Amfetamina: Różnice pomiędzy wersjami

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[wersja przejrzana][wersja nieprzejrzana]
(Anulowanie wersji 47504506 autora 83.53.208.65 (dyskusja), Potrzebne źródło)
(z en.wiki 755248402)
Linia 1: Linia 1:
{{Infobox drug
{{Dopracować|więcej przypisów=2010-12}}
| Watchedfields =
{{Związek chemiczny infobox
| Verifiedfields =
|nazwa = Amfetamina
| verifiedrevid = 629722425
|1. grafika = Amphetamine-2D-skeletal.svg
| INN = Amfetamine
|opis 1. grafiki =
| image = Racemic amphetamine 2.svg
|2. grafika = Amphetamine2.png
|opis 2. grafiki =
| alt = An image of the amphetamine compound
| image2 = D-Amphetamine-3D-balls.png
|3. grafika = Amfetamina.wolna.zasada.jpg
| alt2 = A 3d image of the D-amphetamine compound
|opis 3. grafiki = Próbka amfetaminy
| width = 300px
|nazwa systematyczna = 1-fenylopropano-2-azan{{r|acdlabs}}<br />1-fenylopropano-2-amina{{r|acdlabs|PubChem}}<br />1-fenylopropylo-2-amina{{r|acdlabs}}
| width2 = 250px
|nazwy farmaceutyczne = ''Amfetamini sulfas''

|inne nazwy = 2-amino-1-fenylopropan{{r|NIST1}}<br />1-fenylo-2-aminopropan{{r|PubChem}}<br />2-fenylo-1-metyloetyloamina{{r|psc}},<br />α-metylofenyloetyloamina,<br />benzedryna, psychedryna i in.{{r|NIST2}}
<!-- Clinical data -->
|wzór sumaryczny = C<sub>9</sub>H<sub>13</sub>N
| pronounce = {{IPAc-en|audio=En-us-amphetamine.ogg|æ|m|ˈ|f|ɛ|t|ə|m|iː|n}}
|inne wzory =
| tradename = Adderall, Dyanavel&nbsp;XR, Evekeo, [[#Pharmaceutical products|others]]
|masa molowa = 135,21
| Drugs.com = {{Drugs.com|parent|amphetamine}}
|wygląd =
| licence_US = Amphetamine
|SMILES = CC(CC1=CC=CC=C1)N
| pregnancy_US = C
|numer CAS = {{CAS|300-62-9}} (wolna zasada; [[mieszanina racemiczna|racemat]])<br />{{CAS|51-64-9}} ([[Enancjomery|enancjomer]] S)<br />{{CAS|156-34-3}} (enancjomer R)<br />{{CAS|405-41-4}} ([[Chlorowodorki|chlorowodorek]])<br />{{CAS|60-13-9}} ([[Siarczany|siarczan]])
| dependency_liability = [[Physical dependence|Physical]]: none<ref name="NHM-physical dependence">{{cite book | vauthors = 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 | isbn = 9780071481274 | page = 367 | edition = 2nd | chapter = Chapter 15: Reinforcement and Addictive Disorders | quote= While physical dependence and withdrawal occur with some drugs of abuse (opiates, ethanol), these phenomena are not useful in the diagnosis of addiction because they do not occur with other drugs of abuse (cocaine, amphetamine) and can occur with many drugs that are not abused (propranolol, clonidine).}}</ref><br />[[Psychological dependence|Psychological]]: moderate
|PubChem = {{PubChem|3007}}
| addiction_liability = Moderate
|DrugBank = DB00182
| routes_of_administration= Medical: [[Oral route|oral]], [[intravenous]]<ref name="Amph Uses" /><br />Recreational: [[Oral route|oral]], [[Insufflation (medicine)|insufflation]], [[Suppository|rectal]], [[intravenous]], [[intramuscular administration|intramuscular]]
|gęstość = 0,9306
|gęstość źródło = {{r|CRC}}
| class = {{abbr|CNS|central nervous system}} [[stimulant]]
| ATC_prefix = N06
|stan skupienia w podanej g = ciecz
| ATC_suffix = BA01
|g warunki niestandardowe =

|rozpuszczalność w wodzie = 15 g/l oraz wody w amfetaminie 170 g/l
<!--Legal status-->
|rww źródło =
| legal_AU = Schedule 8
|rww warunki niestandardowe =
| legal_CA = Schedule I
|inne rozpuszczalniki = [[chloroform]], [[etanol]], słabo w [[eter dietylowy|eterze]]{{r|CRC}}
| legal_DE = Anlage III
|temperatura topnienia = 27
|tt źródło =
| legal_NZ = Class B
| legal_UK = Class B
|tt warunki niestandardowe =
|temperatura wrzenia = 203
| legal_US = Schedule II
| legal_UN = Psychotropic Schedule II
|tw źródło = {{r|CRC}}
| legal_status =
|tw warunki niestandardowe =

|temperatura krytyczna =
<!--Pharmacokinetic data-->
|tk źródło =
| bioavailability = {{nowrap|Oral 75–100%}}<ref name="Drugbank-dexamph" />
|ciśnienie krytyczne =
| protein_bound = 15–40%<ref name="Drugbank-amph" />
|ck źródło =
| metabolism = [[CYP2D6]],<ref name="FDA Pharmacokinetics" /> [[Dopamine β-hydroxylase|DBH]],<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="DBH amph primary" /> [[Flavin-containing monooxygenase 3|FMO3]]<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="FMO" /><ref name="FMO3-Primary" />
|logP = 1,76{{r|CRC-logP}}
| metabolites = {{nowrap|[[4-hydroxyamphetamine]]}}, {{nowrap|[[4-hydroxynorephedrine]]}}, {{nowrap|[[4-hydroxyphenylacetone]]}}, [[benzoic acid]], [[hippuric acid]], [[norephedrine]], [[phenylacetone]]<ref name="FDA Pharmacokinetics" /><ref name="Pubchem Kinetics"/><ref name="Metabolites"/>
|kwasowość = 10,1
| onset = {{abbr|IR|Immediate release}} dosing: 30–60&nbsp;minutes<ref name="Medscape Adderall Pharmacology">{{Cite encyclopedia|title = amphetamine/dextroamphetamine | section = Pharmacology |section-url = http://reference.medscape.com/drug/adderall-amphetamine-%20%20dextroamphetamine-342997#10 | website = Medscape | publisher = WebMD | accessdate = 21 January 2016 | quote = Onset of action: 30–60 min }}</ref><br />{{abbr|XR|Extended release}} dosing: 1.5–2&nbsp;hours<ref name="Millichap: onset, peak, and duration">{{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 = 112 | edition = 2nd | chapter = Chapter 9: Medications for ADHD | quote = <br />Table 9.2 Dextroamphetamine formulations of stimulant medication<br />Dexedrine [Peak:2–3&nbsp;h] [Duration:5–6&nbsp;h]&nbsp;...<br />Adderall [Peak:2–3&nbsp;h] [Duration:5–7&nbsp;h]<br />Dexedrine spansules [Peak:7–8&nbsp;h] [Duration:12&nbsp;h]&nbsp;...<br />Adderall XR [Peak:7–8&nbsp;h] [Duration:12&nbsp;h]<br />Vyvanse [Peak:3–4&nbsp;h] [Duration:12&nbsp;h]}}</ref><ref name="XR onset-duration">{{cite journal | vauthors = Brams M, Mao AR, Doyle RL | title = Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder | journal = Postgrad. Med. | volume = 120 | issue = 3 | pages = 69–88 | date = September 2008 | pmid = 18824827 | doi = 10.3810/pgm.2008.09.1909}}</ref>
|zasadowość =
| elimination_half-life = {{abbr|D-amph|Dextroamphetamine}}: 9–11&nbsp;hours<ref name="FDA Pharmacokinetics" /><ref name="Adderall IR" /><br />{{nowrap|{{abbr|L-amph|Levoamphetamine}}: 11–14&nbsp;hours<ref name="FDA Pharmacokinetics" /><ref name="Adderall IR" />}}<br />[[pH]]-dependent: 8–31&nbsp;hours<ref name="pH-dependent half-lives" />
|lepkość =
| duration_of_action = {{abbr|IR|Immediate release}} dosing: 3–7&nbsp;hours<ref name="Millichap: onset, peak, and duration" /><ref name="Narcolepsy guide">{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–752 | date = October 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 }}</ref><br /> {{abbr|XR|Extended release}} dosing: 12&nbsp;hours<ref name="Millichap: onset, peak, and duration" /><ref name="XR onset-duration" /><ref name="Narcolepsy guide"/>
|l źródło =
| excretion = Primarily [[renal]];<br />[[pH]]-dependent {{nowrap|range: 1–75%}}<ref name="FDA Pharmacokinetics" />
|l warunki niestandardowe =

|napięcie powierzchniowe =
<!--Identifiers-->
|np źródło =
| IUPAC_name = <center>(''RS'')-1-phenylpropan-2-amine</center>
|np warunki niestandardowe =
| synonyms = α-methylphenethylamine
|układ krystalograficzny =
| CAS_number_Ref = {{cascite|correct|CAS}}
|moment dipolowy =
|moment dipolowy źródło =
| CAS_number = 300-62-9
| PubChem = 3007
|karta charakterystyki = {{Sigma-Aldrich|link=tak|A1263|Sigma}}
| IUPHAR_ligand = 4804
|zagrożenia GHS źródło = MSDS
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
|piktogram GHS = {{Piktogram GHS|06}}
|hasło GHS = Dgr
| DrugBank = DB00182
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
|zwroty H = {{Zwroty H|301}}
| ChemSpiderID = 13852819
|zwroty EUH = {{Zwroty EUH|brak}}
|zwroty P = {{Zwroty P|301+310}}
| UNII_Ref = {{fdacite|correct|FDA}}
|zagrożenia UE źródło = MSDS
| UNII = CK833KGX7E
|piktogram UE = {{Piktogram ostrzegawczy|T}}
| KEGG_Ref = {{keggcite|correct|kegg}}
|zwroty R = {{Zwroty R|25}}
| KEGG = D07445
|zwroty S = {{Zwroty S|45}}
| ChEBI_Ref = {{ebicite|correct|EBI}}
|NFPA 704 = {{NFPA 704|2|0|0}}
| ChEBI = 2679
|NFPA 704 źródło = {{r|SA-US}}
| ChEMBL_Ref = {{ebicite|correct|EBI}}
|temperatura zapłonu = <100
| ChEMBL = 405
| NIAID_ChemDB = 018564
|tz źródło = {{r|CRC-Fl}}
| PDB_ligand = FRD
|tz warunki niestandardowe = otwarty tygiel

