identified in 2019.<ref name="Microbial amphetamine metabolism - E. coli" /> This enzyme was found to metabolize amphetamine, [[tyramine]], and phenethylamine with roughly the same binding affinity for all three compounds.<ref name="Microbial amphetamine metabolism - E. coli">{{cite journal | vauthors = Kumar K, Dhoke GV, Sharma AK, Jaiswal SK, Sharma VK | title = Mechanistic elucidation of amphetamine metabolism by tyramine oxidase from human gut microbiota using molecular dynamics simulations | journal =Journal of Cellular Biochemistry| date = January 2019 | pmid = 30701587 | doi = 10.1002/jcb.28396 | quote=<!-- Numerous microorganisms reside with the human host in a symbiotic relationship and play an important role in the host metabolic processes and health.<sup>1,2</sup> Several studies in the recent past have reported that there are compositional differences in the human microbiome due to factors such as geographical location, diet, age, and genetic variations.<sup>3</sup> --> Particularly in the case of the human gut, which harbors a large diversity of bacterial species, the differences in microbial composition can significantly alter the metabolic activity in the gut lumen.<sup>4</sup> The differential metabolic activity due to the differences in gut microbial species has been recently linked with various metabolic disorders and diseases.<sup>5–12</sup> In addition to the impact of gut microbial diversity or dysbiosis in various human diseases, there is an increasing amount of evidence which shows that the gut microbes can affect the bioavailability and efficacy of various orally administrated{{sic}} drug molecules through promiscuous enzymatic metabolism.<sup>13,14</sup>&nbsp;... The present study on the atomistic details of amphetamine binding and binding affinity to the tyramine oxidase along with the comparison with two natural substrates of this enzyme namely tyramine and phenylalanine provides strong evidence for the promiscuity-based metabolism of amphetamine by the tyramine oxidase enzyme of E. coli. The obtained results will be crucial in designing a surrogate molecule for amphetamine that can help either in improving the efficacy and bioavailability of the amphetamine drug via competitive inhibition or in redesigning the drug for better pharmacological effects. This study will also have useful clinical implications in reducing the gut microbiota caused variation in the drug response among different populations. | volume=120 | issue = 7 | pages=11206–11215| s2cid = 73413138 }}</ref>

===Related endogenous compounds===
{{Further|topic=related compounds|Trace amine}}
Amphetamine has a very similar structure and function to the [[wikt:endogenous|endogenous]] trace amines, which are naturally occurring [[neuromodulator]] molecules produced in the human body and brain.<ref name="Miller" /><ref name="Trace Amines" /><ref name="Human trace amines and hTAARs October 2016 review">{{cite journal | vauthors = Khan MZ, Nawaz W | title = The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system | journal =Biomedicine & Pharmacotherapy| volume = 83 | pages = 439–449 | date = October 2016 | pmid = 27424325 | doi = 10.1016/j.biopha.2016.07.002 }}</ref> Among this group, the most closely related compounds are [[phenethylamine]], the parent compound of amphetamine, and {{nowrap|[[N-methylphenethylamine|''N''-methylphenethylamine]]}}, a structural [[isomer]] of amphetamine (i.e., it has an identical molecular formula).<ref name="Miller" /><ref name="Trace Amines" /><ref name="Renaissance GPCR">{{cite journal |vauthors=Lindemann L, Hoener MC |title=A renaissance in trace amines inspired by a novel GPCR family |journal=Trends in Pharmacological Sciences|volume=26 |issue=5 |pages=274–281 |date=May 2005 |pmid=15860375 |doi=10.1016/j.tips.2005.03.007 | quote = <!-- 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 {{nowrap|[[L-phenylalanine|<small>L</small>-phenylalanine]]}} by the [[aromatic amino acid decarboxylase]] (AADC) enzyme, which converts {{nowrap|[[L-DOPA|<small>L</small>-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|phenylethanolamine ''N''-methyltransferase]], the same enzyme that metabolizes norepinephrine into epinephrine.<ref name="Trace Amines">{{cite journal | author = Broadley KJ | title = The vascular effects of trace amines and amphetamines | journal =Pharmacology & Therapeutics| volume = 125 | issue = 3 | pages = 363–375 |date=March 2010 | pmid = 19948186 | doi = 10.1016/j.pharmthera.2009.11.005 | quote = <!-- '''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="Human trace amines and hTAARs October 2016 review" /><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" />

