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<small>'''''Synonyms / Brand Names:''''' </small>
{{Drugbox
| verifiedrevid = 629722425
| IUPAC_name = (''RS'')-1-phenylpropan-2-amine<br/>(''RS'')-1-phenyl-2-aminopropane
| image = Amphetamine-2D-skeletal.svg
| width = 250
| alt = An image of the amphetamine compound
| image2 = Amphetamine-3d-CPK.png
| width2 = 250
| alt2 = A 3d image of the amphetamine compound
| imagename = 1 : 1 mixture (racemate)
| drug_name = Amphetamine


<!--Clinical data-->
| tradename =
| Drugs.com = {{Drugs.com|parent|amphetamine}}
| pregnancy_US = C
| legal_AU = Schedule 8
| legal_CA = Schedule I
| legal_UK = CD
| legal_US = Schedule II
| licence_US = Adderall
| legal_status = Rx-only
| dependency_liability = Moderate
| routes_of_administration= Medical: [[Oral route|oral]], [[Nasal administration|nasal inhalation]] <br />Recreational: [[Oral route|oral]], [[Nasal administration|nasal inhalation]], [[Insufflation (medicine)|insufflation]], [[Suppository|rectal]], [[intravenous]]
<!--Pharmacokinetic data-->
| bioavailability = Rectal&nbsp;95–100%; {{nowrap|Oral 75–100%}}<ref name="Drugbank-dexamph">{{cite encyclopedia | title=Dextroamphetamine | section-url=http://www.drugbank.ca/drugs/DB01576#pharmacology | work=DrugBank | publisher= University of Alberta | accessdate=5 November 2013 | date=8 February 2013 | section=Pharmacology }}</ref>
| protein_bound = 15–40%<ref name="Drugbank-amph">{{cite encyclopedia | title=Amphetamine | section-url=http://www.drugbank.ca/drugs/DB00182#pharmacology | work=DrugBank | publisher= University of Alberta | accessdate=5 November 2013 | date=8 February 2013 | section=Pharmacology }}</ref>
| metabolism = [[CYP2D6]],<ref name="FDA Pharmacokinetics" /> [[Dopamine β-hydroxylase|DBH]],<ref name="DBH ref">{{cite book | title=Foye's Principles of Medicinal Chemistry | year=2013 | publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins | location=Philadelphia, USA | isbn= 9781609133450 | page=648 | author=Lemke TL, Williams DA, Roche VF, Zito W|edition=7th | quote=Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.}}</ref><ref name="DBH amph primary">{{cite journal | author = Taylor KB | title = Dopamine-beta-hydroxylase. Stereochemical course of the reaction | journal = J. Biol. Chem. | volume = 249 | issue = 2 | pages = 454–458 | date = January 1974 | pmid = 4809526 | accessdate = 6 November 2014 | url = http://www.jbc.org/content/249/2/454.full.pdf | quote = Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine. }}</ref><ref name="DBH 4-HA primary">{{cite journal | author = Horwitz D, Alexander RW, Lovenberg W, Keiser HR | title = Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity | journal = Circ. Res. | volume = 32 | issue = 5 | pages = 594–599 | date = May 1973 | pmid = 4713201 | doi = 10.1161/01.RES.32.5.594 | quote =  Subjects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascular function and normal β-hydroxylation of an administered synthetic substrate, hydroxyamphetamine. }}</ref> [[Flavin-containing monooxygenase|FMO3]],<ref name="FMO">{{cite journal | author = Krueger SK, Williams DE | title = Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism | journal = Pharmacol. Ther. | volume = 106 | issue = 3 | pages = 357–387 |date=June 2005 | pmid = 15922018 | pmc = 1828602 | doi = 10.1016/j.pharmthera.2005.01.001 }}</ref><ref name="FMO3-Primary" /> [[butyrate-CoA ligase|XM-ligase]],<ref name="Benzoic1" /> and [[glycine N-acyltransferase|ACGNAT]]<ref name="Benzoic2" />
| onset = Immediate
| elimination_half-life = {{abbr|D-amph|Dextroamphetamine}}:9–11h;<ref name="FDA Pharmacokinetics" /><ref name="Adderall IR" /> {{nowrap|{{abbr|L-amph|Levoamphetamine}}:11–14h<ref name="FDA Pharmacokinetics" /><ref name="Adderall IR" />}}
| excretion = [[Renal]]; [[pH]]-dependent {{nowrap|range: 1–75%}}<ref name="FDA Pharmacokinetics">{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | pages = 12–13 | publisher = Shire US Inc | work = United States Food and Drug Administration |date=December 2013 | accessdate = 30 December 2013 }}</ref>
<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 300-62-9
| ATC_prefix = N06
| ATC_suffix = BA01
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 2679
| PDB_ligand = FRD
| IUPHAR_ligand = 4804
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KWTSXDURSIMDCE-UHFFFAOYSA-N
| PubChem = 3007
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00182
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 13852819
| NIAID_ChemDB = 018564
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = CK833KGX7E
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07445
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 405
| synonyms = α-methylphenethylamine
<!--Chemical data-->
| C=9 | H=13 | N=1
| molecular_weight = 135.2084&nbsp;g/mol
| smiles = NC(CC1=CC=CC=C1)C
| InChI = 1/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3
| density = 0.9±0.1
| boiling_point = 203
| boiling_notes = <ref>{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#x27 | work=PubChem Compound | publisher = National Center for Biotechnology Information | accessdate=5 November 2013 | section=Chemical and Physical Properties }}</ref>
| melting_point = 11.3
| melting_notes = <ref name="Chemspider">{{cite encyclopedia | section-url=http://www.chemspider.com/Chemical-Structure.13852819.html | work=Chemspider | title=Amphetamine | accessdate=6 November 2013 | section=Properties: Predicted – EP{{pipe}}Suite }}</ref>
}}
__NOTOC__
{{CMG}}
{{CMG}}


==Dosing and Administration==
==Overview==
<br>
Amphetamine is a potent central nervous system stimulant used in the treatment of [[attention deficit hyperactivity disorder]] and [[narcolepsy]].
----
 
<br>
==Amphetamine==
<font size="4">
'''Amphetamine'''{{#tag:ref|Synonyms and alternate spellings include: {{nowrap|1-phenylpropan-2-amine}} ([[International Union of Pure and Applied Chemistry|IUPAC]] name), {{nowrap|α-methylbenzeneethanamine}}, {{nowrap|α-methylphenethylamine}}, amfetamine ([[International Nonproprietary Name|International Nonproprietary Name [INN]]]), {{nowrap|β-phenylisopropylamine}}, desoxynorephedrine, and speed.<ref name="PubChem Header" /><ref name="DrugBank1" /><ref name="Acute amph toxicity" />| group = "note" }} ({{IPAc-en|pron|audio=En-us-amphetamine.ogg|æ|m|ˈ|f|ɛ|t|ə|m|iː|n}}; contracted from {{nowrap|[[Alpha and beta carbon|alpha]]‑[[methylphenethylamine]]}}) is a potent [[central nervous system]] (CNS) [[stimulant]] of the [[substituted phenethylamine|phenethylamine class]] that is used in the treatment of [[attention deficit hyperactivity disorder]] (ADHD) and [[narcolepsy]]. Amphetamine was discovered in 1887 and exists as two [[enantiomer]]s: [[levoamphetamine]] and [[dextroamphetamine]].{{#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 web|title=Enantiomer|url=http://goldbook.iupac.org/E02069.html|work=IUPAC Goldbook|publisher=International Union of Pure and Applied Chemistry|accessdate=14 March 2014|archiveurl=http://web.archive.org/web/20130317002318/http://goldbook.iupac.org/E02069.html|archivedate=17 March 2013|doi=10.1351/goldbook.E02069|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 L-amph or levamfetamine ([[International Nonproprietary Name|INN]]) and D-amph or dexamfetamine (INN) respectively.<ref name="PubChem Header" />|group = "note"}} ''Amphetamine'' properly refers to a specific chemical,<!--REFS:<ref name="MeSHAmphetamine" /> --> the [[racemic]] [[free base]],<!--REFS:<ref name="WHO INN active moiety" /><ref name="Proper definition" />--> which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, the term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone.<!--REFS:<ref name="DrugBank1" /><ref name="MeSHAmphetamine" /><ref name="Proper definition" />--> Historically, it has been used to treat nasal congestion, depression, and obesity. Amphetamine is also used as a [[performance enhancer|performance]] and [[Nootropic|cognitive enhancer]], and recreationally as an [[aphrodisiac]] and [[euphoriant]]. It is a prescription medication in many countries, and unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use.{{#tag:ref|<ref name="MeSHAmphetamine">{{cite web | title = Amphetamine | url = http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?mode=&term=Amphetamine | work = Medical Subject Headings | publisher = National Institutes of Health, National Library of Medicine | accessdate = 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 | publisher = World Health Organization | accessdate = 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="Proper definition">{{cite book | author = Yoshida T | editor = Klee H | title = Amphetamine Misuse: International Perspectives on Current Trends | date = 1997 | publisher = Harwood Academic Publishers | location = Amsterdam, Netherlands | isbn = 9789057020810 | page = 2 | url = http://books.google.com/books?id=gVw_wzZU4x8C&pg=PA2 | accessdate = 1 December 2014 | 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 can even embrace a large number of structurally and pharmacologically related substances.}}</ref><ref name="UN Convention" /><ref name="FDA Abuse & OD" /><ref name="Ergogenics" /><ref name="Malenka_2009" /><ref name="Libido" /><ref name="Nonmedical" /><ref name="Amph Uses" /><ref name="Benzedrine" />|group="sources"}}
[[{{PAGENAME}}#FDA Package Insert Resources|FDA Package Insert Resources]]
 
<br></font size><small>Indications, Contraindications, Side Effects, Drug Interactions, etc.</small><font size="4"><br>
The first pharmaceutical amphetamine was [[Benzedrine]], a brand of inhalers used to treat a variety of conditions.  Currently, pharmaceutical amphetamine is typically prescribed as [[Adderall]],{{#tag:ref|"Adderall" is a [[brand name]] as opposed to a nonproprietary name; because the latter ("''dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate''"<ref name="NDCD">{{cite web | title = National Drug Code Amphetamine Search Results | url = http://www.accessdata.fda.gov/scripts/cder/ndc/results.cfm?beginrow=1&numberperpage=160&searchfield=amphetamine&searchtype=ActiveIngredient&OrderBy=ProprietaryName | work = National Drug Code Directory|publisher=United States Food and Drug Administration | accessdate = 16 December 2013 | archiveurl = http://web.archive.org/web/20131216080856/http://www.accessdata.fda.gov/scripts/cder/ndc/results.cfm?beginrow=1&numberperpage=160&searchfield=amphetamine&searchtype=ActiveIngredient&OrderBy=ProprietaryName | archivedate = 7 February 2014}}</ref>) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.|name="Adderall"| group="note"}} dextroamphetamine, or the inactive [[prodrug]] [[lisdexamfetamine]]. Amphetamine, through activation of a [[TAAR1|trace amine receptor]], increases [[biogenic amine]] and [[Neurotransmitter#Excitatory and inhibitory|excitatory neurotransmitter]] activity in the brain, with its most pronounced effects targeting the [[catecholamine]] neurotransmitters norepinephrine and dopamine. At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased wakefulness, and improved [[cognitive control]]. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.{{#tag:ref|<ref name="Adderall IR" /><ref name="Ergogenics" /><ref name="Malenka_2009" /><ref name="Libido" /><ref name="Amph Uses" /><ref name="Benzedrine" /><ref name="Miller" /><ref name="FDA Effects" />|group="sources"}}
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[http://www.pace-med-apps.com/gfrcalc.htm Calculate Creatine Clearance]
Much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. [[Addiction|Drug addiction]] is a serious risk of amphetamine abuse, but only rarely arises from medical use. Very high doses can result in [[Stimulant psychosis#Amphetamines|psychosis]] (e.g., delusions 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="FDA Abuse & OD" /><ref name="Malenka_2009" /><ref name="Cochrane" /><ref name="Stimulant Misuse" /><ref name="EncycOfPsychopharm" /><ref name="Westfall" />|group="sources"}}
<br></font size><small>On line calculator of your patients Cr Cl by a variety of formulas.</small><font size="4"><br>
 
<br>
Amphetamine is also the parent compound of its own structural class, the [[substituted amphetamine]]s,{{#tag:ref|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 the class.|group="note"}} which includes prominent substances such as [[bupropion]], [[cathinone]], [[MDMA|MDMA (ecstasy)]], and [[methamphetamine]]. Unlike methamphetamine, amphetamine's salts lack sufficient [[Volatility (chemistry)|volatility]] to be smoked. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring [[trace amine]] neuromodulators, specifically [[phenethylamine]]{{#tag:ref|Again, due to confusion that may arise from use of the plural form, this article will only use "phenethylamine" and "phenethylamines" to refer to the compound itself and reserve the term "substituted phenethylamines" for the class.|group="note"}} and {{nowrap|[[N-methylphenethylamine|''N''-methylphenethylamine]]}}, both of which are produced within the human body.{{#tag:ref|<ref name="EMC">{{cite web | title = Amphetamine | url = http://www.emcdda.europa.eu/publications/drug-profiles/amphetamine | work = European Monitoring Centre for Drugs and Drug Addiction | accessdate = 19 October 2013}}</ref><ref name="Trace Amines" />|group="sources"}}
[http://home.earthlink.net/~sensei11/convert.htm Convert pounds to Kilograms]
 
<br></font size><small>On line calculator of your patients weight in pounds to Kg for dosing estimates.</small><font size="4"><br>
{{TOC limit|3}}
<br> [[{{PAGENAME}}#Publication Resources|Publication Resources]]
 
<br></font size><small>Recent articles, WikiDoc State of the Art Review, Textbook Information</small><font size="4"><br>
== Uses ==
<br>
 
[[{{PAGENAME}}#Trial Resources|Trial Resources]]
=== Medical ===
<br></font size><small>Ongoing Trials, Trial Results</small><font size="4"><br>
<onlyinclude>{{#ifeq:{{{transcludesection|Medical uses}}}|Medical uses|
<br>
 