|temperatura samozapłonu =
<!--Chemical and physical data-->
|ts źródło =
| C=9 | H=13 | N=1
|ts warunki niestandardowe =
| molecular_weight = 135.20622&nbsp;g/mol<ref name="PubChem Header" />
|numer RTECS = SH9450000
| chirality = [[Racemic mixture]]<ref name="Proper definition" />
|dawka śmiertelna = LD<sub>50</sub> 45 mg/kg (mysz, doustnie)
| density = .913
|pochodne = [[benzfetamina]], [[bupropion]], [[efedryna]], [[fentermina]], [[metylofenidat]], [[metylokatynon]], [[propylheksedryna]], [[3,4-Metylenodioksymetamfetamina|MDMA]], [[metamfetamina]], [[3,4-Metylenodioksyamfetamina|MDA]], [[2,5-Dimetoksy-4-metyloamfetamina|DOM]], [[2,5-Dimetoksy-4-bromoamfetamina|DOB]]
| density_notes = at 25&nbsp;°C<ref name="PubChem - amphetamine density">{{cite encyclopedia | title=Amphetamine | section = Density | url = https://pubchem.ncbi.nlm.nih.gov/compound/amphetamine | section-url=https://pubchem.ncbi.nlm.nih.gov/compound/amphetamine#section=Density | work=PubChem Compound | publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=9 November 2016 | date=5 November 2016}}</ref>
|podobne związki =
| melting_point = 11.3
|ATC = [[ATC (N06)|N06BA01]], [[ATC (N06)|N06BA02]]
| melting_notes = (predicted)<ref name="Chemspider">{{cite encyclopedia | section-url=http://www.chemspider.com/Chemical-Structure.13852819.html | work=ChemSpider | publisher = Royal Society of Chemistry | title=Amphetamine | accessdate=6 November 2013 | section=Properties: Predicted – EPISuite }}</ref>
|legalność w Polsce = II-P
| boiling_point = 203
|stosowanie w ciąży =
| boiling_notes = at 760&nbsp;[[Millimeter of mercury|mmHg]]<ref name="Properties" />
|działanie =
|procent wchłaniania =
| smiles = NC(CC1=CC=CC=C1)C
| StdInChI = 1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3
|biodostępność = 20–25% (doustnie), 75% (donosowo), 95–99% (doodbytniczo), 100% (dożylnie)
| StdInChIKey = KWTSXDURSIMDCE-UHFFFAOYSA-N
|okres półtrwania = 10 h dla [[konfiguracja absolutna#Konwencje nazewnicze konfiguracji absolutnej|<small>D</small>-izomeru]]{{r|ess}}, 13 h dla [[konfiguracja absolutna#Konwencje nazewnicze konfiguracji absolutnej|<small>L</small>-izomeru]]{{r|ess}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|wiązanie z białkami osocza = 15–40%
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
|metabolizm = [[wątroba|wątrobowy]]
|wydalanie = z [[mocz]]em
|drogi podawania = doustnie, donosowo, doodbytniczo, dożylnie, podjęzykowo, wziewnie
|objętość dystrybucji =
|commons = Category:Amphetamine
|wikisłownik = amfetamina
}}
}}
'''Amfetamina''' – [[Związki organiczne|organiczny związek chemiczny]], metylowa pochodna [[2-Fenyloetyloamina|2-fenyloetyloaminy]]. Jest rozpowszechnionym nielegalnym [[substancja psychoaktywna|środkiem psychotropowym]]. W Polsce, jak i w wielu innych krajach, posiadanie i rozpowszechnianie amfetaminy jest [[przestępstwo|przestępstwem]]. W Polsce amfetamina została wykreślona z lekospisu{{r|bazyl.karnet.waw}}. W wielu innych krajach jest jednak nadal stosowana jako lek. W amerykańskim ''[[Controlled Substances Act]]'' zaliczona jest do środków z grupy II, czyli&nbsp;o&nbsp;dużym ryzyku nadużywania i pewnym, jednak niewielkim, zastosowaniu medycznym (lek na receptę).


'''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" }} (contracted from {{nowrap|[[Alpha and beta carbon|'''a'''lpha]]‑[[methylphenethylamine|'''m'''ethyl'''ph'''en'''et'''hyl'''amine''']]}}) is a [[Potency (pharmacology)|potent]] [[central nervous system]] (CNS) [[stimulant]] that is used in the treatment of [[attention deficit hyperactivity disorder]] (ADHD), [[narcolepsy]], and [[obesity]]. Amphetamine was discovered in 1887 and exists as two [[enantiomer]]s:{{#tag:ref|Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.<ref name="Enantiomers">{{cite 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=https://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"}} [[levoamphetamine]] and [[dextroamphetamine]]. ''Amphetamine'' properly refers to a specific chemical,<!--REFS:<ref name="MeSHAmphetamine" /> --> the [[Racemic mixture|racemic]] [[free base]],<!--REFS:<ref name="WHO INN active moiety" /><ref name="Proper definition" />--> which is equal parts of the two enantiomers, 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 and depression. Amphetamine is also used as an [[Performance-enhancing substance|athletic performance enhancer]] and [[Nootropic|cognitive enhancer]], and recreationally as an [[aphrodisiac]] and [[Euphoria#Euphoriant|euphoriant]]. It is a [[prescription drug]] in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with [[recreational drug use|recreational use]].{{#tag:ref|<ref name="Amph Uses" /><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 = https://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 [''amphetamines''] can even embrace a large number of structurally and pharmacologically related substances.}}</ref><ref name="Malenka_2009" /><ref name="Ergogenics" /><ref name="FDA Abuse & OD" /><ref name="Benzedrine" /><ref name="UN Convention" /><ref name="Nonmedical" /><ref name="Libido" /><ref name="MeSHAmphetamine">{{cite web | title = Amphetamine | url = https://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?mode=&term=Amphetamine | work = Medical Subject Headings | publisher = United States 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="Evekeo" />|group="sources"}}
== Budowa cząsteczki ==
Amfetamina może być traktowana jako 2-fenyloetyloamina zawierająca w pozycji α dodatkową [[Grupa alkilowa|grupę metylową]]. W efekcie węgiel α stanowi [[centrum stereogeniczne]], a amfetamina może występować w formie dwóch [[enancjomery|enancjomerów]]: 2''S'', czyli [[dekstroamfetamina|dekstroamfetaminy]] (<small>D</small>-amfetaminy{{r|PubChemD}}) i 2''R'', czyli [[lewoamfetamina|lewoamfetaminy]] (<small>L</small>-amfetaminy{{r|PubChemL}}), różniących się działaniem fizjologicznym. Izomer prawoskrętny dwukrotnie mocniej uwalnia [[noradrenalina|noradrenalinę]], jednak czterokrotnie słabiej blokuje jej [[wychwyt zwrotny]]. Zwykły produkt syntetyczny jest [[mieszanina racemiczna|mieszaniną racemiczną]] obu enancjomerów.


The first pharmaceutical amphetamine was [[History of Benzedrine|Benzedrine]], a brand which was used to treat a variety of conditions. Currently, pharmaceutical amphetamine is prescribed as racemic amphetamine, [[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 = https://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=16 December 2013}}</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 [[Monoamine neurotransmitter|monoamine]] and [[Neurotransmitter#Excitatory and inhibitory|excitatory neurotransmitter]] activity in the brain, with its most pronounced effects targeting the [[catecholamine]] neurotransmitters [[norepinephrine]] and [[dopamine]].{{#tag:ref|<ref name="Amph Uses" /><ref name="Adderall IR" /><ref name="Malenka_2009" /><ref name="Benzedrine" /><ref name="Evekeo" /><ref name="Miller" /><ref name="Miller+Grandy 2016" />|group="sources"}}
== Otrzymywanie ==
Amfetaminę stosunkowo łatwo można otrzymać jako mieszaninę racemiczną, na przykład:
* W [[reakcja Leuckarta|reakcji Leuckarta]], czyli [[redukcja (chemia)|redukcyjnego]] [[aminowanie|aminowania]] [[fenyloaceton|benzylometyloketonu]] [[formamid]]em w obecności [[kwas mrówkowy|kwasu mrówkowego]].
* Przez [[kondensacja (chemia)|kondensację]] [[aldehyd benzoesowy|aldehydu benzoesowego]] z [[nitroetan]]em w obecności [[butyloamina|''n''-butyloaminy]] i redukcję powstałego [[β-Nitrostyren|β-nitrostyrenu]] [[tetrahydroglinian litu|glinowodorkiem litu]] do amfetaminy w bezwodnym [[Tetrahydrofuran|THF]] lub [[eter dietylowy|eterze dietylowym]].


At therapeutic doses, amphetamine causes emotional and cognitive effects such as [[euphoria]], change in [[libido|desire for sex]], increased [[wakefulness]], and improved [[Executive functions|cognitive control]]. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce [[Rhabdomyolysis|rapid muscle breakdown]]. [[Addiction|Drug addiction]] is a serious risk with large recreational doses but is unlikely to arise from typical long-term medical use at therapeutic doses. 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="Adderall IR" /><ref name="Malenka_2009" /><ref name="Ergogenics" /><ref name="FDA Abuse & OD" /><ref name="Libido" /><ref name="FDA Effects" /><ref name="Westfall" /><ref name="Cochrane" /><ref name="Stimulant Misuse" /><ref name="NHM-Addiction doses" /><ref name="Addiction risk" /><ref name="EncycOfPsychopharm" />|group="sources"}}
Sole amfetaminy uzyskuje się w wyniku [[reakcja zobojętniania|reakcji zobojętniania]] wolnej aminy z odpowiednim kwasem w roztworze (na przykład etanolowym lub propanolowym).


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


{{TOC limit|3}}
[[Plik:Amphetamine Synthesis V.1.svg|550px|Synteza]]


==Uses==
== Właściwości ==
=== Właściwości fizyczne ===
Wolna [[zasady|zasada]] w temperaturze pokojowej jest [[higroskopijność|higroskopijną]], bezbarwną cieczą o silnie zasadowych właściwościach. Na gorąco matowi [[szkło sodowe]] oraz niszczy [[guma|gumę]]. Ma nieprzyjemny i charakterystyczny „mysi” zapach.