==Chemistry==
<div class="skin-invert-image">
{{Annotated image 4
| image-bg-color = unset
| caption = The [[skeletal structure]]s of {{nowrap|{{abbr|L-amph|levoamphetamine}}}} and {{nowrap|{{abbr|D-amph|dextroamphetamine}}}}
| header = Racemic amphetamine
| header_align = center
| alt = Graphical representation of Amphetamine stereoisomers
| image = Racemic_amphetamine.svg
| align = right
| image-width = 300
| image-left = 0
| image-top = 0
| width = 300
| height = 76
| annot-font-size = 14
| annot-text-align = left
| annotations =
{{Annotation|5|60|[[Levoamphetamine]]}}
{{Annotation|170|60|[[Dextroamphetamine]]}}
}}</div>
{{Multiple image
<!-- Essential parameters -->
| align     = right
| direction = vertical
| width     = 300
<!-- Extra parameters -->
| image1=Amphetamine Freebase.png
| caption1=A vial of the colorless amphetamine free base
| alt1=An image of amphetamine free base
| image2=Amphetamine and P2P.png
| caption2=Amphetamine hydrochloride (left bowl)<br />{{nowrap|[[Phenyl-2-nitropropene]]}} (right cups)
| alt2=An image of phenyl-2-nitropropene and amphetamine hydrochloride
}}
Amphetamine is a [[methyl]] [[homologous series|homolog]] of the mammalian neurotransmitter [[phenethylamine]] with the chemical formula {{Chem2|C9H13N|auto=yes}}. 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]]s.<ref name="Drugbank-amph" /> 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="Drugbank-amph" /> 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=https://pubchem.ncbi.nlm.nih.gov/compound/3007 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information. PubChem Compound Database |access-date=13 October 2013 |section=Chemical and Physical Properties}}</ref> Frequently prepared solid salts of amphetamine include amphetamine adipate,<ref>{{cite web|url=https://www.federalregister.gov/documents/2003/11/10/03-28193/determination-that-delcobese-amphetamine-adipate-amphetamine-sulfate-dextroamphetamine-adipate|title=Determination That Delcobese (Amphetamine Adipate, Amphetamine Sulfate, Dextroamphetamine Adipate, Dextroamphetamine Sulfate) Tablets and Capsules Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness|date=10 November 2003|website=Federal Register|access-date=3 January 2020}}</ref> aspartate,<ref name="FDA" /> hydrochloride,<ref>{{cite encyclopedia |title=Amphetamine Hydrochloride |url=https://pubchem.ncbi.nlm.nih.gov/compound/92939 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information. Pubchem Compound Database |access-date=8 November 2013}}</ref> phosphate,<ref>{{cite encyclopedia |title=Amphetamine Phosphate |url=https://pubchem.ncbi.nlm.nih.gov/compound/62885 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information. Pubchem Compound Database |access-date=8 November 2013}}</ref> saccharate,<ref name="FDA" /> sulfate,<ref name="FDA" /> and tannate.<ref>{{cite journal |vauthors=Cavallito J |date=23 August 1960|title=Amphetamine Tannate. Patent Application No. 2,950,309. |url=https://patentimages.storage.googleapis.com/23/7a/08/1e7b613dc61b17/US2950309.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://patentimages.storage.googleapis.com/23/7a/08/1e7b613dc61b17/US2950309.pdf |archive-date=9 October 2022 |url-status=live|journal=United States Patent Office}}</ref> Dextroamphetamine sulfate is the most common enantiopure 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="Drugbank-amph" /> In organic chemistry, amphetamine is an excellent [[chiral ligand]] for the [[stereoselective synthesis]] of {{nowrap|[[1,1'-bi-2-naphthol]]}}.<ref name="Chiral Ligand">{{cite journal |vauthors=Brussee J, Jansen AC | date = May 1983 | title = A highly stereoselective synthesis of s(−)-[1,1'-binaphthalene]-2,2'-diol | journal =Tetrahedron Letters | volume = 24 | issue = 31 | pages = 3261–3262 | doi = 10.1016/S0040-4039(00)88151-4 }}</ref>

===Substituted derivatives===
{{Main list|Substituted amphetamine}}
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">{{cite journal | vauthors = Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ | title = Biosynthesis of amphetamine analogs in plants | journal =Trends in Plant Science| volume = 17 | issue = 7 | pages = 404–412 | date = 2012 | pmid = 22502775 | doi = 10.1016/j.tplants.2012.03.004 | bibcode = 2012TPS....17..404H | quote = 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).&nbsp;... Beyond (1''R'',2''S'')-ephedrine and (1''S'',2''S'')-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications.&nbsp;... For example, (''S'')-amphetamine (Figure 4b), a key ingredient in Adderall and Dexedrine, 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">{{cite journal |vauthors=Schep LJ, Slaughter RJ, Beasley DM | title=The clinical toxicology of metamfetamine | journal=Clinical Toxicology| volume=48 | issue=7 | pages=675–694 |date=August 2010 | pmid=20849327 | doi=10.3109/15563650.2010.516752 | s2cid=42588722 | 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">{{cite journal | vauthors = Lillsunde P, Korte T | title = Determination of ring- and ''N''-substituted amphetamines as heptafluorobutyryl derivatives | journal =Forensic Science International| volume = 49 | issue = 2 | pages = 205–213 | date = 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" />