[[{{PAGENAME}}#Guidelines & Evidence Based Medicine Resources|Guidelines & Evidence Based Medicine Resources]]
{{if pagename| Dextroamphetamine=Dextroamphetamine is used to treat [[attention deficit hyperactivity disorder]] (ADHD) and [[narcolepsy]], and is sometimes prescribed [[off-label]] for its past [[Indication (medicine)|medical indications]], such as [[treatment-resistant depression|depression]], [[obesity]], and [[nasal congestion]].<ref name="Amph Uses Dex">{{cite journal | author = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–96 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532}}</ref><ref name = DM2>{{cite web|title=DEXEDRINE (dextroamphetamine sulfate) tablet [Amedra Pharmaceuticals LLC]|work=[[DailyMed]]|publisher=Amedra Pharmaceuticals LLC|date=June 2014|accessdate=18 July 2014|location=Horsham, USA|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9ee6fd99-88ea-4cea-8370-a8945581325f}}</ref>| Lisdexamfetamine=Lisdexamfetamine is used primarily as a treatment for [[attention deficit hyperactivity disorder]] (ADHD) and has similar [[off-label]] uses as those of other pharmaceutical amphetamines.<ref name="Vyvanse Drug Insert" /><ref name="Amph Uses Lisdex">{{cite journal | author = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–496 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 |quote=}}</ref>| other={{if pagename|Adderall=Adderall|other=Amphetamine}} is used to treat [[attention deficit hyperactivity disorder]] (ADHD) and [[narcolepsy]]{{if pagename| Adderall=| other=, and is sometimes prescribed [[off-label]] for its past [[Indication (medicine)|medical indications]], such as [[treatment-resistant depression|depression]], [[obesity]], and [[nasal congestion]]}}.<ref name="Adderall IR">{{cite web | title=Adderall IR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf | publisher =  Barr Laboratories, Inc. | work = United States Food and Drug Administration |date=March 2007 | accessdate=2 November 2013 | pages=4–5}}</ref><ref name="Amph Uses">{{cite journal | author = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–496 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532}}</ref>}} Long-term amphetamine exposure in some animal species is known to produce abnormal [[Dopamine receptor|dopamine system]] development or nerve damage,<ref name="pmid22392347" /><ref name="AbuseAndAbnormalities">{{cite journal| author=Berman S, O'Neill J, Fears S, Bartzokis G, London ED| title=Abuse of amphetamines and structural abnormalities in the brain | journal=Ann. N. Y. Acad. Sci. | year= 2008 | volume= 1141 | issue= | pages= 195–220 | pmid=18991959 | doi=10.1196/annals.1441.031 | pmc=2769923 }}</ref> but, in humans with ADHD, amphetamines appear to improve brain development and nerve growth.<ref name="Neuroplasticity 1">{{cite journal |author=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 |url=}}</ref><ref name="Neuroplasticity 2">{{cite journal |author=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=J. Clin. Psychiatry |volume=74 |issue=9 |pages=902–917 |date=September 2013 |pmid=24107764 |doi=10.4088/JCP.12r08287 |url= |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 Scand. | date=February 2012 | volume=125 | issue=2 | pages=114–126 | pmid=22118249 | author=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}}</ref> [[Magnetic resonance imaging]] 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]].<ref name="Neuroplasticity 1" /><ref name="Neuroplasticity 2" /><ref name="Neuroplasticity 3" />
<br></font size><small>US National Guidelines, Cochrane Collaboration, etc.</small><font size="4"><br>
 
<br>
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.<ref name="Millichap_3" /><ref name="Long-Term Outcomes Medications">{{cite journal | author = 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 | url = }}</ref>  Controlled trials spanning two years have demonstrated treatment effectiveness and safety.<ref name="Long-Term Outcomes Medications" /><ref name="Millichap" />  One review highlighted a nine-month [[randomized controlled trial]] in children with ADHD that found an average increase of&nbsp;4.5 [[intelligence quotient|IQ]] points and continued improvements in attention, disruptive behaviors, and hyperactivity.<ref name="Millichap">{{cite book | author = Millichap JG |  editor = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD | year = 2010 | publisher = Springer | location = New York, USA | isbn = 9781441913968 | pages = 121–123, 125–127 | edition = 2nd | chapter = Chapter 3: Medications for ADHD}}</ref>
[[{{PAGENAME}}#Media Resources|Media Resources]]
 
<br></font size><small>Slides, Video, Images, MP3, Podcasts, etc.</small><font size="4"><br><br>
Current 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 [[locus coeruleus]] and [[prefrontal cortex]].<ref name="Malenka_2009_03" /> Psychostimulants 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 | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | pages = 154–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin }}</ref><ref name="cognition enhancers">{{cite journal | author = Bidwell LC, McClernon FJ, Kollins SH | title = Cognitive enhancers for the treatment of ADHD | journal = Pharmacol. Biochem. Behav. | volume = 99 | issue = 2 | pages = 262–274 |date=August 2011 | pmid = 21596055 | pmc = 3353150 | doi = 10.1016/j.pbb.2011.05.002  }}</ref> Approximately&nbsp;70% of those who use these stimulants see improvements in ADHD symptoms.<ref name="ADHD" /><ref name="WebMds Review">{{cite journal | author = Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, Benson RS, Bukstein O, Kinlan J, McClellan J, Rue D, Shaw JA, Stock S | title = Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults | journal = J. Am. Acad. Child Adolesc. Psychiatry | volume = 41 | issue = 2 Suppl | pages = 26S–49S |date=February 2002  | pmid = 11833633 | doi=10.1097/00004583-200202001-00003}}</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 | author = Millichap JG |  editor = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD | year = 2010 | publisher = Springer | location = New York, USA | isbn = 9781441913968 | pages = 111–113 | edition = 2nd | chapter = Chapter 3: 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 | work = WebMD | publisher = Healthwise | date = 12 April 2010 | accessdate=12 November 2013 }}</ref> The [[Cochrane Collaboration]]'s review{{#tag:ref|Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.<ref name="pmid16052183">{{cite journal |author=Scholten RJ, Clarke M, Hetherington J |title=The Cochrane Collaboration |journal=Eur. J. Clin. Nutr. |volume=59 Suppl 1 |issue= |pages=S147–S149; discussion S195–S196 |date=August 2005 |pmid=16052183 |doi=10.1038/sj.ejcn.1602188}}</ref>| group = "note" }} on the treatment of adult ADHD with amphetamines stated that while amphetamines improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse [[side effect]]s.<ref name="Cochrane Amphetamines ADHD">{{cite journal |author=Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M |title=Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults |journal=Cochrane Database Syst. Rev. |volume= |issue=6 |pages=CD007813 |year=2011 |pmid=21678370 |doi=10.1002/14651858.CD007813.pub2 |url= |editor=Castells X}}</ref>
[[{{PAGENAME}}#Patient Resources|Patient Resources]]
 
<br></font size><small>Discussion Groups, Handouts, Blogs, News, etc.</small><font size="4"><br>
A Cochrane Collaboration review on the treatment of ADHD in children with [[tic disorder]]s indicated that stimulants in general do not make [[tic]]s worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.<ref>{{cite journal|author=Pringsheim T, Steeves T|title=Pharmacological treatment for Attention Deficit Hyperactivity Disorder (ADHD) in children with comorbid tic disorders|journal = Cochrane Database Syst. Rev. | date=April 2011 | issue=4 | pages=CD007990 | pmid=21491404 | doi=10.1002/14651858.CD007990.pub2 | editor=Pringsheim T}}</ref> Other Cochrane reviews on the use of amphetamine following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.<ref>{{cite journal | author = Martinsson L, Hårdemark H, Eksborg S|title=Amphetamines for improving recovery after stroke | journal = Cochrane Database Syst. Rev. |date=January 2007 | issue=1 | pages=CD002090 | pmid=17253474 | doi=10.1002/14651858.CD002090.pub2 | editor=Martinsson L}}</ref><ref>{{cite journal | author=Forsyth RJ, Jayamoni B, Paine TC | title=Monoaminergic agonists for acute traumatic brain injury | journal = Cochrane Database Syst. Rev. |date=October 2006 | issue=4 | pages=CD003984 | pmid=17054192 | doi=10.1002/14651858.CD003984.pub2 | editor=Forsyth RJ}}</ref><ref name="SpeedyRecovery">{{cite journal |author=Harbeck-Seu A, Brunk I, Platz T, Vajkoczy P, Endres M, Spies C |title=A speedy recovery: amphetamines and other therapeutics that might impact the recovery from brain injury |journal=Curr. Opin. Anaesthesiol. |volume=24 |issue=2 |pages=144–153 |date=April 2011 |pmid=21386667 |doi=10.1097/ACO.0b013e328344587f |url=}}</ref>
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[[{{PAGENAME}}#International Resources|International Resources]]
 
<br></font size><small>en Español</small><font size="4"><br>
=== Enhancing performance ===
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<onlyinclude>{{#ifeq:{{{transcludesection|Enhancing performance}}}|Enhancing performance|
----
 
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Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on [[working memory]] tests in all individuals.<ref name="Malenka_2009" /><ref name="pmid11337538">{{cite journal |author=Devous MD, Trivedi MH, Rush AJ |title=Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers |journal=J. Nucl. Med. |volume=42 |issue=4 |pages=535–42 |date=April 2001  |pmid=11337538 |doi= |url=}}</ref> Amphetamine and other ADHD stimulants also improve [[Salience (neuroscience)|task saliency]] (motivation to perform a task) and increase [[arousal]] (wakefulness), in turn promoting goal-directed behavior.<ref name="Malenka_2009" /><ref name="Continuum">{{cite journal |author=Wood S, Sage JR, Shuman T, Anagnostaras SG |title=Psychostimulants and cognition: a continuum of behavioral and cognitive activation |journal=Pharmacol. Rev. |volume=66 |issue=1 |pages=193–221 |date=January 2014  |pmid=24344115 |doi=10.1124/pr.112.007054 |url=}}</ref><ref name="Malenka NAcc">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 266 | edition = 2nd | chapter = Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu | quote = Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.}}</ref>  Stimulants such as amphetamine can improve performance on difficult and boring tasks,<ref name="Malenka_2009">{{cite book| author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 318 | 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 in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spacial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug.&nbsp;... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control&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.}}</ref><ref name="Continuum" /> and are used by some students as a study and test-taking aid.<ref>{{cite web | work = JS Online | author = Twohey M | date = 26 March 2006 | title = Pills become an addictive study aid | accessdate = 2 December 2007 | url = http://www.jsonline.com/story/index.aspx?id=410902 | archiveurl = http://web.archive.org/web/20070815200239/http://www.jsonline.com/story/index.aspx?id=410902 | archivedate = 15 August 2007}}</ref> Based upon studies of self-reported illicit stimulant use, performance-enhancing use, rather than [[substance abuse|abuse]] as a recreational drug, is the primary reason that students use stimulants.<ref name="pmid16999660">{{cite journal | author = 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> However, high amphetamine doses that are above the therapeutic range can interfere with working memory and [[cognitive control]].<ref name="Malenka_2009" /><ref name="Continuum" />
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Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness;<ref name="Ergogenics">{{cite journal | author = Liddle DG, Connor DJ | title = Nutritional supplements and ergogenic AIDS | journal = Prim. Care | 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 />{{bull}}Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation<br />{{bull}}Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40<br />{{bull}}Improved reaction time<br />{{bull}}Increased muscle strength and delayed muscle fatigue<br />{{bull}}Increased acceleration<br />{{bull}}Increased alertness and attention to task}}</ref><ref name="Westfall" /> however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies.<ref name="NCAA">{{cite web |date=January 2012 | author=Bracken NM | title=National Study of Substance Use Trends Among NCAA College Student-Athletes | url=http://www.ncaapublications.com/productdownloads/SAHS09.pdf | work=NCAA Publications | publisher = National Collegiate Athletic Association | accessdate=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 = Br. J. Pharmacol. | volume = 154 | issue = 3 | pages = 606–622 | date = June 2008 | pmid = 18500382 | pmc = 2439527 | doi = 10.1038/bjp.2008.124 | url = }}</ref> In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength,<!--Refs:"Ergogenics" & "Ergogenics2"--> acceleration,<!--Refs:"Ergogenics" & "Ergogenics2"--> stamina,<!--Refs:"Ergogenics" & "Roelands_2013"--> and endurance,<!--Refs:"Ergogenics" & "Roelands_2013"--> while reducing [[reaction time]].<ref name="Ergogenics" /><ref name="Ergogenics2" /><ref name="Roelands_2013" /> Amphetamine improves stamina, endurance, and reaction time primarily through [[Reuptake inhibitor|reuptake inhibition]] and [[Releasing agent|effluxion]] of dopamine in the central nervous system.<ref name="Ergogenics2" /><ref name="Roelands_2013">{{cite journal | author = Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R | title = Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing | journal = Sports Med. | volume = 43 | issue = 5 | pages = 301–311 |date=May 2013 | pmid = 23456493 | doi = 10.1007/s40279-013-0030-4 }}</ref><ref name="Amph-DA reaction time">{{cite journal | author = Parker KL, Lamichhane D, Caetano MS, Narayanan NS | title = Executive dysfunction in Parkinson's disease and timing deficits | journal = Front Integr Neurosci | volume = 7 | page = 75 | date = October 2013 | pmid = 24198770 | pmc = 3813949 | doi = 10.3389/fnint.2013.00075 | quote = The neurotransmitter dopamine is released from projections originating in the midbrain. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or “clock,” activity (Maricq and Church, 1983; Buhusi and Meck, 2005, 2009; Lake and Meck, 2013). For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft (Maricq and Church, 1983; Zetterström et al., 1983) advances the start of responding during interval timing (Taylor et al., 2007), whereas antagonists of D2 type dopamine receptors typically slow timing (Drew et al., 2003; Lake and Meck, 2013).&nbsp;... Depletion of dopamine in healthy volunteers impairs timing (Coull et al., 2012), while amphetamine releases synaptic dopamine and speeds up timing (Taylor et al., 2007).}}</ref>  At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;<ref name="Ergogenics" /><ref name="Ergogenics2" /><ref name="Roelands_2013" /> 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 Abuse & OD" /><ref name="FDA Effects" /><ref name="Ergogenics2">{{cite journal |author=Parr JW |title=Attention-deficit hyperactivity disorder and the athlete: new advances and understanding |journal=Clin. Sports Med. |volume=30 |issue=3 |pages=591–610 |date=July 2011 |pmid=21658550 |doi=10.1016/j.csm.2011.03.007 |url=}}</ref>
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==Contraindications==
{{see also|Amphetamine#Interactions}}
<onlyinclude>{{#ifeq:{{{transcludesection|Contraindications}}}|Contraindications|
According to the [[International Programme on Chemical Safety]] (IPCS) and [[United States Food and Drug Administration]] (USFDA),{{#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.|group="note"}} amphetamine is [[contraindicated]] in people with a history of [[drug abuse]], [[heart disease]], severe [[Irritability|agitation]], or severe anxiety.<ref name="FDA Contra Warnings" /><ref name="International" />  It is also contraindicated in people currently experiencing [[arteriosclerosis]] (hardening of the arteries), [[glaucoma]] (an eye condition), [[hyperthyroidism]] (excessive production of thyroid hormone), or [[hypertension]] (elevated blood pressure).<ref name="FDA Contra Warnings" /><ref name="International">{{cite web | author=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 | accessdate=24 June 2014 }}</ref> People who have experienced [[hypersensitivity|allergic reactions]] to other stimulants in the past or are taking [[monoamine oxidase inhibitor]]s (MAOIs) are advised not to take amphetamine.<ref name="FDA Contra Warnings" /><ref name="International" /> These agencies also state that anyone with [[anorexia nervosa]], [[bipolar disorder]], depression, elevated blood pressure, 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 Contra Warnings" /><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 [[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 USFDA advise mothers to avoid breastfeeding when using it.<ref name="FDA Contra Warnings" /><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 continuous stimulant therapy over a 3&nbsp;year period is 2&nbsp;cm.<ref name="pmid18295156" />|group="note"}} the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.<ref name="FDA Contra Warnings" />
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==Side effects==
The [[side effects]] of amphetamine are varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of side effects.<ref name="FDA Abuse & OD" /><ref name="FDA Effects" /><ref name="Westfall" /> Amphetamine products such as [[Adderall]], Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.<ref name="NDCD" /><ref name="FDA Effects" /> [[Recreational drug use#Stimulants|Recreational use]] of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.<ref name="Westfall" />
 