===Medical===
W celu zwiększenia trwałości amfetaminę przeprowadza się w sole z różnymi kwasami. Są one białymi proszkami o gorzkim smaku:
<onlyinclude>{{#ifeq:{{{transcludesection|Medical uses}}}|Medical uses|
* [[Siarczany|siarczan]] amfetaminy ({{chem|C|9|H|13|N}})<sub>2</sub>·{{chem|H|2|SO|4}} (rozpuszczalność w wodzie 110 g/l w 20 °C)
{{if pagename
* [[chlorowodorki|chlorowodorek]] amfetaminy {{chem|C|9|H|13|N}}·HCl ([[higroskopijność|higroskopijny]])
| Amphetamine = Amphetamine is used to treat [[attention deficit hyperactivity disorder]] (ADHD), [[narcolepsy]] (a sleep disorder), and [[obesity]], and is sometimes prescribed {{nowrap|[[off-label]]}} for its past [[Indication (medicine)|medical indications]], such as [[treatment-resistant depression|depression]].<ref name="Amph Uses" /><ref name="Adderall IR">{{cite web | title=Adderall IR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011522s042lbl.pdf | publisher = Teva Pharmaceuticals USA, Inc. | work = United States Food and Drug Administration | date=October 2015 | accessdate=18 May 2016 | pages=1–6}}</ref><ref name="Evekeo" />
* [[fosforany|wodorofosforan]] diamfetaminy ({{chem|C|9|H|13|N}})<sub>2</sub>·{{chem|H|3|PO|4}} (rozpuszczalny w wodzie lepiej niż siarczan)
| other = }}<!--
* [[kwas winowy|winian]] diamfetaminy ({{chem|C|9|H|13|N}})<sub>2</sub>·{{chem|C|4|H|6|O|6}} (rozpuszczalny w wodzie lepiej niż siarczan)
--> Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal [[Dopamine receptor|dopamine system]] development or nerve damage,<ref name="pmid22392347" /><ref name="AbuseAndAbnormalities">{{cite journal|vauthors=Berman S, O'Neill J, Fears S, Bartzokis G, London ED | title=Abuse of amphetamines and structural abnormalities in the brain | journal=Ann. N. Y. Acad. Sci. | date = October 2008 | volume= 1141 | issue= | pages= 195–220 | pmid=18991959 | doi=10.1196/annals.1441.031 | pmc=2769923 }}</ref> but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.<ref name="Neuroplasticity 1">{{cite journal |vauthors=Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K |title=Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects |journal=JAMA Psychiatry |volume=70 |issue=2 |pages=185–198 |date=February 2013 |pmid=23247506 |doi=10.1001/jamapsychiatry.2013.277 |url=}}</ref><ref name="Neuroplasticity 2">{{cite journal |vauthors=Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J |title=Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies |journal=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 |vauthors=Frodl T, Skokauskas N | quote = Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure. | doi=10.1111/j.1600-0447.2011.01786.x}}</ref> Reviews of [[magnetic resonance imaging]] (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right [[caudate nucleus]] of the [[basal ganglia]].<ref name="Neuroplasticity 1" /><ref name="Neuroplasticity 2" /><ref name="Neuroplasticity 3" />


Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.<ref name="Millichap" /><ref name="Long-term 2015">{{cite journal | vauthors = Arnold LE, Hodgkins P, Caci H, Kahle J, Young S | title = Effect of treatment modality on long-term outcomes in attention-deficit/hyperactivity disorder: a systematic review | journal = PLoS ONE | volume = 10 | issue = 2 | pages = e0116407 | date = February 2015 | pmid = 25714373 | pmc = 4340791 | doi = 10.1371/journal.pone.0116407 | quote = The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.&nbsp;... All reported long-term outcomes were organized into 9 main categories/domains based on common characteristics: 1) academic (e.g., achievement test scores, grades, length of education, repeated grades, education level), 2) antisocial behavior (e.g., school expulsion, delinquency, police contacts, arrests, convictions, incarceration, self-reported crimes, types or severity of offenses, age at first incident, repeat convictions), 3) driving (e.g., traffic violations, automobile accidents, license status, driving simulation rating), 4) non-medicinal drug use/addictive behavior (e.g., substance use, abuse, and/or dependence—from caffeine to illicit drugs; age at initiation; quitting substance use; amount of substance used; non-substance addictions such as gambling), 5) obesity (body mass index, weight), 6) occupation (e.g., employment, military service, income/debt, job performance, job loss/changes, occupation level, socioeconomic status), 7) services use (e.g., school services, health services, emergency room visits, work-related services, financial assistance, justice system), 8) self-esteem (self-esteem questionnaires, suicide ideation, suicide attempts, suicide rate), and 9) social function (e.g., peer, family, and romantic relationships; peer nomination scores; marital status; divorce rate, social skills, living arrangements, activities/hobbies).}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340791/figure/pone.0116407.g003/ Figure 3: Treatment benefit by treatment type and outcome group]</ref><ref name="Long-Term Outcomes Medications">{{cite journal |vauthors=Huang YS, Tsai MH | title = Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge | journal = CNS Drugs | volume = 25 | issue = 7 | pages = 539–554 |date=July 2011 | pmid = 21699268 | doi = 10.2165/11589380-000000000-00000 | quote = Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.}}</ref> [[Randomized controlled trial]]s of continuous stimulant therapy for the treatment of ADHD spanning two years have demonstrated treatment effectiveness and safety.<ref name="Millichap" /><ref name="Long-Term Outcomes Medications" /> Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing [[quality of life]] and academic achievement, and producing improvements in a large number of functional outcomes{{#tag:ref|The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (~55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (~65% of obesity-related outcomes improved), self esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved).<ref name="Long-term 2015" /> The largest [[effect size]]s for outcome improvements from long-term stimulant therapy occurs in the domains involving academics (e.g., [[grade point average]], achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).<ref name="Long-term 2015" /><br /><br />Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.<ref name="Long-term 2015" />|group="note"}} across nine outcome categories related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.<ref name="Long-term 2015" /><ref name="Long-Term Outcomes Medications" /> 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, continued increases in attention, and continued decreases in 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 9: Medications for ADHD | quote = Ongoing research has provided answers to many of the parents’ concerns, and has confirmed the effectiveness and safety of the long-term use of medication.}}</ref> Another review indicated that, based upon the longest [[Prospective cohort study|follow-up studies]] conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a [[substance use disorder]] as an adult.<ref name="Long-Term Outcomes Medications" />
=== Właściwości chemiczne ===
Pozostawiona na powietrzu ciemnieje, reagując z tlenem (tworząc polimeryczne produkty) i dwutlenkiem węgla, tworząc stałą [[mieszanina racemiczna|mieszaninę racemiczną]] [[higroskopijność|higroskopijnego]] [[karbaminian amfetaminy|karbaminianu (±)-amfetaminy]], który pod wpływem wilgoci przechodzi w [[węglan amfetaminy]] (dlatego przechowuje się ją w ciemnych butelkach napełnionych argonem lub azotem).


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 |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, 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 |vauthors=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;80% of those who use these stimulants see improvements in ADHD symptoms.<ref name="Long-term 36">{{cite journal | vauthors = Parker J, Wales G, Chalhoub N, Harpin V | title = The long-term outcomes of interventions for the management of attention-deficit hyperactivity disorder in children and adolescents: a systematic review of randomized controlled trials | journal = Psychol. Res. Behav. Manag. | volume = 6 | issue = | pages = 87–99 | date = September 2013 | pmid = 24082796 | pmc = 3785407 | doi = 10.2147/PRBM.S49114 | quote = Only one paper<sup>53</sup> examining outcomes beyond 36 months met the review criteria.&nbsp;... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term.}}</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 9: Medications for ADHD}}</ref><ref name="ADHD">{{cite web | title=Stimulants for Attention Deficit Hyperactivity Disorder | url=http://www.webmd.com/add-adhd/childhood-adhd/stimulants-for-attention-deficit-hyperactivity-disorder | work = WebMD | publisher = Healthwise | date = 12 April 2010 | accessdate=12 November 2013 }}</ref> The [[Cochrane Collaboration]]'s reviews{{#tag:ref|Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.<ref name="pmid16052183">{{cite journal |vauthors=Scholten RJ, Clarke M, Hetherington J |title=The Cochrane Collaboration |journal=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 ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that while these drugs 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 |vauthors=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 |date=June 2011 |pmid=21678370 |doi=10.1002/14651858.CD007813.pub2 |url= |editor=Castells X }}</ref><ref name="pmid26844979">{{cite journal | vauthors = Punja S, Shamseer L, Hartling L, Urichuk L, Vandermeer B, Nikles J, Vohra S | title = Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents | journal = Cochrane Database Syst. Rev. | volume = 2 | issue = | pages = CD009996 | date = February 2016 | pmid = 26844979 | doi = 10.1002/14651858.CD009996.pub2 | quote = }}</ref> A Cochrane Collaboration review on the treatment of ADHD in children with [[tic disorder]]s such as [[Tourette syndrome]] indicated that stimulants in general do not make [[tic]]s worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.<ref>{{cite journal|vauthors=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>
=== Właściwości biologiczne ===
}}</onlyinclude>
Izomer o [[konfiguracja absolutna|absolutnej konfiguracji]] ''S''-(+)-amfetaminy wykazuje działanie [[euforia|euforyzujące]], zaś izomer ''R''-(−) ma działanie bardziej obwodowe wykazując szkodliwe działanie na [[serce]]. Powoduje zmiany w obrazie [[Elektrokardiografia|EKG]] charakterystyczne dla [[zawał mięśnia sercowego|zawału mięśnia sercowego]].