===Synthesis===
{{Further|topic=illicit amphetamine synthesis|History and culture of substituted amphetamines#Illegal synthesis}}
Since the first preparation was reported in 1887,<ref name="Vermont"/> numerous synthetic routes to amphetamine have been developed.<ref name="Allen_Ely_2009">{{cite journal | url = http://www.nwafs.org/newsletters/2011_Spring.pdf | title = Review: Synthetic Methods for Amphetamine | vauthors = Allen A, Ely R | publisher = Northwest Association of Forensic Scientists | volume = 37 | issue = 2 | date = April 2009 | pages = 15–25 | journal = Crime Scene | access-date = 6 December 2014 | archive-date = 2 March 2014 | archive-url = https://web.archive.org/web/20140302003354/http://www.nwafs.org/newsletters/2011_Spring.pdf }}</ref><ref name="Allen_Cantrell_1989">{{cite journal |vauthors=Allen A, Cantrell TS | title = Synthetic reductions in clandestine amphetamine and methamphetamine laboratories: A review | journal =Forensic Science International| date = August 1989 | volume = 42 | issue = 3 | pages = 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&nbsp;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>{{cite journal | doi = 10.1021/jo01145a001 | title = The Mechanism of the Leuckart Reaction |date=May 1951 |vauthors=Pollard CB, Young DC | journal =The Journal of Organic Chemistry| volume = 16 | issue = 5 | pages = 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">{{Cite book |veditors=Johnson DS, Li JJ | author = Gray DL | title = The Art of Drug Synthesis | chapter = Approved Treatments for Attention Deficit Hyperactivity Disorder: Amphetamine (Adderall), Methylphenidate (Ritalin), and Atomoxetine (Straterra) | chapter-url = https://books.google.com/books?id=zvruBDAulWEC&q=The%20Art%20of%20Drug%20Synthesis%20(Wiley%20Series%20on%20Drug%20Synthesis)&pg=SA17-PA4 | year = 2007 | publisher = Wiley-Interscience | location = New York, US | isbn = 978-0-471-75215-8 | page = 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 [[benzene]] by [[allyl chloride]] to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method&nbsp;2).<ref name="pmid20985610">{{cite journal |vauthors=Patrick TM, McBee ET, Hass HB | title = Synthesis of arylpropylamines; from allyl chloride | journal =Journal of the American Chemical Society| volume = 68 | issue = 6 | pages = 1009–1011 | date = June 1946 | pmid = 20985610 | doi = 10.1021/ja01210a032 | bibcode = 1946JAChS..68.1009P }}</ref> Another example employs the [[Ritter reaction]] (method&nbsp;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">{{cite journal |vauthors=Ritter JJ, Kalish J | title = A new reaction of nitriles; synthesis of t-carbinamines | journal =Journal of the American Chemical Society| volume = 70 | issue = 12 | pages = 4048–4050 | date = December 1948 | pmid = 18105933 | doi = 10.1021/ja01192a023 | bibcode = 1948JAChS..70.4048R }}</ref><ref name=Krimen_Cota_1969>{{Cite book | chapter=The Ritter Reaction | vauthors=Krimen LI, Cota DJ | date = March 2011 | volume = 17 | page = 216 | doi = 10.1002/0471264180.or017.03 | title=Organic Reactions | isbn=978-0-471-26418-7 }}</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&nbsp;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&nbsp;5).<ref name="Amph Synth">{{cite web | url = http://www.unodc.org/pdf/scientific/stnar34.pdf | title = Recommended methods of the identification and analysis of amphetamine, methamphetamine, and their ring-substituted analogues in seized materials | pages = 9–12 | access-date = 14 October 2013 | year = 2006 | website = United Nations Office on Drugs and Crime | publisher = United Nations}}</ref><ref name="Delta Isotope">{{cite journal |vauthors=Collins M, Salouros H, Cawley AT, Robertson J, Heagney AC, Arenas-Queralt A | title = δ<sup>13</sup>C and δ<sup>2</sup>H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane | journal =Rapid Communications in Mass Spectrometry| volume = 24 | issue = 11 | pages = 1653–1658 |date=June 2010 | pmid = 20486262 | doi = 10.1002/rcm.4563 | bibcode = <!-- No --> }}</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&nbsp;6).<ref name="Amph Synth" />
<!--Table of chemical synthesis diagrams -->
{| style="margin: 1em auto;"
|+'''Amphetamine synthetic routes'''
|- style="vertical-align: top;"
|<!--Left cell: nested table -->
{|
|<div class="skin-invert-image">{{multiple image
<!-- Essential parameters -->
| align     = center
| direction = vertical
| width     = 372

|image1=Amphetamine Leukart synthesis.svg
|caption1=Method&nbsp;1: Synthesis by the Leuckart reaction&nbsp;
|alt1=Diagram of amphetamine synthesis by the Leuckart reaction

|image2=Amphetamine resolution and chiral synthesis.svg
|caption2=Top: Chiral resolution of amphetamine&nbsp;<br />Bottom: Stereoselective synthesis of amphetamine&nbsp;
|alt2=Diagram of a chiral resolution of racemic amphetamine and a stereoselective synthesis

|image3=Amphetamine Friedel-Crafts alkylation.svg
|caption3=Method&nbsp;2: Synthesis by Friedel–Crafts alkylation&nbsp;
|alt3=Diagram of amphetamine synthesis by Friedel–Crafts alkylation
}}</div>
|}
|<!--Right cell: nested table -->
{|
|<div class="skin-invert-image">{{multiple image
<!-- Essential parameters -->
| align     = center
| direction = vertical
| width     = 372

|image1=Amphetamine Ritter Synthesis.svg
|caption1=Method&nbsp;3: Ritter synthesis
|alt1=Diagram of amphetamine via Ritter synthesis

|image2=Amphetamine Hofmann Curtius Synthesis.svg
|caption2=Method&nbsp;4: Synthesis via Hofmann and Curtius rearrangements
|alt2=Diagram of amphetamine synthesis via Hofmann and Curtius rearrangements

|image3=Amphetamine Knoevenagel synthesis.svg
|caption3=Method&nbsp;5: Synthesis by Knoevenagel condensation
|alt3=Diagram of amphetamine synthesis by Knoevenagel condensation

|image4=Amphetamine p2p ammonia synthesis.svg
|caption4=Method&nbsp;6: Synthesis using phenylacetone and ammonia
|alt4=Diagram of amphetamine synthesis from phenylacetone and ammonia
}}</div>
|}
|}
{{clear}}