<onlyinclude>{{#ifeq:{{{transcludesection|Side effects}}}|Side effects|
 
===Physical===
 
At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.<ref name="FDA Effects" /> [[Cardiovascular]] side effects can include [[arrhythmias|irregular heartbeat]] (usually an [[tachycardia|increased heart rate]]), [[hypertension]] (high blood pressure) or [[hypotension]] (low blood pressure) from a [[vasovagal response]], and [[Raynaud's phenomenon]] (reduced blood flow to extremities).<ref name="FDA Effects" /><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 Adolesc. Psychiatr. Clin. N. Am. | 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 Effects" /> Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss.<ref name="FDA Effects" /> Other potential side effects include [[xerostomia|dry mouth]], [[bruxism|excessive grinding of the teeth]], acne, profuse sweating, blurred vision, reduced [[seizure threshold]], and [[tics]] (a type of movement disorder).<ref name="FDA Effects" /><ref name="Westfall" /><ref name="pmid18295156" /> 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">{{cite book | editor = Brunton LL, Chabner BA, Knollmann BC | title = Goodman & Gilman's Pharmacological Basis of Therapeutics | year = 2010 | publisher = McGraw-Hill | location = New York, USA | isbn = 9780071624428 | author = Westfall DP, Westfall TC | section = Miscellaneous Sympathomimetic Agonists | sectionurl = http://www.accessmedicine.com/content.aspx?aID=16661601 | edition = 12th }}</ref> 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. 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 [[opiates]].<ref name="Westfall" />
 
USFDA 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>{{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=20 December 2011 | url=http://www.fda.gov/Drugs/DrugSafety/ucm277770.htm | work=United States Food and Drug Administration | accessdate=4 November 2013}}</ref><ref name="pmid22043968">{{cite journal | author = 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 = N. Engl. J. Med. | volume = 365 | issue = 20 | pages = 1896–1904 |date=November 2011 | pmid = 22043968 | doi = 10.1056/NEJMoa1110212 }}</ref><ref>{{cite web | title=FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults | date=15 December 2011 | url=http://www.fda.gov/Drugs/DrugSafety/ucm279858.htm | work=United States Food and Drug Administration | accessdate=4 November 2013}}</ref><ref name="pmid22161946">{{cite journal | author = 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"}}
 
===Psychological===
 
Common psychological effects of therapeutic doses can include increased [[alertness]], apprehension, [[concentration]], decreased sense of fatigue, mood swings ([[euphoria|elated mood]] followed by mildly [[dysphoria|depressed mood]]), increased initiative, [[insomnia]] or [[wakefulness]], [[self-confidence]], and sociability.<ref name="FDA Effects" /><ref name="Westfall" /> Less common side effects include [[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 (Edgmont) | volume = 5 | issue = 6 | pages = 50–55 |date=June 2008 | pmid = 19727285 | pmc = 2695750 | doi = }}</ref><ref name="FDA Effects" /><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 | work = Merck Manual for Health Care Professionals | publisher = Merck |date=February 2012 | accessdate = 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., delusions and paranoia) can occur in heavy users.<ref name="FDA Abuse & OD">{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | page = 11 | publisher = Shire US Inc | work = United States Food and Drug Administration |date=December 2013 | accessdate = 30 December 2013 }}</ref><ref name="FDA Effects">{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | pages = 4–8 | publisher = Shire US Inc | work = United States Food and Drug Administration |date=December 2013 | accessdate = 30 December 2013 }}</ref><ref name="Cochrane" /> Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.<ref name="FDA Abuse & OD" /><ref name="FDA Effects" /><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 | work=American College Health Association | publisher=ACHA Professional Development Program | accessdate=2 November 2013 | page=20}}</ref> According to the USFDA, "there is no systematic evidence" that stimulants can produce aggressive behavior or hostility.<ref name="FDA Effects" />
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==Overdose==
<onlyinclude>{{#ifeq:{{{transcludesection|Overdose}}}|Overdose|
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.<ref name="International" /><ref name="Amphetamine toxidrome">{{cite journal | author = 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  |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.}}</ref> The severity of overdose symptoms vary positively with dosage and inversely 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, roughly 100&nbsp;times the maximum daily therapeutic dose, in a day.<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 Abuse & OD" /><ref name="Westfall" /> [[Wikt:chronic|Chronic]] overdose of amphetamine poses a high risk of developing an addiction, since high doses result in increased expression of the addiction gene [[ΔFosB]].{{if pagename| Amphetamine=<ref name="Amphetamine KEGG ΔFosB" />| Other=<ref name="Amphetamine KEGG ΔFosB">{{cite web | title=Amphetamine – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05031 | work=KEGG Pathway | accessdate=31 October 2014 | author=Kanehisa Laboratories | date=10 October 2014}}</ref>}}  Consistent aerobic exercise appears to magnitude-dependently reduce this risk.<ref name="Running vs addiction" />
{{Amphetamine overdose}}
 
===Addiction===
<noinclude>{{Psychostimulant addiction|Colorcode=yes|align=right|header=[[Signaling cascade]] in the [[nucleus accumbens]] that results in amphetamine addiction}}</noinclude><includeonly>{{Addiction glossary}}</includeonly><!--
-->[[Substance dependence|Addiction]] is a serious risk with heavy recreational amphetamine use, but is unlikely to arise from typical medical use at therapeutic doses.<ref name="FDA Abuse & OD" /><ref name="EncycOfPsychopharm">{{Cite book | author = Stolerman IP | editor = Stolerman IP | title = Encyclopedia of Psychopharmacology | year = 2010 | publisher = Springer | location = Berlin, Germany; London, England | isbn = 9783540686989 | page = 78}}</ref><ref name="Westfall" /> [[Drug tolerance|Tolerance]] develops rapidly in amphetamine abuse, so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.<ref>{{cite web| title = Amphetamines: Drug Use and Abuse | work = Merck Manual Home Edition | publisher = Merck | url = http://www.merckmanuals.com/home/special_subjects/drug_use_and_abuse/amphetamines.html | accessdate = 28 February 2007 | archiveurl = http://web.archive.org/web/20070217053619/http://www.merck.com/mmhe/sec07/ch108/ch108g.html |date=February 2003 | archivedate = 17 February 2007}}</ref><ref>{{cite journal |author=Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M |title=Efficacy of psychostimulant drugs for amphetamine abuse or dependence |journal=Cochrane Database Syst. Rev. |volume=9 |issue= |pages=CD009695 |year=2013 |pmid=23996457 |doi=10.1002/14651858.CD009695.pub2 |url= |editor=Pérez-Mañá C}}</ref>
 
====Biomolecular mechanisms====
 
Current models of addiction from chronic drug use involve alterations in [[gene expression]] in certain parts of the brain, particularly the [[nucleus accumbens]].<ref name="Nestler, Hyman, and Malenka 2">{{cite journal |author=Hyman SE, Malenka RC, Nestler EJ |title=Neural mechanisms of addiction: the role of reward-related learning and memory |journal=Annu. Rev. Neurosci. |volume=29 |issue= |pages=565–598 |year=2006 |pmid=16776597 |doi=10.1146/annurev.neuro.29.051605.113009 |url=}}</ref><ref name="Nestler" /><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 | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 94 | edition = 2nd | chapter = Chapter 4: Signal Transduction in the Brain | quote= All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug.}}</ref>|group="note"}} that produce these alterations are [[ΔFosB]], cyclic adenosine monophosphate ([[cyclic adenosine monophosphate|cAMP]]) response element binding protein ([[cAMP response element binding protein|CREB]]), and nuclear factor kappa B ([[nuclear factor kappa B|NFκB]]).<ref name="Nestler" /> ΔFosB is the most significant factor in drug addiction, since its overexpression in the nucleus accumbens is [[necessary and sufficient]] for many of the associated neural adaptations that occur;<ref name="Nestler" /> it has been implicated in addictions to [[alcoholism|alcohol]], [[cannabinoid]]s, [[cocaine]], [[nicotine]], [[opiates]], [[phenylcyclidine]], and [[substituted amphetamines]].<ref name="Nestler" /><ref name="Natural and drug addictions" /><ref name="Alcoholism ΔFosB">{{cite web | title=Alcoholism – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 | work=KEGG Pathway | accessdate=31 October 2014 | author=Kanehisa Laboratories | date=29 October 2014}}</ref> [[ΔJunD]] is the transcription factor which directly opposes ΔFosB.<ref name="Nestler" /> Increases in nucleus accumbens ΔJunD expression using [[viral vector]]s can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).<ref name="Nestler" /> ΔFosB also plays an important role in regulating behavioral responses to [[natural reward]]s, such as palatable food, sex, and exercise.<ref name="Nestler" /><ref name="Natural and drug addictions" /><ref name="ΔFosB reward">{{cite journal | author = 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 = J. Psychoactive Drugs | volume = 44 | issue = 1 | pages = 38–55 | year = 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112| quote = It has been found that deltaFosB gene in the {{abbr|NAc|nucleus accumbens}} 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, {{abbr|VTA|ventral tegmental area}}, 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 natural rewards [[inducible gene|induce expression]] of ΔFosB just like drugs of abuse do, 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 | author = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | 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 {{abbr|NAc|nucleus accumbens}} or {{abbr|OFC|orbitofrontal cortex}} 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 {{abbr|MSNs|medium spiny neurons}} by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. }}</ref> Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction and amphetamine-induced [[sex addiction]]s, a phenomenon known as [[dopamine dysregulation syndrome]] which has been observed in some patients taking dopaminergic medications.<ref name="Natural and drug addictions" /><ref name="ΔFosB reward" /><ref name="Amph and sex addiction"><!--Supplemental primary source-->{{cite journal | author = 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 = J. Neurosci. | volume = 33 | issue = 8 | pages = 3434–3442 |date=February 2013  | pmid = 23426671 | pmc = 3865508 | doi = 10.1523/JNEUROSCI.4881-12.2013 | quote = Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior.&nbsp;... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.&nbsp;... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity}}</ref>
 
The effects of amphetamine on gene regulation are both dose- and route-dependent.<ref name="Addiction genetics">{{cite journal | author=Steiner H, Van Waes V | title=Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants | journal=Prog. Neurobiol. | volume=100 | issue= | pages=60–80 | date=January 2013 | pmid=23085425 | pmc=3525776 | doi=10.1016/j.pneurobio.2012.10.001 }}</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" />
 
====Pharmacological treatments====
 
A [[Cochrane Collaboration]] review on amphetamine and [[methamphetamine]] addiction and abuse indicates that the current evidence on effective treatments is extremely limited.<ref name="Cochrane Addiction">{{cite journal |author=Srisurapanont M, Jarusuraisin N, Kittirattanapaiboon P |title=Treatment for amphetamine dependence and abuse |journal=Cochrane Database Syst. Rev. |volume= |issue=4 |pages=CD003022 |year=2001 |pmid=11687171 |doi=10.1002/14651858.CD003022 |quote=Although there are a variety of amphetamines and amphetamine derivatives, the word "amphetamines" in this review stands for amphetamine, dextroamphetamine and methamphetamine only. |editor=Srisurapanont M}}</ref> The review indicated that [[fluoxetine]]{{#tag:ref|During short-term treatment, fluoxetine may decrease drug craving.<ref name="Cochrane Addiction" />| group = "note" }} and [[imipramine]]{{#tag:ref|During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.<ref name="Cochrane Addiction" />| group = "note" }} have some limited benefits in treating abuse and addiction, but concluded that there is currently no effective pharmacological treatment for amphetamine addiction or abuse.<ref name="Cochrane Addiction" /> A corroborating review indicated that amphetamine addiction is mediated through increased activation of [[dopamine receptor]]s and {{nowrap|[[wikt:colocalize|co-localized]]}} [[NMDA receptor]]s in the [[mesolimbic pathway|mesolimbic dopamine pathway]] (a [[Neural pathway|pathway in the brain]] that connects the [[ventral tegmental area]] to the [[nucleus accumbens]]).<ref name="Magnesium" /> This review also noted that [[magnesium|magnesium ions]] and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's [[calcium channel]]s.<ref name="Magnesium" />  It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.<ref name="Magnesium" />  Supplemental magnesium,{{#tag:ref|The review indicated that [[magnesium aspartate|magnesium L-aspartate]] and [[magnesium chloride]] produce significant changes in addictive behavior;<ref name="Magnesium" /> other forms of magnesium were not mentioned.|group="note"}} like fluoxetine treatment, has been shown to reduce amphetamine [[self-administration]] (doses given to oneself) in both humans and lab animals.<ref name="Cochrane Addiction" /><ref name="Magnesium">{{cite journal |author=Nechifor M |title=Magnesium in drug dependences |journal=Magnes. Res. |volume=21 |issue=1 |pages=5–15 |date=March 2008  |pmid=18557129 |doi= |url=}}</ref>
 
====Behavioral treatments====
 
[[Cognitive behavioral therapy]] is currently the most effective clinical treatment for psychostimulant addiction.<ref name="Nestler CBT">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 386 | edition = 2nd | chapter = Chapter 15: Reinforcement and Addictive Disorders | quote= Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.}}</ref> Additionally, research on the [[neurobiological effects of physical exercise#ΔFosB|neurobiological effects of physical exercise]] suggests that consistent aerobic exercise, especially endurance exercise (e.g., [[marathon running]]), prevents the development of drug addiction and is an effective adjunct (supplemental) treatment for amphetamine addiction.<ref name="Running vs addiction">{{cite journal | author = 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 = Neurosci Biobehav Rev | volume = 37 | issue = 8 | pages = 1622–44 |date=September 2013  | pmid = 23806439 | pmc = 3788047 | doi = 10.1016/j.neubiorev.2013.06.011 | quote = these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the {{abbr|NAc|nucleus accumbens}} (Chen et al., 2008) and striatum (Marques et al., 2008).&nbsp;... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals&nbsp;... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013)&nbsp;... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive 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 (see Table 4).&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="Natural and drug addictions" /> Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.<ref name="Running vs addiction" /> In particular, [[aerobic exercise]] decreases psychostimulant self-administration, reduces the [[reinstatement]] (i.e., relapse) of drug-seeking, and induces opposite effects on [[striatum|striatal]] [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]] (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased 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>
 