===Enhancing performance===
Izomer ''S'' desynchronizuje [[półkula mózgu|półkule mózgowe]] oraz wywołuje zmiany w obrazie [[elektroencefalografia|EEG]] mózgu, które po jednokrotnym zażyciu mogą utrzymywać się nawet do miesiąca. Czysty izomer ''S'' amfetaminy jest nieopłacalny do uzyskania w drodze [[synteza totalna|totalnej syntezy]] i ma on działanie bardzo podobne do [[kokaina|kokainy]].
<onlyinclude>{{#ifeq:{{{transcludesection|Enhancing performance}}}|Enhancing performance|
In 2015, a [[systematic review]] and a [[meta-analysis]] of high quality [[clinical trial]]s found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including [[working memory]], long-term [[episodic memory]], [[inhibitory control]], and some aspects of [[Attention#Clinical model|attention]], in normal healthy adults;<ref name="Unambiguous PFC D1 A2">{{cite journal | vauthors = Spencer RC, Devilbiss DM, Berridge CW | title = The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex | journal = Biol. Psychiatry | volume = 77 | issue = 11 | pages = 940–950 | year = June 2015 | pmid = 25499957 | doi = 10.1016/j.biopsych.2014.09.013 | quote = The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors.&nbsp;... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.&nbsp;... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.}}</ref><ref name="Cognitive and motivational effects">{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = J. Cogn. Neurosci. | volume = | issue = | pages = 1–21 | date = January 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | quote = Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities.&nbsp;... The results of this meta-analysis&nbsp;... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.}}</ref> the cognition-enhancing effects of amphetamine are known to occur through its [[indirect agonist|indirect activation]] of both [[dopamine receptor D1|dopamine receptor D<sub>1</sub>]] and [[Alpha-2 adrenergic receptor|adrenoceptor α<sub>2</sub>]] in the [[prefrontal cortex]].<ref name="Malenka_2009" /><ref name="Unambiguous PFC D1 A2" /> A systematic review from 2014 found that low doses of amphetamine also improve [[memory consolidation]], in turn leading to improved [[Recall (memory)|recall of information]].<ref name="Cognition enhancement 2014 systematic review">{{cite journal | vauthors = Bagot KS, Kaminer Y | title = Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review | journal = Addiction | volume = 109 | issue = 4 | pages = 547–557 | date = April 2014 | pmid = 24749160 | pmc = 4471173 | doi = 10.1111/add.12460 | quote = Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall.}}</ref> Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.<ref name="Malenka_2009" /><ref name="pmid11337538">{{cite journal |vauthors=Devous MD, Trivedi MH, Rush AJ |title=Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers |journal=J. Nucl. Med. |volume=42 |issue=4 |pages=535–542 |date=April 2001 |pmid=11337538 |doi= |url=}}</ref> Amphetamine and other ADHD stimulants also improve [[Incentive salience|task saliency]] (motivation to perform a task) and increase [[arousal]] (wakefulness), in turn promoting goal-directed behavior.<ref name="Malenka_2009" /><ref name="Malenka NAcc">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, 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><ref name="Continuum">{{cite journal |vauthors=Wood S, Sage JR, Shuman T, Anagnostaras SG |title=Psychostimulants and cognition: a continuum of behavioral and cognitive activation |journal=Pharmacol. Rev. |volume=66 |issue=1 |pages=193–221 |date=January 2014 |pmid=24344115 |doi=10.1124/pr.112.007054 |url=}}</ref> Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.<ref name="Malenka_2009">{{cite book|vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | pages = 318, 321 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control | quote = Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks&nbsp;... through indirect stimulation of dopamine and norepinephrine receptors.&nbsp;...<br />Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention. Drugs used for this purpose include, as stated above, methylphenidate, amphetamines, atomoxetine, and desipramine.}}</ref><ref name="Continuum" /><ref name="Test taking aid">{{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 = https://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, 5–35% of college students use [[drug diversion|diverted]] ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs.<ref name="pmid16999660">{{cite journal |vauthors=Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ | title = Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration | journal = Pharmacotherapy | volume = 26 | issue = 10 | pages = 1501–1510 |date=October 2006 | pmid = 16999660 | pmc = 1794223 | doi = 10.1592/phco.26.10.1501 }}</ref><ref name="Diversion prevalence 1">{{cite journal | vauthors = Weyandt LL, Oster DR, Marraccini ME, Gudmundsdottir BG, Munro BA, Zavras BM, Kuhar B | title = Pharmacological interventions for adolescents and adults with ADHD: stimulant and nonstimulant medications and misuse of prescription stimulants | journal = Psychol. Res. Behav. Manag. | volume = 7 | issue = | pages = 223–249 | date = September 2014 | pmid = 25228824 | pmc = 4164338 | doi = 10.2147/PRBM.S47013 | quote = misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well.&nbsp;... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students.}}</ref><ref name="Diversion prevalence 2">{{cite journal | vauthors = Clemow DB, Walker DJ | title = The potential for misuse and abuse of medications in ADHD: a review | journal = Postgrad. Med. | volume = 126 | issue = 5 | pages = 64–81 | date = September 2014 | pmid = 25295651 | doi = 10.3810/pgm.2014.09.2801 | quote = Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.}}</ref> However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.<ref name="Malenka_2009" /><ref name="Continuum" />


Amphetamine is used by some athletes for its psychological and [[ergogenic aid|athletic performance-enhancing effects]], such as increased endurance and alertness;<ref name="Ergogenics">{{cite journal |vauthors=Liddle DG, Connor DJ | title = Nutritional supplements and ergogenic AIDS | journal = 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 />{{•}}Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation<br />{{•}}Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40<br />{{•}}Improved reaction time<br />{{•}}Increased muscle strength and delayed muscle fatigue<br />{{•}}Increased acceleration<br />{{•}}Increased alertness and attention to task}}</ref><ref name="Westfall" /> however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.<ref name="NCAA">{{cite web |date=January 2012 | 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|muscle strength]],<!--Refs:"Ergogenics" & "Ergogenics2"--> acceleration,<!--Refs:"Ergogenics" & "Ergogenics2"--> athletic performance in [[anaerobic exercise|anaerobic conditions]],<!--Refs:"Ergogenics" & "Ergogenics2"--> and [[endurance]] (i.e., it delays the onset of [[fatigue (medical)|fatigue]]),<!--Refs:"Ergogenics" & "Ergogenics2" & "Roelands_2013"--> while improving [[mental chronometry|reaction time]].<ref name="Ergogenics" /><ref name="Ergogenics2" /><ref name="Roelands_2013" /> Amphetamine improves endurance and reaction time primarily through [[Reuptake inhibitor|reuptake inhibition]] and [[Releasing agent|effluxion]] of dopamine in the central nervous system.<ref name="Ergogenics2" /><ref name="Roelands_2013">{{cite journal |vauthors=Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R | title = Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing | journal = Sports Med. | volume = 43 | issue = 5 | pages = 301–311 |date=May 2013 | pmid = 23456493 | doi = 10.1007/s40279-013-0030-4 | quote = In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo.&nbsp;... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is ‘off-limits’ in a normal (placebo) situation.}}</ref><ref name="Amph-DA reaction time">{{cite journal |vauthors=Parker KL, Lamichhane D, Caetano MS, Narayanan NS | title = Executive dysfunction in Parkinson's disease and timing deficits | journal = Front. Integr. Neurosci. | volume = 7 | page = 75 | date = October 2013 | pmid = 24198770 | pmc = 3813949 | doi = 10.3389/fnint.2013.00075 | quote = Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or “clock,” activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing. }}</ref> Amphetamine and other dopaminergic drugs also increase power output at fixed [[rating of perceived exertion|levels of perceived exertion]] by overriding a "safety switch" that allows the [[Human body temperature|core temperature limit]] to increase in order to access a reserve capacity that is normally off-limits.<ref name="Roelands_2013" /><ref name="Central mechanisms affecting exertion">{{cite journal | vauthors = Rattray B, Argus C, Martin K, Northey J, Driller M | title = Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance? | journal = Front. Physiol. | volume = 6 | issue = | pages = 79 | date = March 2015 | pmid = 25852568 | pmc = 4362407 | doi = 10.3389/fphys.2015.00079 | quote = Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009).&nbsp;... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)}}</ref><ref name="Monoamine+drug effects on exercise - fatigue and heat">{{cite journal | vauthors = Roelands B, De Pauw K, Meeusen R | title = Neurophysiological effects of exercise in the heat | journal = Scand. J. Med. Sci. Sports | volume = 25 Suppl 1 | issue = | pages = 65–78 | date = June 2015 | pmid = 25943657 | doi = 10.1111/sms.12350 | url = http://onlinelibrary.wiley.com/doi/10.1111/sms.12350/epdf | accessdate = 10 March 2016 | quote = Physical fatigue has classically been attributed to peripheral factors within the muscle (Fitts, 1996), the depletion of muscle glycogen (Bergstrom & Hultman, 1967) or increased cardiovascular, metabolic, and thermoregulatory strain (Abbiss & Laursen, 2005; Meeusen et al., 2006b). In recent decennia however, it became clear that the central nervous system plays an important role in the onset of fatigue during prolonged exercise (Klass et al., 2008), certainly when ambient temperature is increased&nbsp;... 5-HT, DA, and NA have all been implicated in the control of thermoregulation and are thought to mediate thermoregulatory responses, certainly since their neurons innervate the hypothalamus (Roelands & Meeusen, 2010).&nbsp;... This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the “safety switch” or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.&nbsp;... The combined effects of DA and NA on performance in the heat were studied by our research group on a number of occasions.&nbsp;... the administration of bupropion (DA/NA reuptake inhibitor) significantly improved performance. Coinciding with this ergogenic effect, the authors observed core temperatures that were much higher compared with the placebo situation. Interestingly, this occurred without any change in the subjective feelings of thermal sensation or perceived exertion. Similar to the methylphenidate study (Roelands et al., 2008b), bupropion may dampen or override inhibitory signals arising from the central nervous system to cease exercise because of hyperthermia, and enable an individual to continue maintaining a high power output}}</ref> At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;<ref name="Ergogenics" /><ref name="Ergogenics2" /> however, at much higher doses, amphetamine can induce effects that severely impair performance, such as [[rhabdomyolysis|rapid muscle breakdown]] and [[hyperthermia|elevated body temperature]].<ref name="FDA 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 |quote=In 1980, Chandler and Blair<sup>47</sup> showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.&nbsp;... In 2008, Roelands and colleagues<sup>53</sup> studied the effect of reboxetine, a pure NE reuptake inhibitor, similar to atomoxetine, in 9 healthy, well-trained cyclists. They too exercised in both temperate and warm environments. They showed decreased power output and exercise performance at both 18 and 30 degrees centigrade. Their conclusion was that DA reuptake inhibition was the cause of the increased exercise performance seen with drugs that affect both DA and NE (MPH, amphetamine, and bupropion).}}</ref>
Metabolizowana jest głównie odmiana ''S'' do [[fenyloaceton]]u (o drażniącym działaniu) i [[4-Metoksyamfetamina|''p''-metoksyamfetaminy]] (o działaniu psychotropowym i wywołującym [[psychoza|psychozy]]). Reszta (czyli właściwie odmiana ''R''), wydalana jest w stanie niezmienionym.
}}</onlyinclude>


==Contraindications==
==== Mechanizm i efekty działania ====
{{see also|Amphetamine#Interactions}}
Po dostaniu się do organizmu amfetamina wzmaga przekaźnictwo noradrenergiczne i dopaminergiczne. Jednocześnie hamuje [[wychwyt zwrotny]] i nasila uwalnianie tych przekaźników, prowadząc do zwiększenia koncentracji, polepszenia funkcji wykonawczych i czuwania (oddziaływanie na obszar górno-boczny [[kora przedczołowa|kory przedczołowej]]) oraz wzmaga nadpobudliwość psychoruchową (wzmożenie aktywności dopaminergicznej na poziomie jąder podstawy). Powyższe działanie znajduje zastosowanie w niektórych krajach w terapii [[ADHD]] i [[narkolepsja|narkolepsji]]{{r|Stahl2008-s7-14}}.
<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. USFDA contraindications are not necessarily intended to limit medical practice but limit claims by pharmaceutical companies.<ref name="pmid8545689">{{cite journal | vauthors = Kessler S | title = Drug therapy in attention-deficit hyperactivity disorder | journal = South. Med. J. | volume = 89 | issue = 1 | pages = 33–38 | date = January 1996 | pmid = 8545689 |quote = statements on package inserts are not intended to limit medical practice. Rather they are intended to limit claims by pharmaceutical companies.&nbsp;... the FDA asserts explicitly, and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations. | doi=10.1097/00007611-199601000-00005}}</ref>|group="note"}} amphetamine is [[contraindicated]] in people with a history of [[drug abuse]],{{#tag:ref|According to one review, amphetamine can be prescribed to individuals with a history of abuse provided that appropriate medication controls are employed, such as requiring daily pick-ups of the medication from the prescribing physician.<ref name="Amph Uses" />|group="note"}} [[cardiovascular disease]], severe [[Irritability|agitation]], or severe anxiety.<ref name="FDA Contra Warnings" /><ref name="International" /> It is also contraindicated in people currently experiencing [[arteriosclerosis]] (hardening of the arteries), [[glaucoma]] (increased eye pressure), [[hyperthyroidism]] (excessive production of thyroid hormone), or moderate to severe [[hypertension]].<ref name="FDA Contra Warnings" /><ref name="International">{{cite web |vauthors=Heedes G, Ailakis J | title=Amphetamine (PIM 934) | url=http://www.inchem.org/documents/pims/pharm/pim934.htm | website=INCHEM | publisher=International Programme on Chemical Safety | accessdate=24 June 2014 }}</ref><ref name="Dexedrine FDA" /> People who have experienced [[hypersensitivity|allergic reactions]] to other stimulants in the past or who are taking [[monoamine oxidase inhibitor]]s (MAOIs) are advised not to take amphetamine,<ref name="FDA Contra Warnings" /><ref name="International" /> although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.<ref name="Review MAOI-amph">{{cite journal | vauthors = Feinberg SS | title = Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication | journal = J. Clin. Psychiatry | volume = 65 | issue = 11 | pages = 1520–1524 | date = November 2004 | pmid = 15554766 | quote = | doi=10.4088/jcp.v65n1113}}</ref><ref name="Primary MAOI-amph">{{cite journal | vauthors = Stewart JW, Deliyannides DA, McGrath PJ | title = How treatable is refractory depression? | journal = J. Affect. Disord. | volume = 167 | issue = | pages = 148–152 | date = June 2014 | pmid = 24972362 | doi = 10.1016/j.jad.2014.05.047 | quote = }}</ref> These agencies also state that anyone with [[anorexia nervosa]], [[bipolar disorder]], depression, hypertension, liver or kidney problems, [[mania]], [[psychosis]], [[Raynaud's phenomenon]], [[seizure]]s, [[thyroid]] problems, [[tic]]s, or [[Tourette syndrome]] should monitor their symptoms while taking amphetamine.<ref name="FDA 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 [[Teratology|teratogen]]), but amphetamine abuse does pose risks to the fetus.<ref name="International" /> Amphetamine has also been shown to pass into breast milk, so the IPCS and 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="Millichap" /><ref name="Long-Term Outcomes Medications" /><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 an amphetamine pharmaceutical.<ref name="FDA Contra Warnings" />
}}</onlyinclude>