===Detection in body fluids===
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">{{cite journal |vauthors=Kraemer T, Maurer HH | title = Determination of amphetamine, methamphetamine and amphetamine-derived designer drugs or medicaments in blood and urine | journal =Journal of Chromatography B | volume = 713 | issue = 1 | pages = 163–187 |date=August 1998 | pmid = 9700558 | doi = 10.1016/S0378-4347(97)00515-X }}</ref><ref name="pmid17468860">{{cite journal |vauthors=Kraemer T, Paul LD | title = Bioanalytical procedures for determination of drugs of abuse in blood | journal =Analytical and Bioanalytical Chemistry| volume = 388 | issue = 7 | pages = 1415–1435 |date=August 2007 | pmid = 17468860 | doi = 10.1007/s00216-007-1271-6 | s2cid = 32917584 }}</ref><ref name="pmid8075776">{{cite journal |vauthors=Goldberger BA, Cone EJ | title = Confirmatory tests for drugs in the workplace by gas chromatography-mass spectrometry | journal =Journal of Chromatography A| volume = 674 | issue = 1–2 | pages = 73–86 |date=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 |publisher=United States Food and Drug Administration |access-date=24 December 2019 |date=1 April 2019 |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. |archive-url=https://web.archive.org/web/20191225081836/https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=341.80 |archive-date=25 December 2019 |url-status=live }}</ref><ref>{{cite encyclopedia |title=Levomethamphetamine |section=Identification |section-url=https://pubchem.ncbi.nlm.nih.gov/compound/36604 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information. Pubchem Compound Database |access-date=2 January 2014}}</ref>|name="OTC levmetamfetamine"|group="note"}} or illicitly obtained substituted amphetamines.<ref name="pmid15516295">{{cite journal |vauthors=Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA |title=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) | journal =Journal of Analytical Toxicology| volume = 28 | issue = 6 |pages = 449–455 |date=September 2004 | pmid = 15516295 | doi = 10.1093/jat/28.6.449 | doi-access = free | title-link = doi }}</ref><ref name="pmid16105261">{{cite journal |vauthors=Verstraete AG, Heyden FV | title = Comparison of the sensitivity and specificity of six immunoassays for the detection of amphetamines in urine | journal =Journal of Analytical Toxicology| volume = 29 | issue = 5 | pages = 359–364 | date = August 2005 | pmid = 16105261 | doi =10.1093/jat/29.5.359 | doi-access = free | title-link = doi }}</ref><ref name="Baselt_2011">{{cite book | author = Baselt RC | title = Disposition of Toxic Drugs and Chemicals in Man | year = 2011 | publisher = Biomedical Publications | location=Seal Beach, US | isbn = 978-0-9626523-8-7 | pages = 85–88 | edition = 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">{{cite journal | author = Musshoff F | title = Illegal or legitimate use? Precursor compounds to amphetamine and methamphetamine | journal =Drug Metabolism Reviews| volume = 32 |issue = 1 | pages = 15–44 |date=February 2000 | pmid = 10711406 | doi = 10.1081/DMR-100100562 | s2cid = 20012024 }}</ref><ref name="pmid12024689">{{cite journal | author = Cody JT | title = Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results | journal =Journal of Occupational and Environmental Medicine| volume = 44 | issue = 5 | pages = 435–450 |date=May 2002 | pmid = 12024689 | doi = 10.1097/00043764-200205000-00012 | s2cid = 44614179 }}</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 {{nowrap|2–4}}&nbsp;days.<ref name="NAHMSA_testing">{{cite web | title=Clinical Drug Testing in Primary Care | url=http://www.ucdenver.edu/academics/colleges/PublicHealth/research/centers/CHWE/Documents/SAMHSA_drugtesting.pdf | website=University of Colorado Denver | publisher=United States Department of Health and Human Services&nbsp;– Substance Abuse and Mental Health Services Administration | series=Technical Assistance Publication Series 32 | year=2012 | page=55 | access-date=31 October 2013 | quote=A single dose of amphetamine or methamphetamine can be detected in the urine for approximately 24 hours, depending upon urine pH and individual metabolic differences. People who use chronically and at high doses may continue to have positive urine specimens for 2–4 days after last use (SAMHSA, 2010b). |archive-url=https://web.archive.org/web/20180514022358/http://www.ucdenver.edu/academics/colleges/PublicHealth/research/centers/CHWE/Documents/SAMHSA_drugtesting.pdf | archive-date=14 May 2018|url-status=live}}</ref>

For the assays, a study noted that an [[enzyme multiplied immunoassay technique]] (EMIT) assay for amphetamine and methamphetamine may produce more false positives than [[Liquid chromatography–mass spectrometry#Proteomics/metabolomics|liquid chromatography–tandem mass spectrometry]].<ref name="pmid16105261" /> [[Gas chromatography–mass spectrometry]] (GC–MS) of amphetamine and methamphetamine with the derivatizing agent {{nowrap|(''S'')-(−)-trifluoroacetylprolyl}} chloride allows for the detection of methamphetamine in urine.<ref name="pmid15516295" /> GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent [[Mosher's acid|Mosher's&nbsp;acid chloride]] allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.<ref name="pmid15516295" /> Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug.<ref name="pmid15516295" />