====Withdrawal====
 
According to another Cochrane Collaboration review on withdrawal in highly addicted amphetamine and methamphetamine abusers, "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 | author = Shoptaw SJ, Kao U, Heinzerling K, Ling W | title = Treatment for amphetamine withdrawal | journal = Cochrane Database Syst. Rev. | volume = | issue = 2 | pages = CD003021 | year = 2009 | pmid = 19370579 | doi = 10.1002/14651858.CD003021.pub2 | editor = 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 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005)&nbsp;...}}</ref>  This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.<ref name="Cochrane Withdrawal" />  Amphetamine withdrawal symptoms can include anxiety, [[Craving (withdrawal)|drug craving]], [[Dysphoria|depressed mood]], [[Fatigue (medical)|fatigue]], [[hyperphagia|increased appetite]], increased movement or [[psychomotor retardation|decreased movement]], lack of motivation, sleeplessness or sleepiness, and [[lucid dream]]s.<ref name="Cochrane Withdrawal" />  The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.<ref name="Cochrane Withdrawal" />  Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.<ref>{{cite web | title=Adderall IR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf | publisher = Barr Laboratories, Inc. | work = United States Food and Drug Administration |date=March 2007 | accessdate = 4 November 2013 }}</ref><ref>{{cite web | title = Dexedrine Medication Guide | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017078s046lbl.pdf | publisher = Amedra Pharmaceuticals LLC | work = United States Food and Drug Administration | date = May 2013 | accessdate = 4 November 2013 }}</ref><ref>{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | publisher = Shire US Inc | work = United States Food and Drug Administration |date=December 2013 | accessdate = 30 December 2013 }}</ref>
 
===Psychosis===
{{Main section|Stimulant psychosis|Substituted amphetamines}}
 
Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., [[paranoia]] and [[delusion]]s).<ref name="Cochrane" />  A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about&nbsp;5–15% of users fail to recover completely.<ref name="Cochrane">{{cite journal | editor =<!--Shoptaw SJ--> Shoptaw SJ, Ali R | author = Shoptaw SJ, Kao U, Ling W | title = Treatment for amphetamine psychosis | journal = Cochrane Database Syst. Rev. | volume = | issue = 1 | pages = CD003026 | year = 2009 | pmid = 19160215 | doi = 10.1002/14651858.CD003026.pub3 | 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.}}</ref><ref name="Hofmann">{{cite book | author = Hofmann FG | title = A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects | publisher = Oxford University Press | isbn =  9780195030570 | location = New York, USA | year = 1983 | page = 329 | edition = 2nd }}</ref> According to the same review, there is at least one trial that shows [[antipsychotic]] medications effectively resolve the symptoms of acute amphetamine psychosis.<ref name="Cochrane"/> Psychosis very rarely arises from therapeutic use.<ref name="Stimulant Misuse" /><ref name="FDA Contra Warnings">{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | pages = 4–6 | publisher = Shire US Inc | work = United States Food and Drug Administration | date = December 2013 | accessdate = 30 December 2013 }}</ref>
 
===Toxicity===
 
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic [[neurotoxicity]], or damage to dopamine neurons, which is characterized as reduced transporter and receptor function.<ref name="Humans&Animals">{{cite journal| author=Advokat C| title=Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD | journal=J. Atten. Disord. | year = 2007 | volume= 11 | issue= 1 | pages= 8–16 | pmid=17606768 | doi=10.1177/1087054706295605}}</ref> 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 | work=Hazardous Substances Data Bank | publisher=National Library of Medicine | accessdate=26 February 2014 | 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 | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | 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> High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from [[reactive oxygen species]] and [[autoxidation]] of dopamine.<ref name="pmid22392347">{{cite journal |author=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L |title=Toxicity of amphetamines: an update |journal=Arch. Toxicol. |volume=86 |issue=8 |pages=1167–1231 |date=August 2012  |pmid=22392347 |doi=10.1007/s00204-012-0815-5 |url=}}</ref><ref name="Autoxidation1">{{cite journal | author = Sulzer D, Zecca L | title = Intraneuronal dopamine-quinone synthesis: a review | journal = Neurotox. Res. | volume = 1 | issue = 3 | pages = 181–195 |date=February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289 }}</ref><ref name="Autoxidation2">{{cite journal | author = Miyazaki I, Asanuma M | title = Dopaminergic neuron-specific oxidative stress caused by dopamine itself | journal = Acta Med. Okayama | volume = 62 | issue = 3 | pages = 141–150 |date=June 2008 | pmid = 18596830 | doi = }}</ref>
}}</onlyinclude>
 
==Interactions==
{{see also|Amphetamine#Contraindications}}
Many types of substances are known to [[drug interaction|interact]] with amphetamine, resulting in altered [[drug action]] or [[Drug metabolism|metabolism]] of amphetamine, the interacting substance, or both.<ref name="FDA Pharmacokinetics" /><ref name="FDA Interactions" />  Inhibitors of the enzymes that metabolize amphetamine (i.e., CYP2D6 and flavin-containing monooxygenase 3) will prolong its [[elimination half-life]].<ref name="FMO" /><ref name="FDA Interactions">{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | pages = 8–10 | publisher = Shire US Inc | work = United States Food and Drug Administration |date=December 2013 | accessdate = 30 December 2013 }}</ref>  Amphetamine also interacts with {{abbr|MAOIs|monoamine oxidase inhibitors}}, particularly [[monoamine oxidase A]] inhibitors, since both MAOIs and amphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.<ref name="FDA Interactions" />  Amphetamine will modulate the activity of most psychoactive drugs.  In particular, amphetamine may decrease the effects of [[sedative]]s and [[depressant]]s and increase the effects of [[stimulant]]s and [[antidepressant]]s.<ref name="FDA Interactions" />  Amphetamine may also decrease the effects of [[antihypertensives]] and [[antipsychotic]]s due to its effects on blood pressure and dopamine respectively.<ref name="FDA Interactions" />  In general, there is no significant interaction when consuming amphetamine with food, but the [[pH]] of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.<ref name="FDA Interactions" />  Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.<ref name="FDA Interactions" />  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.<ref name="FDA Interactions" />
 
==Pharmacology==
 
===Pharmacodynamics===
{{hatnote|For a simpler and less technical explanation of amphetamine's mechanism of action, see the [[Adderall#Mechanism of action|mechanism of action section]] in the [[Adderall]] article.}}
{{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, collectively known as the [[mesocorticolimbic projection]].<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 due to its effects on monoamine transporters.<ref name="Miller" /><ref name="cognition enhancers" /><ref name="E Weihe" /> The reinforcing and task [[Salience (neuroscience)|saliency]] effects of amphetamine are mostly due to enhanced dopaminergic activity in the [[mesolimbic pathway]].<ref name="Malenka_2009" />
 
Amphetamine has been identified as a potent [[full agonist]] of [[TAAR1|trace amine-associated receptor 1]] (TAAR1), a {{nowrap|[[Gs alpha subunit|G<sub>s</sub>-coupled]]}} and {{nowrap|[[Gq alpha subunit|G<sub>q</sub>-coupled]]}} [[G protein-coupled receptor]] (GPCR) discovered in 2001, which is important for regulation of brain [[monoamines]].<ref name="Miller" /><ref name="TAAR1 IUPHAR">{{cite web|title=TA<sub>1</sub> receptor|url=http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=364|work=IUPHAR database|publisher=International Union of Basic and Clinical Pharmacology|accessdate=8 December 2014|author=Maguire JJ, Davenport AP|date=2 December 2014|quote=Comments:  Tyramine causes an increase in intracellular cAMP in HEK293 or COS-7 cells expressing the TA1 receptor in vitro [4,6,18]. In addition, coupling to a promiscuous Gαq has been observed, resulting in increased intracellular calcium concentration [24].}}</ref> Activation of {{abbr|TAAR1|trace amine-associated receptor 1}} increases {{abbrlink|cAMP|cyclic adenosine monophosphate}} production via [[adenylyl cyclase]] activation and inhibits [[monoamine transporter]] function.<ref name="Miller" /><ref name="pmid11459929">{{cite journal | author = 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 | title = Trace amines: identification of a family of mammalian G protein-coupled receptors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 16 | pages = 8966–8971 |date=July 2001 | pmid = 11459929 | pmc = 55357 | doi = 10.1073/pnas.151105198}}</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" /> Notably, amphetamine and [[trace amine]]s bind to TAAR1, but not monoamine autoreceptors.<ref name="Miller" /> Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of {{abbr|TAAR1|trace amine-associated receptor 1}} {{nowrap|co-localization}} in the associated monoamine neurons.<ref name="Miller" />  {{As of|2014|alt=As of 2010,}} {{nowrap|co-localization}} of TAAR1 and the [[dopamine transporter]] (DAT) has been visualized in rhesus monkeys, but {{nowrap|co-localization}} of TAAR1 with the [[norepinephrine transporter]] (NET) and the [[serotonin transporter]] (SERT) has only been evidenced by [[messenger RNA]] (mRNA) expression.<ref name="Miller" />
 
In addition to the neuronal monoamine [[Membrane transport protein|transporters]], amphetamine also inhibits [[vesicular monoamine transporter 2]] (VMAT2), [[SLC1A1]], [[SLC22A3]], and [[SLC22A5]].{{#tag:ref|<ref name="E Weihe" /><ref name="EAAT3">{{cite journal | author = 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). }}</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=http://www.ncbi.nlm.nih.gov/gene/6505 | website=NCBI Gene | publisher=National Center for Biotechnology Information | accessdate=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 | author = Zhu HJ, Appel DI, Gründemann D, Markowitz JS | title = Interaction of organic cation transporter 3 (SLC22A3) and amphetamine | journal = J. Neurochem. | volume = 114 | issue = 1 | pages = 142–149 |date=July 2010  | pmid = 20402963 | pmc = 3775896 | doi = 10.1111/j.1471-4159.2010.06738.x | url = }}</ref><ref name="SLC22A5">{{cite journal | author = Rytting E, Audus KL | title = Novel organic cation transporter 2-mediated carnitine uptake in placental choriocarcinoma (BeWo) cells | journal = J. Pharmacol. Exp. Ther. | volume = 312 | issue = 1 | pages = 192–198 |date=January 2005  | pmid = 15316089 | doi = 10.1124/jpet.104.072363 | url = }}</ref><ref name="pmid13677912">{{cite journal | author = Inazu M, Takeda H, Matsumiya T | title = [The role of glial monoamine transporters in the central nervous system] | language = Japanese | journal = Nihon Shinkei Seishin Yakurigaku Zasshi | volume = 23 | issue = 4 | pages = 171–178 |date=August 2003 | pmid = 13677912 | doi = }}</ref>|group="sources"|name="Reuptake inhibition"}} SLC1A1 is [[excitatory amino acid transporter 3]] (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in [[astrocyte]]s and SLC22A5 is a high-affinity [[carnitine]] transporter.<ref name="Reuptake inhibition" group="sources"/> Amphetamine is known to strongly induce [[cocaine- and amphetamine-regulated transcript]] (CART) [[gene expression]],<ref name="CART NAcc">{{cite journal | author = Vicentic A, Jones DC | title = The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction | journal = J. Pharmacol. Exp. Ther. | volume = 320 | issue = 2 | pages = 499–506 |date=February 2007  | pmid = 16840648 | doi = 10.1124/jpet.105.091512 | 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 {{abbr|DA|dopamine}} receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the {{abbr|NAc|nucleus accumbens}} 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 {{abbr|CREB|cAMP response element-binding protein}}. Indeed, CART gene expression is regulated via {{abbr|cAMP|cyclic adenosine monophosphate}} signaling and {{abbr|pCREB|phosphorylated CREB}} in vivo as centrally administered forskolin activated cAMP, phosphorylated CREB, and increased CART {{abbr|mRNA|messenger RNA}} and peptide levels (Jones and Kuhar, 2006).}}</ref> a [[neuropeptide]] involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival ''[[in vitro]]''.<ref name="CART functions">{{cite journal | author = Zhang M, Han L, Xu Y | title = Roles of cocaine- and amphetamine-regulated transcript in the central nervous system | journal = Clin. Exp. Pharmacol. Physiol. | volume = 39 | issue = 6 | pages = 586–592 |date=June 2012  | pmid = 22077697 | doi = 10.1111/j.1440-1681.2011.05642.x | quote =  Numerous studies have established the role of CART in food intake, maintenance of bodyweight, stress control, reward and pain transmission. Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. 3. In fact, little is known about the way in which CART peptide interacts with its receptors, initiates downstream cascades and finally exerts its neuroprotective effect under normal or pathological conditions. The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART}}</ref><ref name="PubChem Targets">{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#x301 | work=PubChem Compound | publisher = National Center for Biotechnology Information | accessdate=13 October 2013 | section=Biomolecular Interactions and Pathways }}</ref><ref name="CART">{{cite journal | author = Vicentic A, Lakatos A, Jones D | title = The CART receptors: background and recent advances | journal = Peptides | volume = 27 | issue = 8 | pages = 1934–1937 |date=August 2006 | pmid = 16713658 | doi = 10.1016/j.peptides.2006.03.031 }}</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 | author = 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]] at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.<ref name="PubChem Header">{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007 | work=PubChem Compound | publisher = National Center for Biotechnology Information | accessdate=13 October 2013 | section=Compound Summary }}</ref><ref name="BRENDA MAO Homo sapiens">{{cite encyclopedia | title=Monoamine oxidase (Homo sapiens)| url=http://www.brenda-enzymes.org/enzyme.php?ecno=1.4.3.4&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0 | work=BRENDA | publisher=Technische Universität Braunschweig | accessdate=4 May 2014 | date=1 January 2014}}</ref>
The full profile of amphetamine's short-term drug effects is derived through increased cellular communication or [[neurotransmission]] of [[dopamine]],<ref name="Miller">{{cite journal | author = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = J. Neurochem. | 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 | author = Eiden LE, Weihe E | title = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal = Ann. N. Y. Acad. Sci. | volume = 1216 | issue = | pages = 86–98 |date=January 2011 | pmid = 21272013 | doi = 10.1111/j.1749-6632.2010.05906.x | quote=VMAT2 is the CNS vesicular transporter for not only the biogenic amines {{abbr|DA|dopamine}}, {{abbr|NE|norepinephrine}}, {{abbr|EPI|epinephrine}}, {{abbr|5-HT|serotonin}}, and {{abbr|HIS|histamine}}, but likely also for the trace amines {{abbr|TYR|tyramine}}, {{abbr|PEA|phenethylamine}}, 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).}}</ref> [[histamine]],<ref name="E Weihe" /> [[cocaine and amphetamine regulated transcript|CART peptides]],<ref name="CART NAcc" /> [[acetylcholine]],<ref name="Acetylcholine">{{cite journal | author = 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 | url = }}</ref><ref name="MEDRS-Cholinergic">{{cite journal | author = Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E | title = The role of the central ghrelin system in reward from food and chemical drugs | journal = Mol. Cell. Endocrinol. | volume = 340 | issue = 1 | pages = 80–87 |date=June 2011 | pmid = 21354264 | doi = 10.1016/j.mce.2011.02.017 }}</ref> and [[glutamate]],<ref name="glutamate1">{{cite journal | author = Stuber GD, Hnasko TS, Britt JP, Edwards RH, Bonci A | title = Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate | journal = J. Neurosci. | volume = 30 | issue = 24 | pages = 8229–8233 |date=June 2010 | pmid = 20554874 | pmc = 2918390 | doi = 10.1523/JNEUROSCI.1754-10.2010 }}</ref><ref name="glutamate2">{{cite journal | author = Gu XL | title = Deciphering the corelease of glutamate from dopaminergic terminals derived from the ventral tegmental area | journal = J. Neurosci. | volume = 30 | issue = 41 | pages = 13549–13551 |date=October 2010 | pmid = 20943895 | pmc = 2974325 | doi = 10.1523/JNEUROSCI.3802-10.2010  }}</ref> which it effects through interactions with {{abbr|CART|cocaine- and amphetamine-regulated transcript}}, {{abbr|EAAT3|excitatory amino acid transporter 3}}, {{abbr|TAAR1|trace amine-associated receptor 1}}, and {{abbr|VMAT2|vesicular monoamine transporter 2}}.{{#tag:ref|<ref name="Miller" /><ref name="E Weihe" /><ref name="SLC1A1" /><ref name="CART NAcc" />|group="sources"}}
 