==Side effects==
Uwalnia [[neuroprzekaźnik]]i z zakończeń nerwowych i blokuje ich wychwyt zwrotny. [[Enancjomery|Enancjomer]] ''R''(−) silniej uwalnia noradrenalinę, enancjomer ''S''(+) uwalnia głównie [[dopamina|dopaminę]], oba enancjomery najsłabiej uwalniają [[serotonina|serotoninę]]. Wskutek tego zwiększa się aktywność układu nerwowego i w efekcie dochodzi do pobudzenia całego [[organizm]]u.
The [[side effect]]s 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|
{| class="wikitable"
|-
!width="500"|Efekty zażycia
!width="500"|Efekty uboczne
|-
| Silne pobudzenie psychomotoryczne, przyśpieszona [[Cykl pracy serca|akcja serca]] i szybki oddech, podwyższone [[ciśnienie tętnicze|ciśnienie krwi]], brak [[głód|łaknienia]] i potrzeby snu, rozszerzenie [[źrenica|źrenic]], bladość [[skóra|skóry]], gonitwa myśli, silna [[euforia]], jadłowstręt i światłowstręt, suchość w ustach, zmniejszona wrażliwość na ból oraz zmęczenie, rozgadanie || Zmniejszony lub zwiększony [[libido|popęd płciowy]], problemy z [[Erekcja (fizjologia)|erekcją]], drżenie [[mięsień|mięśni]], wypłukiwanie [[witaminy|witamin]] z organizmu
|}


== Zastosowanie ==
===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 [[hypertension]] or [[hypotension]] from a [[vasovagal response]], [[Raynaud's phenomenon]] (reduced blood flow to extremities), and [[tachycardia]] (increased heart rate).<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 [[abdominal pain]], [[Anorexia (symptom)|appetite loss]], [[nausea]], and [[weight loss]].<ref name="FDA Effects" /><ref name="Dyanavel">{{cite web|title=Dyanavel XR Prescribing Information|url=http://www.trispharma.com/DXRUSPI.pdf|publisher=Tris Pharmaceuticals|accessdate=23 November 2015|pages=1–16|date=October 2015|quote=DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1&nbsp;... The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6–12 years) were: epistaxis, allergic rhinitis and upper abdominal pain.&nbsp;... <br />DOSAGE FORMS AND STRENGTHS<br />Extended-release oral suspension contains 2.5 mg amphetamine base per mL.}}</ref> Other potential side effects include [[blurred vision]], [[xerostomia|dry mouth]], [[bruxism|excessive grinding of the teeth]], nosebleed, profuse sweating, [[rhinitis medicamentosa]] (drug-induced nasal congestion), reduced [[seizure threshold]], and [[tics]] (a type of movement disorder).{{#tag:ref|<ref name="FDA Effects" /><ref name="Westfall" /><ref name="pmid18295156" /><ref name="Dyanavel" /><ref name="rhinitis">{{cite journal | vauthors = Ramey JT, Bailen E, Lockey RF | title = Rhinitis medicamentosa | journal = J. Investig. Allergol. Clin. Immunol. | volume = 16 | issue = 3 | pages = 148–155 | year = 2006 | pmid = 16784007 | accessdate = 29 April 2015 | url = http://www.jiaci.org/issues/vol16issue03/1.pdf | quote = Table 2. Decongestants Causing Rhinitis Medicamentosa<br /> – Nasal decongestants:<br />&nbsp; – Sympathomimetic:<br />&nbsp;&nbsp; • Amphetamine}}</ref>|group="sources"}} Dangerous physical side effects are rare at typical pharmaceutical doses.<ref name="Westfall" />
Amfetamina jest zażywana przez ludzi w różnych celach:
* jako [[używka]]
* jako [[doping wydolnościowy|środek dopingujący]] w sporcie
* jako środek pobudzający zdolność uczenia
* jako środek wzmacniający podczas długotrwałego wysiłku
* w lecznictwie (np. w Stanach Zjednoczonych w terapii [[ADHD]] i [[narkolepsja|narkolepsji]] w odpowiednio zmniejszonych dawkach)
* w celach odchudzających (wykorzystywanie faktu, iż amfetamina zmniejsza łaknienie)


Amphetamine stimulates the [[Respiratory center|medullary respiratory centers]], producing faster and deeper breaths.<ref name="Westfall">{{cite book |veditors=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 |vauthors=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.<ref name="Westfall" /> This effect can be useful in treating [[enuresis|bed wetting]] and [[urinary incontinence|loss of bladder control]].<ref name="Westfall" /> The effects of amphetamine on the gastrointestinal tract are unpredictable.<ref name="Westfall" /> If intestinal activity is high, amphetamine may reduce [[gastrointestinal motility]] (the rate at which content moves through the digestive system);<ref name="Westfall" /> however, amphetamine may increase motility when the [[smooth muscle tissue|smooth muscle]] of the tract is relaxed.<ref name="Westfall" /> Amphetamine also has a slight [[analgesic]] effect and can enhance the pain relieving effects of [[opioid]]s.<ref name="Westfall" />
== Historia ==
W 1887 roku w Stanach Zjednoczonych po raz pierwszy uzyskano [[Fenylopropanoloamina|fenylopropanolaminę]], pochodną amfetaminy. W 1910 dwóch amerykańskich naukowców opisało amfetaminę jako substancję pobudzającą [[ośrodkowy układ nerwowy]]. W ciągu kilku lat powstał szereg związków o podobnym działaniu. W roku 1927 uzyskano siarczan amfetaminy, który po niecałych 6 latach trafił do [[produkcja masowa|masowej produkcji]]. Amfetamina została zsyntetyzowana w latach 30. XX wieku w USA, a podczas II wojny światowej była powszechnie stosowaną substancją przez wojska wszystkich większych armii, pozwalając żołnierzom pozostać czujnym w okopach. Każdy amerykański żołnierz nosił w swoim [[ekwipunek|ekwipunku]] jedną tabletkę 50 mg benzedryny, którą miał prawo zażyć w sytuacji skrajnego zmęczenia na polu walki, a [[Alianci|alianckim]] załogom bombowców dalekiego zasięgu wydawano amfetaminę w formie „witaminizowanej” czekolady.


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 name="FDA - cardiovascular effects in young individuals">{{cite web | title=FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults | date=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 |vauthors=Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA | title = ADHD drugs and serious cardiovascular events in children and young adults | journal = N. Engl. J. Med. | volume = 365 | issue = 20 | pages = 1896–1904 |date=November 2011 | pmid = 22043968 | doi = 10.1056/NEJMoa1110212 }}</ref><ref name="FDA - cardiovascular effects in adults">{{cite web | title=FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults | date=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 |vauthors=Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA, Selby JV | title = ADHD medications and risk of serious cardiovascular events in young and middle-aged adults |date=December 2011 | journal = JAMA | volume = 306 | issue = 24 | pages = 2673–2683 | pmid = 22161946 | pmc = 3350308 | doi = 10.1001/jama.2011.1830 }}</ref>|group="sources"}} However, amphetamine pharmaceuticals are [[contraindicated]] in individuals with [[cardiovascular disease]].{{#tag:ref|<ref name="FDA Contra Warnings" /><ref name="International" /><ref name="FDA - cardiovascular effects in young individuals" /><ref name="FDA - cardiovascular effects in adults" />|group="sources"}}
Szacuje się, że żołnierze amerykańscy spożyli w czasie II wojny światowej ok. 2 milionów tych tabletek. Badania epidemiologiczne po zakończeniu wojny wykazały pięciokrotny wzrost zachorowań na [[depresja maniakalna|depresję maniakalną]] u żołnierzy, którzy spożywali więcej niż jedną tabletkę benzedryny miesięcznie w stosunku do żołnierzy, którzy nigdy z tych tabletek nie skorzystali.