==History, society, and culture==
{{Main|History and culture of substituted amphetamines}}
{{Global estimates of illegal drug users}}

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist [[Lazăr Edeleanu]] who named it ''phenylisopropylamine'';<ref name="Vermont">{{cite web |url=http://healthvermont.gov/adap/meth/brief_history.aspx |archive-url=https://web.archive.org/web/20121005022228/http://healthvermont.gov/adap/meth/brief_history.aspx |archive-date=5 October 2012 |title=Historical overview of methamphetamine | website=Vermont Department of Health | publisher=Government of Vermont | access-date=29 January 2012}}</ref><ref>{{cite book | author = Rassool GH | title=Alcohol and Drug Misuse: A Handbook for Students and Health Professionals | year=2009 | publisher=Routledge | location=London, England | isbn=978-0-203-87117-1 | page=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">{{cite journal |vauthors=Sulzer D, Sonders MS, Poulsen NW, Galli A |title=Mechanisms of neurotransmitter release by amphetamines: a review |journal=Progress in Neurobiology|volume=75 |issue=6 |pages=406–433 |date=April 2005 |pmid=15955613 |doi=10.1016/j.pneurobio.2005.04.003|s2cid=2359509 }}</ref> Amphetamine had no medical use until late 1933, when [[Smith, Kline and French]] began selling it as an [[inhaler]] under the brand name [[History of Benzedrine|Benzedrine]] as a decongestant.<ref name="Benzedrine">{{cite journal | vauthors = Rasmussen N | title=Making the first anti-depressant: amphetamine in American medicine, 1929–1950 | journal=Journal of the History of Medicine and Allied Sciences| volume=61 | issue=3 | pages=288–323 | date=July 2006 | pmid=16492800 | doi=10.1093/jhmas/jrj039 | s2cid=24974454 | quote = However the firm happened to discover the drug, SKF first packaged it as an inhaler so as to exploit the base's volatility and, after sponsoring some trials by East Coast otolaryngological specialists, began to advertise the Benzedrine Inhaler as a decongestant in late 1933.}}</ref> Benzedrine sulfate was introduced 3&nbsp;years later and was used to treat a wide variety of [[medical condition]]s, including [[narcolepsy]], [[obesity]], [[low blood pressure]], [[Hypoactive sexual desire disorder|low libido]], and [[chronic pain]], among others.<ref name="Benzedrine sulfate">{{cite journal | vauthors = Bett WR | title = Benzedrine sulphate in clinical medicine; a survey of the literature | journal =Postgraduate Medical Journal| volume = 22 | issue = 250 | pages = 205–218 | date = August 1946 | pmid = 20997404 | pmc = 2478360 | doi = 10.1136/pgmj.22.250.205}}</ref><ref name="Benzedrine" /> During [[World War II]], amphetamine and [[methamphetamine]] were used extensively by both the [[Allies of World War II|Allied]] and [[Axis powers|Axis]] forces for their stimulant and performance-enhancing effects.<ref name="Vermont" /><ref>{{cite journal | author = Rasmussen N | title=Medical science and the military: the Allies' use of amphetamine during World War II | journal=Journal of Interdisciplinary History| date=August 2011 | volume=42 | issue=2 | pages=205–233 | pmid=22073434 | doi=10.1162/JINH_a_00212 | s2cid=34332132 }}</ref><ref name="pmid22849208">{{cite journal |vauthors=Defalque RJ, Wright AJ | title = Methamphetamine for Hitler's Germany: 1937 to 1945 | journal =Bulletin of Anesthesia History| volume = 29 | issue = 2 | pages = 21–24, 32 | date=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 [[Controlled Substances Act#Schedule II controlled substances|schedule&nbsp;II controlled substance]] under the [[Controlled Substances Act]].<ref name=":USAS2" /> In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,<ref>{{cite web | author = Gyenis A | website = wordsareimportant.com | publisher = DHARMA beat | title = Forty Years of ''On the Road'' 1957–1997| url = http://www.wordsareimportant.com/ontheroad.htm | access-date = 18 March 2008 | archive-url = https://web.archive.org/web/20080214171739/http://www.wordsareimportant.com/ontheroad.htm | archive-date = 14 February 2008}}</ref> musicians,<ref>{{cite journal|title=Mixing the Medicine: The unintended consequence of amphetamine control on the Northern Soul Scene | vauthors = Wilson A |url=http://www.internetjournalofcriminology.com/Wilson%20-%20Mixing%20the%20Medicine.pdf |journal=Internet Journal of Criminology |year=2008 |access-date=25 May 2013 |archive-url=https://web.archive.org/web/20110713045851/http://www.internetjournalofcriminology.com/Wilson%20-%20Mixing%20the%20Medicine.pdf |archive-date=13 July 2011 }}</ref> mathematicians,<ref>{{cite web | title = Paul Erdos, Mathematical Genius, Human (In That Order) |url = http://www.untruth.org/~josh/math/Paul%20Erd%F6s%20bio-rev2.pdf | author = Hill J | access-date = 2 November 2013 | date = 4 June 2004}}</ref> and athletes.<ref name="Ergogenics" />