Dextroamphetamine is a more potent agonist of {{abbr|TAAR1|trace amine-associated receptor 1}} than levoamphetamine.<ref name="TAAR1 stereoselective" /> Consequently, dextroamphetamine produces greater {{abbr|CNS|central nervous system}} stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.<ref name="Westfall" /><ref name="TAAR1 stereoselective">{{cite journal | author= Lewin AH, Miller GM, Gilmour B | title=Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | journal=Bioorg. Med. Chem. |date=December 2011 | volume=19 | issue=23 | pages=7044–7048 | pmid=22037049 | doi= 10.1016/j.bmc.2011.10.007 | pmc= 3236098}}</ref>
 
====Dopamine====
 
In certain brain regions, amphetamine increases the concentration of dopamine in the [[synaptic cleft]].<ref name="Miller" /> Amphetamine can enter the [[presynaptic neuron]] either through {{abbr|DAT|dopamine transporter}} or by diffusing across the neuronal membrane directly.<ref name="Miller" /> As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.<ref name="Miller" /> Upon entering the presynaptic neuron, amphetamine activates {{abbr|TAAR1|trace amine-associated receptor 1}} which, through [[protein kinase A]] (PKA) and [[protein kinase C]] (PKC) signaling, causes DAT [[phosphorylation]].<ref name="Miller" /> Phosphorylation by either protein kinase can result in DAT [[endocytosis|internalization]] ({{nowrap|non-competitive}} reuptake inhibition), but {{nowrap|PKC-mediated}} phosphorylation alone induces reverse transporter function (dopamine [[wikt:efflux|efflux]]).<ref name="Miller" /><ref name="TAAR1 Review">{{cite journal | author = Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP | title = International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature | journal = Pharmacol. Rev. | volume = 61 | issue = 1 | pages = 1–8 |date=March 2009 | pmid = 19325074 | pmc = 2830119 | doi = 10.1124/pr.109.001107 }}</ref> Amphetamine is also known to increase intracellular calcium, a known effect of TAAR1 activation, which is associated with DAT phosphorylation through a [[Ca2+/calmodulin-dependent protein kinase]] (CAMK)-dependent pathway, in turn producing dopamine efflux.<ref name="TAAR1 IUPHAR" /><ref name="EAAT3" /><ref name="DAT regulation review">{{cite journal | author = Vaughan RA, Foster JD | title = Mechanisms of dopamine transporter regulation in normal and disease states | journal = Trends Pharmacol. Sci. | 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> Through direct activation of [[G protein-coupled inwardly-rectifying potassium channel]]s and increased dopamine release, {{abbr|TAAR1|trace amine associated receptor 1}} reduces the [[action potential|firing rate]] of postsynaptic dopamine receptors, preventing a hyper-dopaminergic state.<ref name="TAAR1-Paradoxical">{{cite journal |author=Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC |title=TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=108 |issue=20 |pages=8485–8490 |date=May 2011 |pmid=21525407 |pmc=3101002 |doi=10.1073/pnas.1103029108}}</ref><ref name="GIRK">{{cite journal | author = Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB | title = Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons | journal = Front Syst Neurosci | volume = 5 | issue = | pages = 56 | year = 2011 | pmid = 21772817 | pmc = 3131148 | doi = 10.3389/fnsys.2011.00056 | quote = inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. }}</ref><ref name="Genatlas TAAR1">{{cite web | url = http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=TAAR1 | title = TAAR1 | author = mct | date = 28 January 2012 | work = GenAtlas | publisher = University of Paris | accessdate = 29 May 2014 | quote=<br />{{bull}} tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA) }}</ref>
 
Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, {{abbr|VMAT2|vesicular monoamine transporter 2}}.<ref name="E Weihe" /> Following amphetamine uptake at VMAT2, the [[synaptic vesicle]] releases dopamine molecules into the [[cytosol]] in exchange.<ref name="E Weihe" /> Subsequently, the cytosolic dopamine molecules exit the presynaptic neuron via reverse transport at {{abbr|DAT|dopamine transporter}}.<ref name="Miller" /><ref name="E Weihe" />
 
====Norepinephrine====
 
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of [[epinephrine]].<ref name="Trace Amines" /><ref name="cognition enhancers" /> Based upon neuronal {{abbr|TAAR1|trace amine-associated receptor 1}} {{abbr|mRNA|messenger RNA}} expression, amphetamine is thought to affect norepinephrine analogously to dopamine.<ref name="Miller" /><ref name="E Weihe" /><ref name="TAAR1 Review" /> In other words, amphetamine induces TAAR1-mediated efflux and {{nowrap|non-competitive}} reuptake inhibition at phosphorylated {{abbr|NET|norepinephrine transporter}}, competitive NET reuptake inhibition, and norepinephrine release from {{abbr|VMAT2|vesicular monoamine transporter 2}}.<ref name="Miller" /><ref name="E Weihe" />
 
====Serotonin====
 
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.<ref name="Miller" /><ref name="cognition enhancers" /> Amphetamine affects serotonin via {{abbr|VMAT2|vesicular monoamine transporter 2}} and, like norepinephrine, is thought to phosphorylate {{abbr|SERT|serotonin transporter}} via {{abbr|TAAR1|trace amine-associated receptor 1}}.<ref name="Miller" /><ref name="E Weihe" />
 
====Other neurotransmitters====
 
Amphetamine has no direct effect on [[acetylcholine]] neurotransmission, but several studies have noted that acetylcholine release increases after its use.<ref name="Acetylcholine" /><ref name="MEDRS-Cholinergic" /> In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream effect.<ref name="Acetylcholine" />  In humans, a similar phenomenon occurs via the [[ghrelin]]-mediated [[cholinergic–dopaminergic reward link]] in the [[ventral tegmental area]].<ref name="MEDRS-Cholinergic" /> This heightened [[cholinergic]] activity leads to increased [[nicotinic receptor]] activation in the {{abbr|CNS|central nervous system}}, a factor which likely contributes to the [[nootropic]] effects of amphetamine.<ref name="pmid21334367">{{cite journal | author = Levin ED, Bushnell PJ, Rezvani AH | title = Attention-modulating effects of cognitive enhancers | journal = Pharmacol. Biochem. Behav. | volume = 99 | issue = 2 | pages = 146–154 |date=August 2011 | pmid = 21334367 | pmc = 3114188 | doi = 10.1016/j.pbb.2011.02.008 }}</ref>
 
Extracellular levels of [[glutamate]], the primary [[Neurotransmitter#Excitatory and inhibitory|excitatory neurotransmitter]] in the brain, have been shown to increase upon exposure to amphetamine.<ref name="glutamate1" /><ref name="glutamate2" />  This [[cotransmission]] effect was found in the mesolimbic pathway, an area of the brain implicated in reward, where amphetamine is known to affect dopamine neurotransmission.<ref name="glutamate1" /><ref name="glutamate2" />  Amphetamine also induces effluxion of [[histamine]] from synaptic vesicles in {{abbr|CNS|central nervous system}} [[mast cell]]s and histaminergic neurons through {{abbr|VMAT2|vesicular monoamine transporter 2}}.<ref name="E Weihe" />
 
===Pharmacokinetics===
 
The oral [[bioavailability]] of amphetamine varies with gastrointestinal pH;<ref name="FDA Interactions" /> it is well absorbed from the gut, and bioavailability is typically over&nbsp;75% for dextroamphetamine.<ref name="Drugbank-dexamph" /> Amphetamine is a weak base with a [[Acid dissociation constant|pKa]] of {{nowrap|9–10}};<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 Interactions" /> Conversely, an acidic pH means the drug is predominantly in a water soluble [[cation]]ic (salt) form, and less is absorbed.<ref name="FDA Pharmacokinetics" /> Approximately {{nowrap|15–40%}} of amphetamine circulating in the bloodstream is bound to [[plasma protein]]s.<ref name="Drugbank-amph" />
 
The [[Biological half-life|half-life]] of amphetamine enantiomers differ and vary with urine pH.<ref name="FDA Pharmacokinetics" />  At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are {{nowrap|9–11}}&nbsp;hours and {{nowrap|11–14}}&nbsp;hours, respectively.<ref name="FDA Pharmacokinetics" /> An acidic diet will reduce the enantiomer half-lives to {{nowrap|8–11}}&nbsp;hours; an alkaline diet will increase the range to {{nowrap|16–31}}&nbsp;hours.<ref name="Pubchem Kinetics" /><ref>{{cite encyclopedia | title=AMPHETAMINE| section=Biological Half-Life| section-url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+300-62-9| work=United States National Library of Medicine – Toxnet| publisher=Hazardous Substances Data Bank| accessdate=5 January 2014 |quote=Concentrations of (14)C-amphetamine declined less rapidly in the plasma of human subjects maintained on an alkaline diet (urinary pH > 7.5) than those on an acid diet (urinary pH < 6). Plasma half-lives of amphetamine ranged between 16-31 hr & 8-11 hr, respectively, & the excretion of (14)C in 24 hr urine was 45 & 70%.}}</ref> The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3&nbsp;hours and 7&nbsp;hours post-dose respectively.<ref name="FDA Pharmacokinetics" />  Amphetamine is eliminated via the kidneys, with {{nowrap|30–40%}} of the drug being excreted unchanged at normal urinary pH.<ref name="FDA Pharmacokinetics" />  When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.<ref name="FDA Pharmacokinetics" />  When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of&nbsp;1% to a high of&nbsp;75%, depending mostly upon whether urine is too basic or acidic, respectively.<ref name="FDA Pharmacokinetics" />  Amphetamine is usually eliminated within two days of the last oral dose.<ref name="Pubchem Kinetics" />  Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.<ref name="Flomenbaum_2006">{{cite encyclopedia | author = Richard RA | title = Chapter 5—Medical Aspects of Stimulant Use Disorders | series = Treatment Improvement Protocol 33 | year = 1999 | work = National Center for Biotechnology Information Bookshelf | publisher = Substance Abuse and Mental Health Services Administration | section-url = http://www.ncbi.nlm.nih.gov/books/NBK64323/ | section = Route of Administration}}</ref>
 
The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;<ref name="FDA Vyvanse">{{cite web | title = Vyvanse Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021977s030lbl.pdf | pages = 12–13 | publisher = Shire US Inc | work = United States Food and Drug Administration |date=December 2013 | accessdate = 25 February 2013 }}</ref> following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via [[hydrolysis]].<ref name="FDA Vyvanse" /> The elimination half-life of lisdexamfetamine is generally less than one hour.<ref name="FDA Vyvanse" />
 
[[CYP2D6]], [[dopamine β-hydroxylase]], [[flavin-containing monooxygenase 3]], [[butyrate-CoA ligase]], and [[glycine N-acyltransferase]] are the enzymes known to metabolize amphetamine or its metabolites in humans.{{#tag:ref|<ref name="FDA Pharmacokinetics" /><ref name="DBH ref" /><ref name="DBH amph primary" /><ref name="DBH 4-HA primary" /><ref name="FMO" /><ref name="FMO3-Primary">{{cite journal | author = Cashman JR, Xiong YN, Xu L, Janowsky A | title = N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication | journal = J. Pharmacol. Exp. Ther. | volume = 288 | issue = 3 | pages = 1251–1260 | date = March 1999 |pmid = 10027866 }}</ref><ref name="Benzoic1" /><ref name="Benzoic2" />| group = "sources" }} Amphetamine has a variety of excreted metabolic products, including {{nowrap|[[4-hydroxyamfetamine]]}}, {{nowrap|[[4-hydroxynorephedrine]]}}, {{nowrap|[[4-hydroxyphenylacetone]]}}, [[benzoic acid]], [[hippuric acid]], [[norephedrine]], and [[phenylacetone]].<ref name="FDA Pharmacokinetics" /><ref name="Pubchem Kinetics">{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#x332 | work=Pubchem Compound | publisher = National Center for Biotechnology Information | accessdate=12 October 2013 | section=Biomedical Effects and Toxicity }}</ref><ref name="Metabolites">{{cite journal | author = Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G | title = Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection | journal = J. Pharm. Biomed. Anal. | volume = 30 | issue = 2 | pages = 247–255 |date=September 2002 | pmid = 12191709 | doi =10.1016/S0731-7085(02)00330-8 }}</ref>  Among these metabolites, the active [[sympathomimetics]] are {{nowrap|4‑hydroxyamphetamine}},<ref>{{cite encyclopedia | title=p-Hydroxyamphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3651 | work=PubChem Compound | publisher = National Center for Biotechnology Information | accessdate=15 October 2013 | section=Compound Summary }}</ref> {{nowrap|4‑hydroxynorephedrine}},<ref>{{cite encyclopedia | title=p-Hydroxynorephedrine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11099 | work=PubChem Compound | publisher = National Center for Biotechnology Information | accessdate=15 October 2013 | section=Compound Summary }}</ref> and norephedrine.<ref>{{cite encyclopedia | title=Phenylpropanolamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=26934 | work=PubChem Compound | publisher = National Center for Biotechnology Information | accessdate=15 October 2013 | section=Compound Summary }}</ref> The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.<ref name="FDA Pharmacokinetics" /><ref name="Pubchem Kinetics" />  The known pathways and detectable metabolites in humans include the following:<ref name="FDA Pharmacokinetics" /><ref name="FMO" /><ref name="Metabolites" />
{{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&nbsp;50% is excreted as the inactive metabolites (bottom row).<ref name="FDA Pharmacokinetics" /> The remaining {{nowrap|10–20%}} is excreted as the active metabolites.<ref name="FDA Pharmacokinetics" /> Benzoic acid is metabolized by butyrate-CoA ligase into an intermediate product, [[benzoyl-CoA]],<ref name="Benzoic1">{{cite encyclopedia| title=butyrate-CoA ligase| section-url=http://www.brenda-enzymes.org/php/result_flat.php4?ecno=6.2.1.2&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0| work=BRENDA| publisher=Technische Universität Braunschweig.| accessdate=7 May 2014| section=Substrate/Product}}</ref> which is then metabolized by glycine N-acyltransferase into hippuric acid.<ref name="Benzoic2">{{cite encyclopedia | title=glycine N-acyltransferase| section-url=http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.13&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0| work=BRENDA| publisher=Technische Universität Braunschweig.| accessdate=7 May 2014| section=Substrate/Product}}</ref>}}
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===Related endogenous compounds===
<onlyinclude>{{#ifeq:{{{transcludesection|Related endogenous compounds}}}|Related endogenous compounds|
{{Details|Trace amines|related compounds}}
 