===Psychological===
Żołnierze sił zbrojnych III Rzeszy otrzymywali z kolei [[metamfetamina|metamfetaminę]] w tabletkach o nazwie ''Pervitim'', w warunkach znacznej przewagi liczebnej [[Armia Czerwona|Armii Czerwonej]] w czasie walk na [[front wschodni (II wojna światowa)|froncie wschodnim]]. ''Pervitim'' był powszechnie wykorzystywany, między innymi znajdował się w ostatnich lotniczych transportach zaopatrzeniowych do oddziałów oblegających [[Bitwa stalingradzka|Stalingrad]].
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 (mood)|anxiety]], change in [[libido]], [[grandiosity]], [[irritability]], repetitive or [[Fixation (psychology)|obsessive]] behaviors, and restlessness;{{#tag:ref|<ref name="Libido">{{cite journal | author = Montgomery KA | title = Sexual desire disorders | journal = Psychiatry (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 | archiveurl=https://web.archive.org/web/20131103155156/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 | archivedate=3 November 2013 | page=20}}</ref> According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.<ref name="FDA Effects" />


Amphetamine has also been shown to produce a [[conditioned place preference]] in humans taking therapeutic doses,<ref name="Cochrane Amphetamines ADHD" /><ref name="Human CPP">{{cite journal | vauthors = Childs E, de Wit H | title = Amphetamine-induced place preference in humans | journal = Biol. Psychiatry | volume = 65 | issue = 10 | pages = 900–904 | date = May 2009 | pmid = 19111278 | pmc = 2693956 | doi = 10.1016/j.biopsych.2008.11.016 | quote = This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.}}</ref> meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.<ref name="Human CPP" /><ref name="Addiction glossary" />
Zapiski lekarza osobistego [[Adolf Hitler|Adolfa Hitlera]] dowodzą, że Hitler również regularnie dostawał zastrzyki z metyloamfetaminy, od 1942 roku aż do śmierci.
}}</onlyinclude>


==Overdose==
Amfetamina była w Stanach Zjednoczonych legalnym lekiem, który można było kupić bez recepty, aż do końca lat 60. XX wieku. Stosowali ją masowo m.in. kierowcy ciężarówek, jednak liczne przypadki śmierci z wyczerpania i powodowanie przez nich wypadków pod wpływem tego leku spowodowały, że amerykańska [[Agencja Żywności i Leków]] zdecydowała się zakazać sprzedaży amfetaminy bez recepty i zaliczyła ją do zabronionych środków pobudzających. Obecnie lek ten jest jeszcze czasami stosowany przy leczeniu głębokich [[Zaburzenia depresyjne|depresji]] i [[śpiączka|śpiączek]], jest on jednak zastępowany przez bezpieczniejsze w użyciu leki antydepresyjne nowej generacji, jak na przykład [[fluoksetyna]].
<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 |vauthors=Spiller HA, Hays HL, Aleguas A | title = Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management | journal = CNS Drugs | volume = 27| issue = 7| pages = 531–543|date=June 2013 | pmid = 23757186 | doi = 10.1007/s40263-013-0084-8 |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 increases with dosage and decreases with [[drug tolerance]] to amphetamine.<ref name="Westfall" /><ref name="International" /> Tolerant individuals have been known to take as much as 5&nbsp;grams of amphetamine in a day, which is roughly 100&nbsp;times the maximum daily therapeutic dose.<ref name="International" /> Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and [[coma]].<ref name="FDA Abuse & OD" /><ref name="Westfall" /> In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "[[ICD-10 Chapter V: Mental and behavioural disorders#(F10–F19) Mental and behavioural disorders due to psychoactive substance use|amphetamine use disorder]]" resulted in an estimated 3,788&nbsp;deaths worldwide (3,425–4,145&nbsp;deaths, [[95% confidence interval|95%&nbsp;confidence]]).{{#tag:ref|The 95%&nbsp;confidence interval indicates that there is a 95%&nbsp;probability that the true number of deaths lies between 3,425 and 4,145.|group="note"}}<ref name=GDB2013>{{cite journal | vauthors = Collaborators | title = Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 | journal = Lancet | volume = 385 | issue = 9963 | pages = 117–171 | year = 2015 | pmid = 25530442 | pmc = 4340604 | doi = 10.1016/S0140-6736(14)61682-2 | url = http://www.thelancet.com/cms/attachment/2023546115/2043770889/mmc1.pdf | accessdate = 3 March 2015 | quote = Amphetamine use disorders&nbsp;... 3,788&nbsp;(3,425–4,145) }}</ref>


Pathological overactivation of the [[mesolimbic pathway]], a [[dopamine pathway]] that connects the [[ventral tegmental area]] to the [[nucleus accumbens]], plays a central role in amphetamine addiction.<ref name="Amphetamine KEGG – ΔFosB">{{cite web | title=Amphetamine – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05031 | work=KEGG Pathway | accessdate=31 October 2014 | author=Kanehisa Laboratories | date=10 October 2014}}</ref><ref name="Magnesium" /> Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since repeated overdoses gradually increase the level of [[accumbal]] [[ΔFosB]], a "molecular switch" and "master control protein" for addiction.<ref name="What the ΔFosB?" /><ref name="Cellular basis" /><ref name="Nestler_1">{{cite journal |vauthors=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 serves as one of the master control proteins governing this structural plasticity.}}</ref> Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression.<ref name="What the ΔFosB?">{{cite journal | author = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = Am. J. Drug Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–437 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | quote = ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. }}</ref><ref name="Natural and drug addictions" /> While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction.<ref name="Running vs addiction" /><ref name="Exercise, addiction prevention, and ΔFosB">{{cite journal | vauthors = Zhou Y, Zhao M, Zhou C, Li R | title = Sex differences in drug addiction and response to exercise intervention: From human to animal studies | journal = Front. Neuroendocrinol. | volume = | issue = | pages = | date = July 2015 | pmid = 26182835 | doi = 10.1016/j.yfrne.2015.07.001 | quote = Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use.&nbsp;... As briefly reviewed above, a large number of human and rodent studies clearly show that there are sex differences in drug addiction and exercise. The sex differences are also found in the effectiveness of exercise on drug addiction prevention and treatment, as well as underlying neurobiological mechanisms. The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.&nbsp;... In particular, more studies on the neurobiological mechanism of exercise and its roles in preventing and treating drug addiction are needed.}}</ref> Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;<ref name="Exercise therapy" group="sources" /> exercise therapy improves [[wikt:clinical|clinical]] treatment outcomes and may be used as a [[combination therapy]] with [[cognitive behavioral therapy]], which is currently the best clinical treatment available.<ref name="Running vs addiction" /><ref name="Exercise Rev 3" /><ref name="Nestler CBT"/>
Historia nadużywania amfetaminy, jak i innych środków pobudzających, jest stosunkowo krótka. W latach 60. i 70. nadużywane były głównie środki [[halucynacje|halucynogenne]] i uspokajające. Popularność amfetaminy wzrosła dopiero w latach 80., a zwłaszcza na początku lat 90., kiedy wzrosło zapotrzebowanie na środki pobudzające w związku z modą na wielodniowe imprezy taneczne [[techno]], które wymagały od uczestników długotrwałego wysiłku fizycznego.
{{Amphetamine overdose}}


== Zagrożenia ==
===Addiction===
<!--The line below this only affects the transclusions to other amphetamine articles-->
Możliwe są poważne konsekwencje zdrowotne z powodu wyczerpania organizmu. W przypadku spożycia dużych ilości mogą się pojawiać:
<includeonly>{{Addiction glossary}}</includeonly>
* zaburzenia wzroku i słuchu
<!--The lines below specify these templates for use in this article-->
* [[zaburzenia rytmu serca|arytmia serca]], mogąca w skrajnych przypadkach prowadzić do zgonu na skutek niewydolności krążenia
<noinclude>
* wycieńczenie organizmu
{{Addiction glossary|class="wikitable mw-collapsible mw-collapsed"|width=610}}
* [[psychoza amfetaminowa]]
{{Psychostimulant addiction|align=right|header=[[Signaling cascade]] in the [[nucleus accumbens]] that results in amphetamine addiction}}
</noinclude><!--


-->[[Addiction]] is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical long-term medical use at therapeutic doses.<ref name="NHM-Addiction doses">{{cite book | vauthors = 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 | isbn = 9780071481274 | page = 368 | edition = 2nd | chapter = Chapter 15: Reinforcement and Addictive Disorders | quote= INITIAL ACTIONS OF DRUGS OF ABUSE AND NATURAL REINFORCERS<br />Psychostimulants<br />Cocaine, amphetamines, and methamphetamine are the major psychostimulants of abuse. The related drug methylphenidate is also abused, although it is far less potent. These drugs elicit similar initial subjective effects; differences generally reflect the route of administration and other pharmacokinetic factors. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.}}</ref><ref name="Addiction risk">{{cite journal | vauthors = Kollins SH | title = A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders | journal = Curr. Med. Res. Opin. | volume = 24 | issue = 5 | pages = 1345–1357 | date = May 2008 | pmid = 18384709 | doi = 10.1185/030079908X280707 | quote = When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.}}</ref><ref name="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> {{if pagename | Lisdexamfetamine= Compared to other amphetamine pharmaceuticals, lisdexamfetamine may have a lower liability for abuse as a recreational drug.<ref name="LDX abuse">{{cite journal | vauthors = Coghill DR, Caballero B, Sorooshian S, Civil R | title = A systematic review of the safety of lisdexamfetamine dimesylate | journal = CNS Drugs | volume = 28 | issue = 6 | pages = 497–511 | date = June 2014 | pmid = 24788672 | pmc = 4057639 | doi = 10.1007/s40263-014-0166-2 | quote = The prodrug formulation of LDX may also lead to reduced abuse potential of LDX compared with immediate-release d-AMP. }}</ref>| other=}} [[Drug tolerance]] develops rapidly in amphetamine abuse (i.e., a recreational amphetamine overdose), 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 = https://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 |vauthors=Perez-Mana C, Castells X, Torrens M, Capella D, Farre M |title=Efficacy of psychostimulant drugs for amphetamine abuse or dependence |journal=Cochrane Database Syst. Rev. |volume=9 |issue= |pages=CD009695 |date=September 2013 |pmid=23996457 |doi=10.1002/14651858.CD009695.pub2 |url= |editor=Pérez-Mañá C}}</ref>
Następnego dnia po zażyciu występują objawy wyczerpania, jak między innymi potrzeba snu. Najskuteczniejszym lekarstwem jest przespanie kilku dodatkowych godzin. Po zażywaniu kolejnych dawek przez wiele dni (tzw. ciąg amfetaminowy) mogą wystąpić objawy bardzo dużego wyczerpania organizmu, takie jak bardzo silna potrzeba snu, ogólna ospałość, depresja, spadek wagi, spadek odporności na [[zakażenie|infekcje]], silne [[migrena|migreny]] i [[zawroty głowy]]. Już pierwsze zażycie może doprowadzić do tak zwanej [[Psychoza amfetaminowa|psychozy amfetaminowej]].