Amphetamine is illegally synthesized in [[clandestine chemistry|clandestine labs]] and sold on the [[black market]], primarily in European countries.<ref name="WDR2014">{{cite web | title = World Drug Report 2014 | veditors = Mohan J | date = June 2014 | page = 3 | website = United Nations Office on Drugs and Crime | url = https://www.unodc.org/documents/wdr2014/World_Drug_Report_2014_web.pdf | access-date = 18 August 2014 }}</ref> Among European Union (EU) member states {{As of|alt=in 2018|2018|post=,}} 11.9&nbsp;million adults of ages {{nowrap|15–64}} have used amphetamine or methamphetamine at least once in their lives and 1.7&nbsp;million have used either in the last year.<ref name="Bulletin2018">{{cite web|url=http://www.emcdda.europa.eu/data/stats2018/gps_en|title=Statistical Bulletin 2018&nbsp;− prevalence of drug use|publisher=European Monitoring Centre for Drugs and Drug Addiction |access-date=5 February 2019}}</ref> During 2012, approximately 5.9&nbsp;[[metric ton]]s of illicit amphetamine were seized within EU member states;<ref name="EMCDDA 2014">{{cite report|date=May 2014|title=European drug report 2014: Trends and developments|url=http://www.emcdda.europa.eu/attachements.cfm/att_228272_EN_TDAT14001ENN.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://www.emcdda.europa.eu/attachements.cfm/att_228272_EN_TDAT14001ENN.pdf |archive-date=9 October 2022 |url-status=live|location=Lisbon, Portugal|publisher=European Monitoring Centre for Drugs and Drug Addiction|pages=13, 24|doi=10.2810/32306|issn=2314-9086|access-date=18 August 2014|quote=1.2 million or 0.9% of young adults (15–34) used amphetamines in the last year|author1=European Monitoring Centre for Drugs Drug Addiction }}</ref> the "street price" of illicit amphetamine within the EU ranged from {{nowrap|[[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" />

===Legal status===
As a result of the [[United Nations]] 1971 [[Convention on Psychotropic Substances]], amphetamine became a schedule&nbsp;II controlled substance, as defined in the treaty, in all 183 state parties.<ref name="UN Convention">{{cite web|title=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 |website=United Nations Treaty Collection |publisher=United Nations |access-date=11 November 2013 |url-status=live }}</ref> Consequently, it is heavily regulated in most countries.<ref name="UNODC2007">{{cite book | author = United Nations Office on Drugs and Crime | title = Preventing Amphetamine-type Stimulant Use Among Young People: A Policy and Programming Guide | publisher = United Nations | location = New York, US | year = 2007 | isbn = 978-92-1-148223-2 | url = http://www.unodc.org/pdf/youthnet/ATS.pdf | access-date = 11 November 2013 | archive-date = 16 October 2013 | archive-url = https://web.archive.org/web/20131016082310/http://www.unodc.org/pdf/youthnet/ATS.pdf }}</ref><ref>{{cite web | title = List of psychotropic substances under international control | website = International Narcotics Control Board | publisher = United Nations | url = http://www.incb.org/pdf/e/list/green.pdf | access-date = 19 November 2005 | archive-url = https://web.archive.org/web/20051205125434/http://www.incb.org/pdf/e/list/green.pdf | archive-date= 5 December 2005 |date=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">{{cite web | url = https://www.koreatimes.co.kr/www/news/nation/2012/10/319_111757.html | title = Moving to Korea brings medical, social changes | website = The Korean Times | date = 25 May 2012 | access-date = 14 November 2013 | author = Park Jin-seng}}</ref><ref>{{cite web | url = http://www.mhlw.go.jp/english/topics/import/ | title = Importing or Bringing Medication into Japan for Personal Use | website = Japanese Ministry of Health, Labour and Welfare | access-date=3 November 2013 | date=1 April 2004}}</ref> In other nations, such as Brazil ([[Brazilian Controlled Drugs and Substances Act|class A3]]),<ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control |url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=3 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref> Canada ([[Controlled Drugs and Substances Act|schedule&nbsp;I drug]]),<ref name="Canada Control">{{cite web|url=http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-24.html#h-28 |title=Controlled Drugs and Substances Act |website=Canadian Justice Laws Website |publisher=Government of Canada |access-date=11 November 2013 |archive-url=https://web.archive.org/web/20131122143804/http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-24.html |archive-date=22 November 2013 }}</ref> the Netherlands ([[Opium Law|List I drug]]),<ref name="Opiumwet">{{cite web | url = http://wetten.overheid.nl/BWBR0001941/geldigheidsdatum_03-08-2009 | title = Opiumwet | publisher = Government of the Netherlands | access-date = 3 April 2015 }}</ref> the United States ([[List of Schedule II drugs (US)|schedule II drug]]),<ref name=":USAS2" /> Australia ([[Standard for the Uniform Scheduling of Medicines and Poisons#Schedule 8 Controlled Drug|schedule&nbsp;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 | access-date = 15 December 2015 | date = October 2015}}</ref> Thailand ([[Law of Thailand#Criminal Law|category&nbsp;1 narcotic]]),<ref>{{cite web | url = http://narcotic.fda.moph.go.th/faq/upload/Thai%20Narcotic%20Act%202012.doc._37ef.pdf | archive-url=https://web.archive.org/web/20140308001155/http://narcotic.fda.moph.go.th/faq/upload/Thai%20Narcotic%20Act%202012.doc._37ef.pdf | title = Table of controlled Narcotic Drugs under the Thai Narcotics Act | website = Thailand Food and Drug Administration | date = 22 May 2013 | access-date = 11 November 2013 | archive-date=8 March 2014 }}</ref> and United Kingdom ([[Misuse of Drugs Act 1971|class&nbsp;B drug]]),<ref>{{cite web | title = Class A, B and C drugs | website = Home Office, Government of the United Kingdom | url = http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/ | access-date = 23 July 2007 | archive-url = https://web.archive.org/web/20070804233232/http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/ | archive-date = 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">{{cite journal |vauthors=Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S | title = Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature | journal =Journal of the American Academy of Child & Adolescent Psychiatry| volume = 47 | issue = 1 | pages = 21–31 |date=January 2008 | pmid = 18174822 | doi = 10.1097/chi.0b013e31815a56f1 | quote=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>