Amphetamine has a very similar structure and function to the [[wikt:endogenous|endogenous]] trace amines, which are naturally occurring [[neurotransmitter]] molecules produced in the human body and brain.<ref name="Miller" /><ref name="Trace Amines" />  Among this group, the most closely related compounds are [[phenethylamine]], the parent compound of amphetamine, and {{nowrap|[[N-methylphenethylamine|''N''-methylphenethylamine]]}}, an [[isomer]] of amphetamine (i.e., it has an identical molecular formula).<ref name="Miller" /><ref name="Trace Amines" /><ref name="Renaissance GPCR">{{cite journal |author=Lindemann L, Hoener MC |title=A renaissance in trace amines inspired by a novel GPCR family |journal=Trends Pharmacol. Sci. |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 [[L-phenylalanine]] by the [[aromatic amino acid decarboxylase]] (AADC) enzyme, which converts [[L-DOPA]] into dopamine as well.<ref name="Trace Amines" /><ref name="Renaissance GPCR" /> In turn, {{nowrap|''N''‑methylphenethylamine}} is metabolized from phenethylamine by [[phenylethanolamine N-methyltransferase]], the same enzyme that metabolizes norepinephrine into epinephrine.<ref name="Trace Amines">{{cite journal | author = Broadley KJ | title = The vascular effects of trace amines and amphetamines | journal = Pharmacol. Ther. | 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="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" />
}}</onlyinclude>
 
==Physical and chemical properties==
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|image1=Amphetamine Freebase.png
|width1=300
|caption1=A vial of the colorless amphetamine free base
|alt1=An image of amphetamine free base
|image2=Amphetamine Structural Formulae.png
|width2=300
|caption2=The [[skeletal structure]]s of {{abbr|L-amph|Levoamphetamine}} and {{abbr|D-amph|Dextroamphetamine}}
|alt2=Graphical representation of Amphetamine stereoisomers
|image3=Amphetamine and P2P.png
|width3=300
|caption3=Amphetamine hydrochloride (left bowl)<br />[[Phenyl-2-nitropropene]] (right cups)
|alt3=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 {{chemical formula|C|9|H|13|N}}.  The carbon atom adjacent to the [[primary amine]] is a [[stereogenic center]], and amphetamine is composed of a [[racemic]] 1:1 mixture of two [[enantiomer]]ic mirror images.<ref name="DrugBank1" />  This racemic mixture can be separated into its optical isomers:{{#tag:ref|Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.<ref name="Enantiomers" />|group = "note"}} [[levoamphetamine]] and [[dextroamphetamine]].<ref name="DrugBank1" /> Physically, at room temperature, the pure free base of amphetamine is a mobile, colorless, and [[Volatility (chemistry)|volatile]] [[liquid]] with a characteristically strong [[amine]] odor, and acrid, burning taste.<ref name="Properties">{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#x27 | work=PubChem Compound | publisher = National Center for Biotechnology Information | accessdate=13 October 2013 | section=Chemical and Physical Properties }}</ref>  Frequently prepared solid salts of amphetamine include amphetamine aspartate,<ref name="FDA Abuse & OD" /> hydrochloride,<ref>{{cite encyclopedia | title=Amphetamine Hydrochloride | url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=92939 | work = Pubchem Compound | publisher = National Center for Biotechnology Information | accessdate = 8 November 2013}}</ref> phosphate,<ref>{{cite encyclopedia | title=Amphetamine Phosphate | url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=62885 | work=Pubchem Compound | publisher = National Center for Biotechnology Information | accessdate=8 November 2013}}</ref> saccharate,<ref name="FDA Abuse & OD" /> and sulfate,<ref name="FDA Abuse & OD" /> the last of which is the most common amphetamine salt.<ref name="EMC" /> Amphetamine is also the parent compound of [[Substituted amphetamine|its own structural class]], which includes a number of psychoactive [[derivative (chemistry)|derivatives]].<ref name="DrugBank1" /> In organic chemistry, amphetamine is an excellent [[chiral ligand]] for the [[stereoselective synthesis]] of {{nowrap|[[1,1'-bi-2-naphthol]]}}.<ref name="Chiral Ligand">{{cite journal | author = Brussee J, Jansen ACA | year = 1983 | title = A highly stereoselective synthesis of s(-)-[1,1'-binaphthalene]-2,2'-diol | journal = Tetrahedron Lett. | volume = 24 | issue = 31 | pages = 3261–3262 | doi = 10.1016/S0040-4039(00)88151-4 }}</ref>
 
===Derivatives===
{{Main list|Substituted amphetamine}}
 
Amphetamine derivatives, often referred to as "amphetamines" or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone".<ref name="DrugBank Header">{{cite encyclopedia | title=Amphetamine | section-url=http://www.drugbank.ca/drugs/DB00182 | work=DrugBank | publisher= University of Alberta | accessdate=30 September 2013 | date=8 February 2013 | section=Compound Summary }}</ref><ref name="Schep">{{cite journal | author=Schep LJ, Slaughter RJ, Beasley DM | title=The clinical toxicology of metamfetamine | journal=Clin. Toxicol. (Phila.) | volume=48 | issue=7 | pages=675–694 |date=August 2010 | pmid=20849327 | doi=10.3109/15563650.2010.516752 | issn=1556-3650}}</ref> The class includes stimulants like methamphetamine, serotonergic [[empathogens]] like [[MDMA]] (ecstasy), and [[decongestant]]s like [[ephedrine]], among other subgroups.<ref name="DrugBank Header" /><ref name="Schep" />  This class of chemicals is sometimes referred to collectively as the "amphetamine family."<ref>{{cite web | title = Amphetamine, Methamphetamine, & Cystal Meth | url = http://www.cqld.ca/livre/en/en/07-amphetamine.htm | work = Addiction Prevention Centre | accessdate = 10 October 2013 }}</ref>
 
===Synthesis===
{{Details3|[[History and culture of substituted amphetamines#Illegal synthesis|Illegal synthesis of substituted amphetamines]]|illicit amphetamine synthesis}}
Since the first preparation was reported in 1887,<ref name="Vermont"/> numerous synthetic routes to amphetamine have been developed.<ref name = "Allen_Cantrell_1989">{{cite journal | author = 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><ref name = "Allen_Ely_2009">{{cite journal | url = http://www.nwafs.org/newsletters/2011_Spring.pdf | title = Review: Synthetic Methods for Amphetamine | author = Allen A, Ely R | format = PDF | work = | publisher = Northwest Association of Forensic Scientists | volume = 37 | issue = 2 | year = 2009 | pages = 15–25 | journal = Crime Scene | accessdate = 6 December 2014}}</ref>  Many of these syntheses are based on classic organic reactions.  One such example is the [[Friedel–Crafts reaction#Friedel.E2.80.93Crafts alkylation|Friedel–Crafts]] alkylation of [[chlorobenzene]] by [[allyl chloride]] to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 1).<ref name="pmid20985610">{{cite journal | author = Patrick TM, McBee ET, Hass HB | title = Synthesis of arylpropylamines; from allyl chloride | journal = J. Am. Chem. Soc. | volume = 68 | issue = | pages = 1009–1011 | date = June 1946 | pmid = 20985610 | doi = 10.1021/ja01210a032 }}</ref>  Another example employs the [[Ritter reaction]] (method 2).  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 | author = Ritter JJ, Kalish J | title = A new reaction of nitriles; synthesis of t-carbinamines | journal = J. Am. Chem. Soc. | volume = 70 | issue = 12 | pages = 4048–4050 | date = December 1948 | pmid = 18105933 | doi = 10.1021/ja01192a023 }}</ref><ref name=Krimen_Cota_1969>{{cite journal | author = Krimen LI, Cota DJ | journal = Organic Reactions | year = 1969 | volume = 17 | page = 216 | doi = 10.1002/0471264180.or017.03}}</ref> A third route starts with {{nowrap|[[ethyl acetoacetate|ethyl 3-oxobutanoate]]}} which through a double alkylation with [[methyl iodide]] followed by [[benzyl chloride]] can be converted into {{nowrap|2-methyl-3-phenyl-propanoic}} acid. This synthetic intermediate can be transformed into amphetamine using either a [[Hofmann rearrangement|Hofmann]] or [[Curtius rearrangement]] (method 3).<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]].<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 4).<ref name="Delta Isotope">{{cite journal | author = 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 Commun. Mass Spectrom. | volume = 24 | issue = 11 | pages = 1653–1658 |date=June 2010 | pmid = 20486262 | doi = 10.1002/rcm.4563 }}</ref><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 | accessdate = 14 October 2013 | year = 2006 | work = United Nations Office on Drugs and Crime | publisher = United Nations}}</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 5).<ref name="Amph Synth" />
 
The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the [[Leuckart reaction]] (method 6).<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 | author = Pollard CB, Young DC | journal = J. Org. Chem. | 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  | editor = 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) | chapterurl = http://books.google.com/books?id=zvruBDAulWEC&lpg=PP1&dq=The%20Art%20of%20Drug%20Synthesis%20(Wiley%20Series%20on%20Drug%20Synthesis)&pg=SA17-PA4#v=onepage&q=amphetamine&f=false | year = 2007 | publisher = Wiley-Interscience | location = New York, USA | isbn = 9780471752158 | page = 247 }}</ref>
<center>
{|
|- valign="top"
|+'''Amphetamine synthetic routes'''
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|image1=Amphetamine Friedel-Crafts alkylation.svg
|caption1=Method 1: Synthesis by Friedel–Crafts alkylation
|alt1=Diagram of amphetamine synthesis by Friedel–Crafts alkylation
|image2=Amphetamine Ritter Synthesis.svg
|caption2=Method 2: Ritter synthesis
|alt2=Diagram of amphetamine via Ritter synthesis
|image3=Amphetamine Hofmann Curtius Synthesis.svg
|caption3=Method 3: Synthesis via Hofmann and Curtius rearrangements
|alt3=Diagram of amphetamine synthesis via Hofmann and Curtius rearrangements
|image4=Amphetamine Knoevenagel synthesis.svg
|caption4=Method 4: Synthesis by Knoevenagel condensation
|alt4=Diagram of amphetamine synthesis by Knoevenagel condensation
}}
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|image1=Amphetamine p2p ammonia synthesis.svg
|caption1=Method 5: Synthesis using phenylacetone and ammonia<br />&nbsp;
|alt1=Diagram of amphetamine synthesis from phenylacetone and ammonia
|image2=Amphetamine Leukart synthesis.svg
|caption2=Method 6: Synthesis by the Leuckart reaction<br />&nbsp;
|alt2=Diagram of amphetamine synthesis by the Leuckart reaction
|image3=Amphetamine resolution and chiral synthesis.svg
|caption3=Top: Chiral resolution of amphetamine <br />Bottom: Stereoselective synthesis of amphetamine
|alt3=Diagram of a chiral resolution of racemic amphetamine and a stereoselective synthesis
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===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 | author = Kraemer T, Maurer HH | title = Determination of amphetamine, methamphetamine and amphetamine-derived designer drugs or medicaments in blood and urine | journal = J. Chromatogr. B Biomed. Sci. Appl. | 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 | author = Kraemer T, Paul LD | title = Bioanalytical procedures for determination of drugs of abuse in blood | journal = Anal. Bioanal. Chem. | volume = 388 | issue = 7 | pages = 1415–1435 |date=August 2007 | pmid = 17468860 | doi = 10.1007/s00216-007-1271-6 }}</ref><ref name="pmid8075776">{{cite journal | author = Goldberger BA, Cone EJ | title = Confirmatory tests for drugs in the workplace by gas chromatography-mass spectrometry | journal = J. Chromatogr. 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 (e.g., [[Vicks VapoInhaler]], which contains [[levomethamphetamine]]) or illicitly obtained substituted amphetamines.<ref name="pmid15516295">{{cite journal | author = 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 = J. Anal. Toxicol. | volume = 28 | issue = 6 | pages = 449–455 |date=September 2004 | pmid = 15516295 | doi = 10.1093/jat/28.6.449 }}</ref><ref name="pmid16105261">{{cite journal | author = Verstraete AG, Heyden FV | title = Comparison of the sensitivity and specificity of six immunoassays for the detection of amphetamines in urine | journal = J. Anal. Toxicol. | volume = 29 | issue = 5 | pages = 359–364 | year = 2005 | pmid = 16105261 | doi =10.1093/jat/29.5.359 }}</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, USA | isbn = 9780962652387 | 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 Metab. Rev. | volume = 32 | issue = 1 | pages = 15–44 |date=February 2000 | pmid = 10711406 | doi = 10.1081/DMR-100100562 }}</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 = J. Occup. Environ. Med. | volume = 44 | issue = 5 | pages = 435–450 |date=May 2002 | pmid = 12024689 | doi = 10.1097/00043764-200205000-00012 }}</ref> These compounds may produce positive results for amphetamine on drug tests.<ref name="pmid10711406" /><ref name="pmid12024689" /> Amphetamine is generally only detectable by a standard drug test for approximately 24&nbsp;hours, although a high dose may be detectable for two to four days.<ref name="NAHMSA_testing">{{cite web | title=Clinical Drug Testing in Primary Care | url=http://162.99.3.213/products/manuals/pdfs/TAP32.pdf | work=Substance Abuse and Mental Health Services Administration | publisher=United States Department of Health and Human Services | series=Technical Assistance Publication Series 32 | year=2012 | accessdate=31 October 2013}}</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}}
{| class="wikitable sortable" style="text-align:center" align=right
|+ Global estimates of illicit drug users in 2012<br />(in millions of users)<ref name="WDR2014">{{cite web | title = World Drug Report 2014 | editor = Mohan J | date = June 2014 | pages = 3, 123–152 | work = United Nations Office on Drugs and Crime | url = https://www.unodc.org/documents/wdr2014/World_Drug_Report_2014_web.pdf | accessdate = 18 August 2014 }}</ref>
! Substance !! Mean<br />estimate !! Low<br />estimate !! High<br />estimate
|-
| Cannabis || 177.63 || 125.30 || 227.27
|-
| Cocaine || 17.24 || 13.99 || 20.92
|-
| MDMA || 18.75 || 9.4 || 28.24
|-
| Opiates || 16.37 || 12.80 || 20.23
|-
| Opioids || 33.04 || 28.63 || 38.16
|-
| Substituted<br />amphetamines || 34.40 || 13.94 || 54.81
|-
|}
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 | title=Historical overview of methamphetamine | work=Vermont Department of Health | publisher=Government of Vermont | accessdate=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=9780203871171 | 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 |author=Sulzer D, Sonders MS, Poulsen NW, Galli A |title=Mechanisms of neurotransmitter release by amphetamines: a review |journal=Prog. Neurobiol. |volume=75 |issue=6 |pages=406–433 |date=April 2005 |pmid=15955613 |doi=10.1016/j.pneurobio.2005.04.003 |url=}}</ref>  Amphetamine had no pharmacological use until 1934, when [[Smith, Kline and French]] began selling it as an [[inhaler]] under the trade name [[Benzedrine]] as a decongestant.<ref name="Benzedrine">{{cite journal | author=Rasmussen N | title=Making the first anti-depressant: amphetamine in American medicine, 1929–1950 | journal=J . Hist. Med. Allied Sci. | volume=61 | issue=3 | pages=288–323 |date=July 2006 | pmid=16492800 | doi=10.1093/jhmas/jrj039}}</ref>  During World War II, amphetamines and methamphetamine were used extensively by both the Allied and 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=J. Interdiscip. Hist. | year=2011 | volume=42 | issue=2 | pages=205–233 | pmid=22073434 | doi=10.1162/JINH_a_00212 }}</ref><ref name="pmid22849208">{{cite journal | author = Defalque RJ, Wright AJ | title = Methamphetamine for Hitler's Germany: 1937 to 1945 | journal = Bull. Anesth. Hist. | volume = 29 | issue = 2 | pages = 21–24, 32 |date=April 2011 | pmid = 22849208 | doi =  }}</ref> As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.<ref name="Vermont" />  For example, during the early 1970s in the United States, amphetamine became a [[Schedule II (US)|schedule II controlled substance]] under the [[Controlled Substances Act]].<ref>{{cite web | title=Controlled Substances Act | url=http://www.fda.gov/regulatoryinformation/legislation/ucm148726.htm | publisher=United States Food and Drug Administration | date=11 June 2009 | accessdate=4 November 2013}}</ref> In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,<ref>{{cite web | author = Gyenis A | work = wordsareimportant.com | publisher = DHARMA beat | title = Forty Years of ''On the Road'' 1957–1997| url = http://www.wordsareimportant.com/ontheroad.htm | accessdate = 18 March 2008 | archiveurl = http://web.archive.org/web/20080214171739/http://www.wordsareimportant.com/ontheroad.htm | archivedate = 14 February 2008}}</ref> musicians,<ref>{{cite journal | title = Mixing the Medicine: The unintended consequence of amphetamine control on the Northern Soul Scene | author = Wilson A | url = http://www.internetjournalofcriminology.com/Wilson%20-%20Mixing%20the%20Medicine.pdf | journal = Internet Journal of Criminology | year = 2008 | accessdate=25 May 2013 }}</ref> mathematicians,<ref>{{cite web | title =  Paul Erdos, Mathematical Genius, Human (In That Order) | work = untruth.org |url = http://www.untruth.org/~josh/math/Paul%20Erd%F6s%20bio-rev2.pdf | author = Hill J | accessdate = 2 November 2013 | date = 4 June 2004}}</ref> and athletes.<ref name="Ergogenics" />
 