====Biomolecular mechanisms====
Ze względu na fakt, że amfetamina powoduje zanik poczucia głodu i zmęczenia – spożywanie jej, połączone z sytuacją wzmożonego wysiłku fizycznego (dyskoteka, uprawianie sportu ekstremalnego, ciężka praca fizyczna, duży wysiłek umysłowy), powoduje niekiedy bardzo poważne konsekwencje na skutek wyczerpania i odwodnienia, ze zgonem włącznie.
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 |vauthors=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 |date=July 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 |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, 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|cAMP]] response element binding protein ([[cAMP response element binding protein|CREB]]), and nuclear factor kappa B ([[NF-κB]]).<ref name="Nestler" /> ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in [[D1-type]] [[medium spiny neuron]]s in the nucleus accumbens is [[necessary and sufficient#Definitions|necessary and sufficient]]{{#tag:ref|In simpler terms, this ''necessary and sufficient'' relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.|group="note"}} for most of the behavioral and neural adaptations that arise from addiction.<ref name="What the ΔFosB?" /><ref name="Cellular basis" /><ref name="Nestler" /> Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.<ref name="What the ΔFosB?" /><ref name="Cellular basis" /> It has been implicated in addictions to [[alcoholism|alcohol]], [[cannabinoid]]s, [[cocaine]], [[methylphenidate]], [[nicotine]], [[opioid]]s, [[phencyclidine]], [[propofol]], and [[substituted amphetamines]], among others.{{#tag:ref|<ref name="What the ΔFosB?" /><!--Preceding review covers ΔFosB in propofol addiction--><ref name="Natural and drug addictions" /><ref name="Nestler" /><ref name="Alcoholism ΔFosB">{{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><ref name="MPH ΔFosB">{{cite journal | vauthors = Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P | title = Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 8 | pages = 2915–2920 | date = February 2009 | pmid = 19202072 | pmc = 2650365 | doi = 10.1073/pnas.0813179106 | quote = <!--Despite decades of clinical use of methylphenidate for ADHD, concerns have been raised that long-term treatment of children with this medication may result in subsequent drug abuse and addiction. However, meta analysis of available data suggests that treatment of ADHD with stimulant drugs may have a significant protective effect, reducing the risk for addictive substance use (36, 37). Studies with juvenile rats have also indicated that repeated exposure to methylphenidate does not necessarily lead to enhanced drug-seeking behavior in adulthood (38). However, the recent increase of methylphenidate use as a cognitive enhancer by the general public has again raised concerns because of its potential for abuse and addiction (3, 6–10). Thus, although oral administration of clinical doses of methylphenidate is not associated with euphoria or with abuse problems, nontherapeutic use of high doses or i.v. administration may lead to addiction (39, 40).-->}}</ref>|group="sources"}}


[[ΔJunD]], a transcription factor, and [[EHMT2|G9a]], a [[histone methyltransferase]] enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression).<ref name="Cellular basis" /><ref name="Nestler" /><ref name="Nestler 2014 epigenetics">{{cite journal | vauthors = Nestler EJ | title = Epigenetic mechanisms of drug addiction | journal = Neuropharmacology | volume = 76 Pt B | issue = | pages = 259–268 | date = January 2014 | pmid = 23643695 | pmc = 3766384 | doi = 10.1016/j.neuropharm.2013.04.004 | quote = <!-- Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine’s effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors.&nbsp;... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).<br />G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a).&nbsp;... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine’s behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. -->}}</ref> Sufficiently overexpressing ΔJunD in the nucleus accumbens with [[viral vector]]s can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).<ref name="Nestler" /> ΔFosB also plays an important role in regulating behavioral responses to [[natural reward]]s, such as palatable food, sex, and exercise.<ref name="Natural and drug addictions" /><ref name="Nestler" /><ref name="ΔFosB reward">{{cite journal |vauthors=Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M | title = Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms | journal = J. Psychoactive Drugs | volume = 44 | issue = 1 | pages = 38–55 | date = March 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112| quote = <!-- It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus.&nbsp;... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance.&nbsp;... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. -->}}</ref> Since both natural rewards and addictive drugs [[inducible gene|induce expression]] of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.<ref name="Natural and drug addictions" /><ref name="Nestler">{{cite journal |vauthors=Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = 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 NAc or OFC blocks these key effects of drug exposure<sup>14,22–24</sup>. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. --> }}</ref> Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced [[sex addiction]]s, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.<ref name="Natural and drug addictions" /><ref name="Amph-Sex X-sensitization through D1 signaling"><!--Supplemental primary source-->{{cite journal |vauthors=Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM | title = Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator | journal = J. Neurosci. | volume = 33 | issue = 8 | pages = 3434–3442 |date=February 2013 | pmid = 23426671 | pmc = 3865508 | doi = 10.1523/JNEUROSCI.4881-12.2013 | quote = }}</ref><ref name="Amph-Sex X-sensitization through NMDA signaling"><!--Supplemental primary source-->{{cite journal | vauthors = Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM | title = Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats | journal = Neuropharmacology | volume = 101 | issue = | pages = 154–164 | date = February 2016 | pmid = 26391065 | doi = 10.1016/j.neuropharm.2015.09.023 | quote = }}</ref> These sex addictions are associated with a [[dopamine dysregulation syndrome]] which occurs in some patients taking [[dopaminergic#Supplements and drugs|dopaminergic drugs]].<ref name="Natural and drug addictions" /><ref name="ΔFosB reward" />
Osoby często zażywające amfetaminę mogą wpaść w ciąg amfetaminowy. Amfetamina nie powoduje [[Uzależnienie#Uzależnienie fizjologiczne|uzależnienia fizycznego]] lub jest ono bardzo słabe (może objawiać się dusznościami i lekkimi zawrotami głowy w momencie odstawienia), może wywołać jednak – jak każdy środek pobudzający – [[uzależnienie psychiczne]].


The effects of amphetamine on gene regulation are both dose- and route-dependent.<ref name="Addiction genetics">{{cite journal |vauthors=Steiner H, Van Waes V | title=Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants | journal=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" /> This suggests that medical use of amphetamine does not significantly affect gene regulation.<ref name="Addiction genetics" />
Amfetamina przyjmowana dożylnie w postaci stężonych roztworów (zbliżonych do nasyconego) powoduje rozpad [[erytrocyt|czerwonych krwinek]] i uwolnienie [[hemoglobina|hemoglobiny]]. Amfetamina jako [[ligandy|ligand]] tworzy z żelazem(II) [[związki kompleksowe]] poprzez które zachodzi utlenianie żelaza w hemoglobinie ze [[stopień utlenienia|stopnia utlenienia]] +2 na +3, a więc nieodwracalne tworzenie nieprzenoszącej tlenu [[Methemoglobina|methemoglobiny]]. Objawia się to sinieniem końców palców oraz ust, co może prowadzić do mikrouszkodzeń mózgu z powodu [[hipoksja|niedotlenienia]].