===Pharmaceutical products===
Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, Adderall&nbsp;XR, Mydayis,<ref group=note name=AdderallDiff /> Adzenys&nbsp;ER, {{nowrap|Adzenys XR-ODT}}, Dyanavel&nbsp;XR, Evekeo, and Evekeo&nbsp;ODT. Of those, Evekeo (including Evekeo&nbsp;ODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose [[Moiety (chemistry)#Active moiety|active moiety]] can be accurately referred to simply as "amphetamine".<ref name="Stahl's Essential Psychopharmacology" /><ref name="Evekeo" /><ref name="Dyanavel" /> Dextroamphetamine, marketed under the brand names Dexedrine and Zenzedi, is the only [[Enantiopure drug|enantiopure]] amphetamine product currently available. A [[prodrug]] form of dextroamphetamine, [[lisdexamfetamine]], is also available and is marketed under the brand name Vyvanse. As it is a prodrug, lisdexamfetamine is structurally different from dextroamphetamine, and is inactive until it metabolizes into dextroamphetamine.<ref name="NDCD" /><ref name=USVyvanselabel/> The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.<ref name="Amph Uses" /> Levoamphetamine was previously available as Cydril.<ref name="Amph Uses" /> Many current amphetamine pharmaceuticals are [[salt (chemistry)|salts]] due to the comparatively high volatility of the free base.<ref name="Amph Uses" /><ref name="NDCD" /><ref name="EMC" /> However, oral suspension and [[orally disintegrating tablet]] (ODT) [[dosage form]]s composed of the free base were introduced in 2015 and 2016, respectively.<ref name="Dyanavel" /><ref name="FDA Dyanavel approval date" /><ref name="Adzenys" /> Some of the current brands and their generic equivalents are listed below.
{| class="wikitable sortable" style="text-align:center;"
|+ Amphetamine pharmaceuticals
! scope="col" | Brand<br />name
! scope="col" | [[United States Adopted Name|United&nbsp;States<br />Adopted&nbsp;Name]]
! scope="col" class="unsortable" style="text-align:center" | [[wikt:enantiomeric ratio|(D:L)&nbsp;ratio]]<br />
! scope="col"| Dosage<br />form
! scope="col" class="unsortable" | Marketing<br />start&nbsp;date
! scope="col" class="unsortable" | <small>Sources</small>
|-
| Adderall || – || 3:1&nbsp;<small>(salts)</small> <!--DO NOT CHANGE THIS RATIO: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666194/table/table1-0269881113482532/ -->|| tablet || 1996 || <ref name="Amph Uses" /><ref name="NDCD" />
|-
| Adderall&nbsp;XR || – || 3:1&nbsp;<small>(salts)</small> || capsule || 2001 || <ref name="Amph Uses" /><ref name="NDCD" />
|-
| Mydayis || – || 3:1&nbsp;<small>(salts)</small> || capsule || 2017 || <ref name="Mydayis">{{cite web | title=Mydayis- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, and amphetamine sulfate capsule, extended release | website=DailyMed | publisher = Shire US Inc. | date=11 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=141a7970-3f06-44ea-9ab7-aeece2c085fc | access-date=22 December 2019}}</ref><ref>{{cite web | title=Drug Approval Package: Mydayis (mixed salts of a single-entity amphetamine product) | website=United States Food and Drug Administration | date=6 June 2018 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/022063Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20191223015540/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/022063Orig1s000TOC.cfm | archive-date=23 December 2019 | access-date=22 December 2019}}</ref>
|-
| Adzenys&nbsp;ER || amphetamine || 3:1&nbsp;<small>(base)</small> || suspension || 2017 || <ref name="Adzenys ER">{{cite web | title=Adzenys ER- amphetamine suspension, extended release | website=DailyMed | date=8 December 2017 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eb1cc8d0-4231-41ea-8535-4fd872129713 | access-date=25 December 2019 | publisher = Neos Therapeutics, Inc. }}</ref>
|-
| {{nowrap|Adzenys XR-ODT}} || amphetamine || 3:1&nbsp;<small>(base)</small> || [[Orally disintegrating tablet|ODT]] || 2016 || <ref name="Adzenys">{{cite web | title=Adzenys XR-ODT- amphetamine tablet, orally disintegrating | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c1179269-00b5-48ea-972d-31e614e99b7e | website = DailyMed | publisher = Neos Therapeutics, Inc. | access-date=22 December 2019 | date=9 February 2018 | quote = 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">{{cite web | title=Drug Approval Package: Adzenys XR-ODT (amphetamine)| url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/204326Orig1_toc.cfm | archive-url=https://web.archive.org/web/20170110181756/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/204326Orig1_toc.cfm | archive-date=10 January 2017 | website=United States Food and Drug Administration | access-date=22 December 2019}}</ref>