Amphetamine is still illegally synthesized today in [[clandestine chemistry|clandestine labs]] and sold on the black market, primarily in European countries.<ref name="WDR2014" /> Among European Union (EU) member states, 1.2&nbsp;million young adults used illicit amphetamine or methamphetamine in 2013.<ref name="EMCDDA 2014">{{cite journal | title=European drug report 2014: Trends and developments | date=May 2014 | pages=13, 24 | doi=10.2810/32306 | url=http://www.emcdda.europa.eu/attachements.cfm/att_228272_EN_TDAT14001ENN.pdf | accessdate=18 August 2014 | publisher=European Monitoring Centre for Drugs and Drug Addiction | location=Lisbon, Portugal | format=PDF | issn=2314-9086 | quote=1.2 million or 0.9% of young adults (15–34) used amphetamines in the last year}}</ref> During 2012, approximately 5.9&nbsp;[[metric ton]]s of illicit amphetamine were seized within EU member states;<ref name="EMCDDA 2014" /> the "street price" of illicit amphetamine within the EU ranged from €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 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 | work=United Nations Treaty Collection | publisher=United Nations | accessdate=11 November 2013}}</ref> Consequently, it is heavily regulated in most countries.<ref name="isbn92-1-148223-2">{{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, USA | year = 2007 | isbn = 9789211482232 | url = http://www.unodc.org/pdf/youthnet/ATS.pdf | accessdate = 11 November 2013}}</ref><ref>{{cite web | title = List of psychotropic substances under international control | work = International Narcotics Control Board | publisher = United Nations | url = http://www.incb.org/pdf/e/list/green.pdf | accessdate = 19 November 2005 | archiveurl = http://web.archive.org/web/20051205125434/http://www.incb.org/pdf/e/list/green.pdf | archivedate= 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 = http://www.koreatimes.co.kr/www/news/nation/2012/10/319_111757.html | title = Moving to Korea brings medical, social changes | work = The Korean Times | date = 25 May 2012 | accessdate = 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 | work = Japanese Ministry of Health, Labour and Welfare | accessdate=3 November 2013 | date=1 April 2004}}</ref>  In other nations, such as Canada ([[Controlled Drugs and Substances Act|schedule 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 | work = Canadian Justice Laws Website | publisher = Government of Canada | accessdate = 11 November 2013 | date=11 November 2013}}</ref> the United States ([[Schedule II (US)|schedule II drug]]),<ref name="FDA Abuse & OD" /> Thailand ([[Law of Thailand#Criminal Law|category 1 narcotic]]),<ref>{{cite web | url = 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 | work = Thailand Food and Drug Administration | date = 22 May 2013 | accessdate = 11 November 2013}}</ref> and United Kingdom ([[Misuse of Drugs Act 1971|class B drug]]),<ref>{{cite web | title = Class A, B and C drugs | work = Home Office, Government of the United Kingdom | url = http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/ | accessdate = 23 July 2007 | archiveurl =  http://web.archive.org/web/20070804233232/http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/ | archivedate= 4 August 2007 }}</ref> amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.<ref name="Nonmedical">{{cite journal | author = 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 = J. Am. Acad. Child Adolesc. 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><ref name="WDR2014" />
 
===Pharmaceutical products===
 
The only currently prescribed amphetamine formulation that contains both enantiomers is Adderall.<ref name="Adderall" group="note" /><ref name="DrugBank1" /><ref name="Amph Uses" /> Amphetamine is also prescribed in [[Enantiopure drug|enantiopure]] and [[prodrug]] form as dextroamphetamine and lisdexamfetamine respectively.<ref name="NDCD" /><ref name="Vyvanse" /> Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.<ref name="Vyvanse" /> The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.<ref name="DrugBank1">{{cite encyclopedia | title=Amphetamine | section-url=http://www.drugbank.ca/drugs/DB00182#identification | section=Identification | work=DrugBank | publisher= University of Alberta | accessdate=13 October 2013 | date=8 February 2013 }}</ref><ref name="Amph Uses" /> Levoamphetamine was previously available as Cydril.<ref name="Amph Uses" /> All 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" /> Some of the current brands and their generic equivalents are listed below.
<!--This is a simple 1x2 matrix of nested tables-->
{| style="width: 80%"
|<!--Left cell: nested table-->
{| class="wikitable sortable" style="text-align:center; width:430px;"
|+ Amphetamine pharmaceuticals
! scope="col" | Brand<br />name
! scope="col" | [[United States Adopted Name|United States<br />Adopted Name]]
! scope="col" class="unsortable" style="text-align:center"| [[wikt:enantiomeric ratio|(D:L) ratio]]<br />of salts
! scope="col"|  Dosage<br />form
! scope="col" class="unsortable" | <small>Source</small>
|-
| Adderall || – || 3:1 <!--DO NOT CHANGE THIS RATIO: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666194/table/table1-0269881113482532/ -->|| tablet ||<ref name="Amph Uses" /><ref name="NDCD" />
|-
| Adderall XR || – || 3:1 || capsule  ||<ref name="Amph Uses" /><ref name="NDCD" />
|-
| Dexedrine || dextroamphetamine sulfate || 1:0 || capsule  ||<ref name="Amph Uses" /><ref name="NDCD" />
|-
| ProCentra || dextroamphetamine sulfate || 1:0 || liquid ||<ref name="NDCD" />
|-
| Vyvanse || lisdexamfetamine dimesylate || 1:0|| capsule ||<ref name="Amph Uses" /><ref name="Vyvanse">{{cite encyclopedia | title=Lisdexamfetamine | section-url=http://www.drugbank.ca/drugs/DB01255#identification | work=Drugbank | publisher= University of Alberta | accessdate=13 October 2013 | date=8 February 2013 | section=Identification }}</ref>
|-
| Zenzedi || dextroamphetamine sulfate || 1:0 || tablet ||<ref name="NDCD" />
|}
|<!--Right cell: nested image table-->
{|
|+&nbsp;
|-
|[[File:Lisdexamfetamine-Structural Formula V.1.svg|thumb|left|The skeletal structure of lisdexamfetamine|alt=An image of the lisdexamphetamine compound]]
|}
|}
 
==Notes==
 
<references group="note" />
;Image legend
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==FDA Package Insert Resources==
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[[{{PAGENAME}} indications|Indications]]
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==Trial Resources==
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==Guidelines & Evidence Based Medicine Resources==
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{{Commons|amphetamine}}
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* {{PubChemLink|5826}} (dextroamphetamine)
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* {{PubChemLink|3007}} (racemic amphetamine)
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=pubmed&term={{urlencode:({{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}) AND (Cochrane Database Syst Rev[ta])}} Cochrane Collaboration on {{PAGENAME}}]
* {{PubChemLink|32893}} (levoamphetamine)
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* [http://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]
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* [http://ctdbase.org/detail.go?type=gene&acc=9607&qid=2119242 Comparative Toxicogenomics Database entry: CARTPT]
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=pubmed&term={{urlencode:({{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}) AND (Cost effectiveness)}} Cost Effectiveness of {{PAGENAME}}]
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Amphetamine U.S. National Library of Medicine: Drug Information Portal – Amphetamine]
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{{FDA}}


[[Category:Drugs]]
[[Category:Amphetamine]]
[[Category:Amphetamines]]
[[Category:Anorectics]]
[[Category:Attention deficit hyperactivity disorder]]
[[Category:Drugs acting on the cardiovascular system]]
[[Category:Drugs acting on the nervous system]]
[[Category:Drugs in sport]]
[[Category:Euphoriants]]
[[Category:Excitatory amino acid reuptake inhibitors]]
[[Category:German inventions]]
[[Category:Nootropics]]
[[Category:Norepinephrine-dopamine releasing agents]]
[[Category:Phenethylamines]]
[[Category:Stimulants]]
[[Category:TAAR1 agonists]]
[[Category:VMAT inhibitors]]

Latest revision as of 16:48, 12 December 2014

Amphetamine
An image of the amphetamine compound
A 3d image of the amphetamine compound
Clinical data
Synonymsα-methylphenethylamine
AHFS/Drugs.comamphetamine
[[Regulation of therapeutic goods |Template:Engvar data]]
Pregnancy
category
  • US: C (Risk not ruled out)
Dependence
liability
Moderate
Routes of
administration
Medical: oral, nasal inhalation
Recreational: oral, nasal inhalation, insufflation, rectal, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRectal 95–100%; Oral 75–100%[9]
Protein binding15–40%[10]
MetabolismCYP2D6,[1] DBH,[2][3][4] FMO3,[5][6] XM-ligase,[7] and ACGNAT[8]
Onset of actionImmediate
Elimination half-lifeD-amph:9–11h;[1][11] L-amph:11–14h[1][11]
ExcretionRenal; pH-dependent range: 1–75%[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC9H13N
Molar mass135.2084 g/mol
3D model (JSmol)
Density0.9±0.1 g/cm3
Melting point11.3 °C (52.34 °F) [12]
Boiling point203 °C (397.4 °F) [13]
  (verify)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Amphetamine is a potent central nervous system stimulant used in the treatment of attention deficit hyperactivity disorder and narcolepsy.