|-
| Dyanavel&nbsp;XR || amphetamine || 3.2:1&nbsp;<small>(base)</small> || suspension || 2015 || <ref name="Dyanavel" /><ref name="FDA Dyanavel approval date">{{cite web | title=Drug Approval Package: Amphetamine (Amphetamine) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208147Orig1DyanavelTOC.cfm | website=United States Food and Drug Administration | access-date=22 December 2019}}</ref>
|-
| Evekeo || amphetamine&nbsp;sulfate || 1:1&nbsp;<small>(salts)</small> || tablet || 2012 || <ref name="Evekeo" /><ref name="Racemic amph - FDA Evekeo status">{{cite web | title=Evekeo | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=200166 | archive-url=https://web.archive.org/web/20170217113250/http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=200166 | archive-date=17 February 2017 | website=United States Food and Drug Administration | access-date=11 August 2015}}</ref>
|-
| Evekeo&nbsp;ODT|| amphetamine&nbsp;sulfate || 1:1&nbsp;<small>(salts)</small> || [[Orally disintegrating tablet|ODT]] || 2019 || <ref name="Evekeo ODT">{{cite web | title=Evekeo ODT- amphetamine sulfate tablet, orally disintegrating | website=DailyMed | date=7 June 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e25f905-6c0b-4b19-a3b6-b2a386afa1c3 | access-date=25 December 2019 | publisher = Arbor Pharmaceuticals, LLC }}</ref>
|-
| Dexedrine || dextroamphetamine&nbsp;sulfate || 1:0&nbsp;<small>(salts)</small> || capsule || 1976 || <ref name="Amph Uses" /><ref name="NDCD" />
|-
| Zenzedi || dextroamphetamine&nbsp;sulfate || 1:0&nbsp;<small>(salts)</small> || tablet || 2013 || <ref name="NDCD" /><ref>{{cite web | title=Zenzedi- dextroamphetamine sulfate tablet | website=DailyMed | publisher = Arbor Pharmaceuticals, LLC | date=14 August 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6394df5-f2c9-47eb-b57e-f3e9cfd94f84 | access-date=22 December 2019}}</ref>
|-
| rowspan=2 | Vyvanse || rowspan=2 | lisdexamfetamine&nbsp;dimesylate || rowspan=2 | 1:0&nbsp;<small>(prodrug)</small> || capsule || rowspan=2 | 2007 || rowspan=2 | <ref name="Amph Uses">{{cite journal |vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal =Journal of Psychopharmacology| volume = 27 | issue = 6 | pages = 479–496 | date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 | quote = 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=USVyvanselabel/><ref>{{cite web | title=Drug Approval Package: Vyvanse (Lisdexamfetamine Dimesylate) NDA #021977 | website=United States Food and Drug Administration | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021977s000TOC.cfm | archive-url=https://web.archive.org/web/20161222163314/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021977s000TOC.cfm | archive-date=22 December 2016 | access-date=22 December 2019}}</ref>
|-
| tablet
|-
| Xelstrym || dextroamphetamine || 1:0&nbsp;<small>(base)</small> || patch || 2022 || <ref name="US-Xelstrym-Label">{{cite web | title=Xelstrym- dextroamphetamine patch, extended release | website=DailyMed | date=28 March 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0862f02a-72a8-41cc-8845-57cf4974bb6f | access-date=3 May 2023}}</ref>
|}
{{Amphetamine base in marketed amphetamine medications}}

==Notes==
<!--Notes list -->
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==Reference notes==
{{Reflist|group=sources|2}}

==References==
{{Reflist}}

==External links==
<!-- List of external links -->
* {{Cite web | url = https://www.euda.europa.eu/publications/drug-profiles/amphetamine_en | publisher = European Union Drugs Agency (EUDA) | title = Amphetamine }}
* {{PubChem|5826}}&nbsp;– Dextroamphetamine
* {{PubChem|32893}}&nbsp;– Levoamphetamine
* [https://ctdbase.org/query.go?type=ixn&chemqt=equals&chem=name%3AAmphetamine&actionDegreeTypes=increases&actionDegreeTypes=decreases&actionDegreeTypes=affects&actionTypes=ANY&geneqt=equals&gene=&pathwayqt=equals&pathway=&taxonqt=equals&taxon=TAXON%3A9606&goqt=equals&go=&sort=chemNmSort&perPage=500&action=Search Comparative Toxicogenomics Database entry: Amphetamine]
* [https://ctdbase.org/detail.go?type=gene&acc=9607&qid=2119242 Comparative Toxicogenomics Database entry: CARTPT]

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