Amphetamine

Amphetamine[note 1] (Lua error: expandTemplate: template "Template:IPA audio link" does not exist.; contracted from alphamethylphenethylamine) is a potent central nervous system (CNS) stimulant of the phenethylamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine.[note 2] Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, the term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion, depression, and obesity. Amphetamine is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription medication in many countries, and unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use.[sources 1]

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions. Currently, pharmaceutical amphetamine is typically prescribed as Adderall,[note 3] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases biogenic amine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine. At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased wakefulness, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[sources 2]

Much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk of amphetamine abuse, but only rarely arises from medical use. Very high doses can result in psychosis (e.g., delusions 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.[sources 3]

Amphetamine is also the parent compound of its own structural class, the substituted amphetamines,[note 4] which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), and methamphetamine. Unlike methamphetamine, amphetamine's salts lack sufficient volatility to be smoked. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine[note 5] and N-methylphenethylamine, both of which are produced within the human body.[sources 4]

Uses

Medical

Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy, and is sometimes prescribed off-label for its past medical indications, such as depression, obesity, and nasal congestion.[11][27] Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage,[38][39] but, in humans with ADHD, amphetamines appear to improve brain development and nerve growth.[40][41][42] Magnetic resonance imaging 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.[40][41][42]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[43][44] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.[44][45] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points and continued improvements in attention, disruptive behaviors, and hyperactivity.[45]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[46] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[46] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[24][46][47] Approximately 70% of those who use these stimulants see improvements in ADHD symptoms.[48][49] 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.[43][48] The Cochrane Collaboration's review[note 6] on the treatment of adult ADHD with amphetamines stated that while amphetamines improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[51]

A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[52] Other Cochrane reviews on the use of amphetamine following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.[53][54][55]

Enhancing performance

Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on working memory tests in all individuals.[24][56] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[24][57][58] Stimulants such as amphetamine can improve performance on difficult and boring tasks,[24][57] and are used by some students as a study and test-taking aid.[59] Based upon studies of self-reported illicit stimulant use, performance-enhancing use, rather than abuse as a recreational drug, is the primary reason that students use stimulants.[60] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and cognitive control.[24][57]

Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness;[23][35] however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies.[61][62] In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time.[23][63][64] Amphetamine improves stamina, endurance, and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[63][64][65] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[23][63][64] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[22][31][63]

Contraindications

According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 7] amphetamine is contraindicated in people with a history of drug abuse, heart disease, severe agitation, or severe anxiety.[66][67] It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (an eye condition), hyperthyroidism (excessive production of thyroid hormone), or hypertension (elevated blood pressure).[66][67] People who have experienced allergic reactions to other stimulants in the past or are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine.[66][67] These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine.[66][67] 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 teratogen), but amphetamine abuse does pose risks to the fetus.[67] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[66][67] Due to the potential for reversible growth impairments,[note 8] the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.[66]

Side effects

The side effects of amphetamine are varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of side effects.[22][31][35] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[29][31] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.[35]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[31] Cardiovascular side effects can include irregular heartbeat (usually an increased heart rate), hypertension (high blood pressure) or hypotension (low blood pressure) from a vasovagal response, and Raynaud's phenomenon (reduced blood flow to extremities).[31][35][68] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[31] Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss.[31] Other potential side effects include dry mouth, excessive grinding of the teeth, acne, profuse sweating, blurred vision, reduced seizure threshold, and tics (a type of movement disorder).[31][35][68] Dangerous physical side effects are rare at typical pharmaceutical doses.[35]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[35] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[35] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control.[35] The effects of amphetamine on the gastrointestinal tract are unpredictable.[35] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[35] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[35] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opiates.[35]

USFDA commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 5]

Psychological

Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[31][35] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 6] these effects depend on the user's personality and current mental state.[35] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[22][31][32] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[22][31][33] According to the USFDA, "there is no systematic evidence" that stimulants can produce aggressive behavior or hostility.[31]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[67][74] The severity of overdose symptoms vary positively with dosage and inversely with drug tolerance to amphetamine.[35][67] Tolerant individuals have been known to take as much as 5 grams of amphetamine, roughly 100 times the maximum daily therapeutic dose, in a day.[67] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[22][35] Chronic overdose of amphetamine poses a high risk of developing an addiction, since high doses result in increased expression of the addiction gene ΔFosB.[75] Consistent aerobic exercise appears to magnitude-dependently reduce this risk.[76] Template:Amphetamine overdose

Addiction

Signaling cascade in the nucleus accumbens that results in amphetamine addiction
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[77][78] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[77][75] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[77][79][80] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[81] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[79][80] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[79][80]

Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to arise from typical medical use at therapeutic doses.[22][34][35] Tolerance develops rapidly in amphetamine abuse, so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[82][83]

Biomolecular mechanisms

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.[84][85][86] The most important transcription factors[note 9] that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).[85] ΔFosB is the most significant factor in drug addiction, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the associated neural adaptations that occur;[85] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, opiates, phenylcyclidine, and substituted amphetamines.[85][88][89] ΔJunD is the transcription factor which directly opposes ΔFosB.[85] Increases in nucleus accumbens ΔJunD expression using viral vectors can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[85] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[85][88][90] Since natural rewards induce expression of ΔFosB just like drugs of abuse do, chronic acquisition of these rewards can result in a similar pathological state of addiction.[88][85] Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction and amphetamine-induced sex addictions, a phenomenon known as dopamine dysregulation syndrome which has been observed in some patients taking dopaminergic medications.[88][90][91]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[86] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[86] 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.[86]

Pharmacological treatments

A Cochrane Collaboration review on amphetamine and methamphetamine addiction and abuse indicates that the current evidence on effective treatments is extremely limited.[92] The review indicated that fluoxetine[note 10] and imipramine[note 11] have some limited benefits in treating abuse and addiction, but concluded that there is currently no effective pharmacological treatment for amphetamine addiction or abuse.[92] A corroborating review indicated that amphetamine addiction is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic dopamine pathway (a pathway in the brain that connects the ventral tegmental area to the nucleus accumbens).[93] This review also noted that magnesium ions and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's calcium channels.[93] It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[93] Supplemental magnesium,[note 12] like fluoxetine treatment, has been shown to reduce amphetamine self-administration (doses given to oneself) in both humans and lab animals.[92][93]

Behavioral treatments

Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction.[94] Additionally, research on the neurobiological effects of physical exercise suggests that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct (supplemental) treatment for amphetamine addiction.[76][88] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[76] In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces opposite effects on striatal dopamine receptor D2 (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density).[88]

Withdrawal

According to another Cochrane Collaboration review on withdrawal in highly addicted amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[95] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.[95] Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[95] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[95] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[96][97][98]

Psychosis

Template:Main section

Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia and delusions).[32] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely.[32][99] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[32] Psychosis very rarely arises from therapeutic use.[33][66]

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function.[100] There is no evidence that amphetamine is directly neurotoxic in humans.[101][102] High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[38][103][104]

Interactions

Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.[1][105] Inhibitors of the enzymes that metabolize amphetamine (i.e., CYP2D6 and flavin-containing monooxygenase 3) will prolong its elimination half-life.[5][105] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[105] Amphetamine will modulate the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants.[105] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[105] In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.[105] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[105] Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which increase gastrointestinal pH.[105]

Pharmacology

Pharmacodynamics

Pharmacodynamics of amphetamine in a dopamine neuron
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[30] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[30][106] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[106][107] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[30][108][109] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[30] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[30] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[110][111]

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, collectively known as the mesocorticolimbic projection.[30][47] 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 due to its effects on monoamine transporters.[30][47][106] The reinforcing and task saliency effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[24]

Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[30][112] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function.[30][113] Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[30] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.[30] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.[30] As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[30]

In addition to the neuronal monoamine transporters, amphetamine also inhibits vesicular monoamine transporter 2 (VMAT2), SLC1A1, SLC22A3, and SLC22A5.[sources 7] SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes and SLC22A5 is a high-affinity carnitine transporter.[sources 7] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[118] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[119][120][121] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[121][122] Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.[14][123] The full profile of amphetamine's short-term drug effects is derived through increased cellular communication or neurotransmission of dopamine,[30] serotonin,[30] norepinephrine,[30] epinephrine,[106] histamine,[106] CART peptides,[118] acetylcholine,[124][125] and glutamate,[126][127] which it effects through interactions with CART, EAAT3, TAAR1, and VMAT2.[sources 8]

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[128] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[35][128]

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[30] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[30] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[30] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[30] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).[30][129] Amphetamine is also known to increase intracellular calcium, a known effect of TAAR1 activation, which is associated with DAT phosphorylation through a Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux.[112][110][111] Through direct activation of G protein-coupled inwardly-rectifying potassium channels and increased dopamine release, TAAR1 reduces the firing rate of postsynaptic dopamine receptors, preventing a hyper-dopaminergic state.[130][108][109]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[106] Following amphetamine uptake at VMAT2, the synaptic vesicle releases dopamine molecules into the cytosol in exchange.[106] Subsequently, the cytosolic dopamine molecules exit the presynaptic neuron via reverse transport at DAT.[30][106]

Norepinephrine

Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[37][47] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[30][106][129] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.[30][106]

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[30][47] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[30][106]

Other neurotransmitters

Amphetamine has no direct effect on acetylcholine neurotransmission, but several studies have noted that acetylcholine release increases after its use.[124][125] In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream effect.[124] In humans, a similar phenomenon occurs via the ghrelin-mediated cholinergic–dopaminergic reward link in the ventral tegmental area.[125] This heightened cholinergic activity leads to increased nicotinic receptor activation in the CNS, a factor which likely contributes to the nootropic effects of amphetamine.[131]

Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase upon exposure to amphetamine.[126][127] This cotransmission effect was found in the mesolimbic pathway, an area of the brain implicated in reward, where amphetamine is known to affect dopamine neurotransmission.[126][127] Amphetamine also induces effluxion of histamine from synaptic vesicles in CNS mast cells and histaminergic neurons through VMAT2.[106]

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;[105] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[9] Amphetamine is a weak base with a pKa of 9–10;[1] 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.[1][105] Conversely, an acidic pH means the drug is predominantly in a water soluble cationic (salt) form, and less is absorbed.[1] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[10]

The half-life of amphetamine enantiomers differ and vary with urine pH.[1] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[1] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[132][133] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[1] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[1] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[1] 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.[1] Amphetamine is usually eliminated within two days of the last oral dose.[132] Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.[134]

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[135] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[135] The elimination half-life of lisdexamfetamine is generally less than one hour.[135]

CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase 3, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize amphetamine or its metabolites in humans.[sources 9] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[1][132][136] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[137] 4‑hydroxynorephedrine,[138] and norephedrine.[139] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[1][132] The known pathways and detectable metabolites in humans include the following:[1][5][136] Template:Amphetamine Pharmacokinetics

Related endogenous compounds

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain.[30][37] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula).[30][37][140] In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.[37][140] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[37][140] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;[30][140] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[37][140]

Physical and chemical properties

Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula Template:Chemical formula. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomeric mirror images.[15] This racemic mixture can be separated into its optical isomers:[note 13] levoamphetamine and dextroamphetamine.[15] Physically, at room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste.[141] Frequently prepared solid salts of amphetamine include amphetamine aspartate,[22] hydrochloride,[142] phosphate,[143] saccharate,[22] and sulfate,[22] the last of which is the most common amphetamine salt.[36] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[15] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[144]

Derivatives

Amphetamine derivatives, often referred to as "amphetamines" or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone".[145][146] The class includes stimulants like methamphetamine, serotonergic empathogens like MDMA (ecstasy), and decongestants like ephedrine, among other subgroups.[145][146] This class of chemicals is sometimes referred to collectively as the "amphetamine family."[147]

Synthesis

Template:Details3 Since the first preparation was reported in 1887,[148] numerous synthetic routes to amphetamine have been developed.[149][150] Many of these syntheses are based on classic organic reactions. One such example is the Friedel–Crafts alkylation of chlorobenzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 1).[151] Another example employs the Ritter reaction (method 2). 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.[152][153] A third route starts with ethyl 3-oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 3).[154]

A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime or other nitrogen-containing functional group.[149] In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 4).[155][156] 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 5).[156]

The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 6).[36][156] In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields 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.[156][157]

A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[150] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[158] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[159] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (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.[159]

Amphetamine synthetic routes
Method 1: Synthesis by Friedel–Crafts alkylation
Method 3: Synthesis via Hofmann and Curtius rearrangements
Method 4: Synthesis by Knoevenagel condensation
Method 5: Synthesis using phenylacetone and ammonia
 
Method 6: Synthesis by the Leuckart reaction
 
Top: Chiral resolution of amphetamine
Bottom: Stereoselective synthesis of amphetamine

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.[sources 10] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[163] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[164] 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 (e.g., Vicks VapoInhaler, which contains levomethamphetamine) or illicitly obtained substituted amphetamines.[164][165][166] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[27][167][168] These compounds may produce positive results for amphetamine on drug tests.[167][168] Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for two to four days.[163]

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–tandem mass spectrometry.[165] Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine.[164] GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.[164] 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.[164]

History, society, and culture

Global estimates of illicit drug users in 2012
(in millions of users)[169]
Substance Mean
estimate
Low
estimate
High
estimate
Cannabis 177.63 125.30 227.27
Cocaine 17.24 13.99 20.92
MDMA 18.75 9.4 28.24
Opiates 16.37 12.80 20.23
Opioids 33.04 28.63 38.16
Substituted
amphetamines
34.40 13.94 54.81

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[148][170][171] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[171] Amphetamine had no pharmacological use until 1934, when Smith, Kline and French began selling it as an inhaler under the trade name Benzedrine as a decongestant.[28] During World War II, amphetamines and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[148][172][173] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[148] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[174] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[175] musicians,[176] mathematicians,[177] and athletes.[23]

Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[169] Among European Union (EU) member states, 1.2 million young adults used illicit amphetamine or methamphetamine in 2013.[178] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[178] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.[178] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[169]

Legal status

As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all (183) state parties.[21] Consequently, it is heavily regulated in most countries.[179][180] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[181][182] In other nations, such as Canada (schedule I drug),[183] the United States (schedule II drug),[22] Thailand (category 1 narcotic),[184] and United Kingdom (class B drug),[185] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[26][169]

Pharmaceutical products

The only currently prescribed amphetamine formulation that contains both enantiomers is Adderall.[note 3][15][27] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[29][186] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[186] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[15][27] Levoamphetamine was previously available as Cydril.[27] All current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[27][29][36] Some of the current brands and their generic equivalents are listed below.

Amphetamine pharmaceuticals
Brand
name
United States
Adopted Name
(D:L) ratio
of salts
Dosage
form
Source
Adderall 3:1 tablet [27][29]
Adderall XR 3:1 capsule [27][29]
Dexedrine dextroamphetamine sulfate 1:0 capsule [27][29]
ProCentra dextroamphetamine sulfate 1:0 liquid [29]
Vyvanse lisdexamfetamine dimesylate 1:0 capsule [27][186]
Zenzedi dextroamphetamine sulfate 1:0 tablet [29]
 
An image of the lisdexamphetamine compound
The skeletal structure of lisdexamfetamine

Notes

  1. Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name), α-methylbenzeneethanamine, α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, desoxynorephedrine, and speed.[14][15][16]
  2. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[17]
    Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.[14]
  3. 3.0 3.1 "Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"[29]) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.
  4. 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 the class.
  5. Again, due to confusion that may arise from use of the plural form, this article will only use "phenethylamine" and "phenethylamines" to refer to the compound itself and reserve the term "substituted phenethylamines" for the class.
  6. Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[50]
  7. The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.
  8. 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.[44][45][68] The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.[68]
  9. Transcription factors are proteins that increase or decrease the expression of specific genes.[87]
  10. During short-term treatment, fluoxetine may decrease drug craving.[92]
  11. During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.[92]
  12. The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[93] other forms of magnesium were not mentioned.
  13. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[17]
Image legend

Reference notes

References

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  74. 75.0 75.1 Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
  75. 76.0 76.1 76.2 Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci Biobehav Rev. 37 (8): 1622–44. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. PMID 23806439. these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... 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.
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    Figure 2: Psychostimulant-induced signaling events
  77. Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
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    Figure 4: Epigenetic basis of drug regulation of gene expression
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  87. 88.0 88.1 88.2 88.3 88.4 88.5 Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. 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). ... 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).
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  90. Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity
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