====Pharmacological treatments====
Wstrzykiwanie stężonych roztworów powoduje powstawanie [[zakrzep]]ów w [[naczynie krwionośne|naczyniach krwionośnych]], które mogą stać się bezpośrednią przyczyną niewydolności mięśnia sercowego lub [[zator (medycyna)|zatorów]] w [[układ krwionośny człowieka|układzie krwionośnym]]. Dodatkowym zagrożeniem przy gwałtownym podaniu dożylnym stężonego roztworu amfetaminy jest ryzyko [[Krwotok podpajęczynówkowy|wylewu podpajęczynówkowego]]. Ryzyko to bardzo rośnie z wiekiem, gdyż naczynia tracą normalną elastyczność, a więc i odporność na wzrost ciśnienia.
{{Further information|Addiction#Research}}
{{As of|May 2014}}, there is no effective [[pharmacotherapy]] for amphetamine addiction.<ref name="pmid24716825">{{cite journal | vauthors = Stoops WW, Rush CR | title = Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research | journal = Expert Rev Clin Pharmacol | volume = 7 | issue = 3 | pages = 363–374 | date = May 2014 | pmid = 24716825 | doi = 10.1586/17512433.2014.909283 | quote = Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved. }}</ref><ref name="Cochrane 2013 treatments">{{cite journal | vauthors = Perez-Mana C, Castells X, Torrens M, Capella D, Farre M | title = Efficacy of psychostimulant drugs for amphetamine abuse or dependence | journal = Cochrane Database Syst. Rev. | volume = 9 | issue = | pages = CD009695 | date = September 2013 | pmid = 23996457 | doi = 10.1002/14651858.CD009695.pub2 | quote = To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment.&nbsp;... Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy}}</ref><ref name="pmid23039267">{{cite journal | vauthors = Forray A, Sofuoglu M | title = Future pharmacological treatments for substance use disorders | journal = Br. J. Clin. Pharmacol. | volume = 77 | issue = 2 | pages = 382–400 | date = February 2014 | pmid = 23039267 | pmc = 4014020 | doi = 10.1111/j.1365-2125.2012.04474.x }}</ref> Reviews from 2015 and 2016 indicated that [[TAAR1]]-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;<ref name="Miller+Grandy 2016" /><ref name="TAAR1 addiction 2015" /> however, {{As of|February 2016|lc=y}}, the only compounds which are known to function as TAAR1-selective agonists are [[experimental drug]]s.<ref name="Miller+Grandy 2016">{{cite journal | vauthors = Grandy DK, Miller GM, Li JX | title = "TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference | journal = Drug Alcohol Depend. | volume = 159 | issue = | pages = 9–16 | date = February 2016 | pmid = 26644139 | doi = 10.1016/j.drugalcdep.2015.11.014 | quote = When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.}}</ref><ref name="TAAR1 addiction 2015">{{cite journal | vauthors = Jing L, Li JX | title = Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction | journal = Eur. J. Pharmacol. | volume = 761 | issue = | pages = 345–352 | date = August 2015 | pmid = 26092759 | doi = 10.1016/j.ejphar.2015.06.019 | quote = Taken together,the data reviewed here strongly support that TAAR1 is implicated in the functional regulation of monoaminergic systems, especially dopaminergic system, and that TAAR1 serves as a homeostatic “brake” system that is involved in the modulation of dopaminergic activity. Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction.&nbsp;... Given that TAAR1 is primarily located in the intracellular compartments and existing TAAR1 agonists are proposed to get access to the receptors by translocation to the cell interior (Miller, 2011), future drug design and development efforts may need to take strategies of drug delivery into consideration (Rajendran et al., 2010).}}</ref> Amphetamine addiction is largely mediated through increased activation of [[dopamine receptor]]s and {{nowrap|[[wikt:colocalize|co-localized]]}} [[NMDA receptor]]s{{#tag:ref|NMDA receptors are voltage-dependent [[ligand-gated ion channels]] that requires simultaneous binding of glutamate and a co-agonist ([[D-serine|{{smallcaps all|D}}-serine]] or [[glycine]]) to open the ion channel.<ref name="NHM-NMDA">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | pages = 124–125 | edition = 2nd | chapter = Chapter 5: Excitatory and Inhibitory Amino Acids | quote = <!-- At membrane potentials more negative than approximately −50 mV, the Mg2+ in the extracellular fluid of the brain virtually abolishes ion flux through NMDA receptor channels, even in the presence of glutamate.&nbsp;... The NMDA receptor is unique among all neurotransmitter receptors in that its activation requires the simultaneous binding of two different agonists. In addition to the binding of glutamate at the conventional agonist-binding site, the binding of glycine appears to be required for receptor activation. Because neither of these agonists alone can open this ion channel, glutamate and glycine are referred to as coagonists of the NMDA receptor. The physiologic significance of the glycine binding site is unclear because the normal extracellular concentration of glycine is believed to be saturating. However, recent evidence suggests that D-serine may be the endogenous agonist for this site. -->}}</ref>|group="note"}} in the nucleus accumbens;<ref name="Magnesium" /> [[magnesium|magnesium ions]] inhibit NMDA receptors by blocking the receptor [[calcium channel]].<ref name="Magnesium" /><ref name="NHM-NMDA" /> One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.<ref name="Magnesium" /> [[Dietary supplement|Supplemental magnesium]]{{#tag:ref|The review indicated that [[magnesium aspartate|magnesium L-aspartate]] and [[magnesium chloride]] produce significant changes in addictive behavior;<ref name="Magnesium" /> other forms of magnesium were not mentioned.|group="note"}} treatment has been shown to reduce amphetamine [[self-administration]] (i.e., doses given to oneself) in humans, but it is not an effective [[monotherapy]] for amphetamine addiction.<ref name="Magnesium">{{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====
Najczęstszą przyczyną śmierci po przedawkowaniu amfetaminy jest [[Porażenie|paraliż]] [[mięśnie oddechowe|mięśni oddechowych]], a więc uduszenie się lub zatrzymanie [[Cykl pracy serca|akcji serca]] wskutek [[zaburzenia rytmu serca|arytmii]] lub [[zawał mięśnia sercowego|zawału]]. Najczęstszymi powikłaniami są mikrowylewy. Niewielka część osób popełnia samobójstwo wskutek [[psychoza amfetaminowa|psychozy amfetaminowej]]. Ratowanie osoby która przedawkowała polega na podaniu [[leki przeciwpsychotyczne|neuroleptyków]] blokujących [[receptory adrenergiczne]] i [[receptory dopaminergiczne|dopaminergiczne]] w celu niedopuszczenia do nadmiernego ich pobudzenia oraz leków obniżających [[ciśnienie tętnicze]]. W przypadku psychozy amfetaminowej podaje się neuroleptyki ([[chloropromazyna|chloropromazynę]]) [[Zastrzyk domięśniowy|domięśniowo]] lub [[diazepam|relanium]] dożylnie. Osoby uzależnione od amfetaminy są bardzo wrażliwe na neuroleptyki, tak więc zwykle wystarczają dawki o połowę mniejsze niż u osób nieuzależnionych.
[[Cognitive behavioral therapy]] is currently the most effective clinical treatment for psychostimulant addictions.<ref name="Nestler CBT">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, 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]] suggests that daily aerobic exercise, especially endurance exercise (e.g., [[marathon running]]), prevents the development of drug addiction and is an effective [[adjunct therapy]] (i.e., a supplemental treatment) for amphetamine addiction.{{#tag:ref|<ref name="Natural and drug addictions" /><ref name="Running vs addiction" /><ref name="Exercise, addiction prevention, and ΔFosB" /><ref name="Exercise Rev 3" /><ref name="Addiction review 2016" />|group="sources"|name="Exercise therapy"}} Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.<ref name="Running vs addiction">{{cite journal |vauthors=Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA | title = Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis | journal = Neurosci. Biobehav. Rev. | volume = 37 | issue = 8 | pages = 1622–1644 |date=September 2013 | pmid = 23806439 | pmc = 3788047 | doi = 10.1016/j.neubiorev.2013.06.011 | quote = These findings suggest that exercise may “magnitude”-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.}}</ref><ref name="Exercise Rev 3">{{cite journal | vauthors = Linke SE, Ussher M | title = Exercise-based treatments for substance use disorders: evidence, theory, and practicality | journal = Am. J. Drug Alcohol Abuse | volume = 41 | issue = 1 | pages = 7–15 | date = January 2015 | pmid = 25397661 | doi = 10.3109/00952990.2014.976708 | quote = The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published.&nbsp;... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.}}</ref><ref name="Addiction review 2016">{{cite journal | vauthors = Carroll ME, Smethells JR | title = Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments | journal = Front. Psychiatry | volume = 6 | issue = | pages = 175 | date = February 2016 | pmid = 26903885 | pmc = 4745113 | doi = 10.3389/fpsyt.2015.00175 | quote = Environmental Enrichment&nbsp;...<br />In humans, non-drug rewards delivered in a contingency management (CM) format successfully reduced drug dependence&nbsp;... In general, CM programs promote drug abstinence through a combination of positive reinforcement for drug-free urine samples. For instance, voucher-based reinforcement therapy in which medication compliance, therapy session attendance, and negative drug screenings reinforced with vouchers to local business (e.g., movie theater, restaurants, etc.) directly reinforces drug abstinence, provides competing reinforcers, enriches the environment, and it is a robust treatment across a broad range of abused drugs (189).&nbsp;...<br />Physical Exercise<br />There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction&nbsp;... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse.&nbsp;... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis.&nbsp;... However, a <abbr title="randomized controlled trial">RTC</abbr> study was recently reported by Rawson et al. (226), whereby they used 8 weeks of exercise as a post-residential treatment for METH addiction, showed a significant reduction in use (confirmed by urine screens) in participants who had been using meth 18 days or less a month.&nbsp;... '''Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.''' [emphasis added]}}</ref> In particular, [[aerobic exercise]] decreases psychostimulant self-administration, reduces the [[reinstatement]] (i.e., relapse) of drug-seeking, and induces increased [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]] (DRD2) density in the [[striatum]].<ref name="Natural and drug addictions" /><ref name="Addiction review 2016" /> This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.<ref name="Natural and drug addictions">{{cite journal | author = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–1122 | date = December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005).&nbsp;... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008). }}</ref> One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or [[c-Fos]] [[immunoreactivity]] in the striatum or other parts of the [[reward system]].<ref name="Exercise, addiction prevention, and ΔFosB" />
{{FOSB addiction table|Table title=Summary of addiction-related plasticity}}


===Dependence and withdrawal===
Amfetamina w postaci wolnej zasady w dłuższym kontakcie z ciałem powoduje trudno gojące się oparzenia, a połknięta uszkadza ścianę żołądka, powodując dotkliwy ból.
According to another Cochrane Collaboration review on [[drug withdrawal|withdrawal]] in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24&nbsp;hours of their last dose."<ref name="Cochrane Withdrawal">{{cite journal |vauthors=Shoptaw SJ, Kao U, Heinzerling K, Ling W | title = Treatment for amphetamine withdrawal | journal = Cochrane Database Syst. Rev. | volume = | issue = 2 | pages = CD003021 | date = April 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 the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.<ref name="Cochrane Withdrawal" /> Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.<ref name="Dexedrine FDA">{{cite web | title = Dexedrine Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017078s047lbl.pdf | publisher = Amedra Pharmaceuticals LLC | work = United States Food and Drug Administration | date = October 2013 | accessdate = 4 November 2013 }}</ref><ref>{{cite web | title=Adderall IR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011522s042lbl.pdf | publisher = Teva Pharmaceuticals USA, Inc. | work = United States Food and Drug Administration | date=October 2015 | accessdate=18 May 2016 }}</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>


===Toxicity and psychosis===
== Pochodne ==
{{see also|Stimulant psychosis}}
[[Plik:Amphetamine numbered.svg|thumb|Szkielet amfetaminy z numeracją atomów]]
Liczne naturalne i syntetyczne [[pochodna (chemia)|pochodne]] amfetaminy także wykazują właściwości psychoaktywne, np. [[3,4-Metylenodioksymetamfetamina|3,4-metylenodioksymetamfetamina]] (MDMA, tzw. ''ecstasy''), [[metamfetamina|''N''-metyloamfetamina]] (metamfetamina), [[efedryna|β-hydroksylo-''N''-metyloamfetamina]] (efedryna), [[3,4-Metylenodioksyamfetamina|3,4-metylenodioksyamfetamina]] (MDA), [[2,5-Dimetoksy-4-metyloamfetamina|2,5-dimetoksy-4-metyloamfetamina]], (DOM), [[2,5-Dimetoksy-4-bromoamfetamina|2,5-dimetoksy-4-bromoamfetamina]] (DOB).


In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic [[neurotoxicity]], or damage to dopamine neurons, which is characterized by dopamine [[axon terminal|terminal]] [[Neurodegeneration|degeneration]] and reduced transporter and receptor function.<ref name="Humans&Animals">{{cite journal| author=Advokat C| title=Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD | journal=J. Atten. Disord. | date = July 2007 | volume= 11 | issue= 1 | pages= 8–16 | pmid=17606768 | doi=10.1177/1087054706295605}}</ref><ref name="Amph-induced hyperthermia and neurotoxicity review" /> There is no evidence that amphetamine is directly neurotoxic in humans.<ref>{{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=United States National Library of Medicine&nbsp;– Toxicology Data Network | 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 |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, 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> However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of [[hyperpyrexia]], the excessive formation of [[reactive oxygen species]], and increased [[autoxidation]] of dopamine.{{#tag:ref|<ref name="pmid22392347">{{cite journal |vauthors=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L |title=Toxicity of amphetamines: an update |journal=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="Amph-induced hyperthermia and neurotoxicity review" /><ref name="Autoxidation1">{{cite journal |vauthors=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 |vauthors=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>|group="sources"}} [[Animal model]]s of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., [[core body temperature]]&nbsp;≥&nbsp;40&nbsp;°C) is necessary for the development of amphetamine-induced neurotoxicity.<ref name="Amph-induced hyperthermia and neurotoxicity review">{{cite journal | vauthors = Bowyer JF, Hanig JP | title = Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity | journal = Temperature (Austin) | volume = 1 | issue = 3 | pages = 172–182 | date = November 2014 | pmid = 27626044 | pmc = 5008711 | doi = 10.4161/23328940.2014.982049 | quote = Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. Forebrain neurotoxicity can also be indirectly influenced through the effects of AMPH- and METH- induced hyperthermia on vasculature. The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals.&nbsp;... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.}}</ref> Prolonged elevations of brain temperature above 40&nbsp;°C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing [[blood–brain barrier]] permeability.<ref name="Amph-induced hyperthermia and neurotoxicity review" />
{{wikicytaty|amfetamina}}


A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as [[paranoia]] and [[delusion]]s.<ref name="Cochrane" /> A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about&nbsp;5–15% of users fail to recover completely.<ref name="Cochrane">{{cite journal | editor =<!--Shoptaw SJ--> Shoptaw SJ, Ali R |vauthors=Shoptaw SJ, Kao U, Ling W | title = Treatment for amphetamine psychosis | journal = Cochrane Database Syst. Rev. | volume = | issue = 1 | pages = CD003026 | date = January 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>
== Przypisy ==
}}</onlyinclude>
{{Przypisy-lista|l. kolunm=2|1=

* <ref name="acdlabs">{{cytuj stronę | tytuł = IUPAC nomenclature: R-5.4.1 Primary amines | url = http://www.acdlabs.com/iupac/nomenclature/93/r93_398.htm | opublikowany = Advanced Chemistry Development, Inc. | data dostępu = 2011-03-27}}</ref>
==Interactions==
* <ref name="CRC">{{CRC90|strony=3-432}}</ref>
{{see also|Amphetamine#Contraindications}}
* <ref name="CRC-logP">{{CRC90|strony=16-44}}</ref>
Many types of substances are known to [[drug interaction|interact]] with amphetamine, resulting in altered [[drug action]] or [[Drug metabolism|metabolism]] of amphetamine, the interacting substance, or both.<ref name="FDA Pharmacokinetics" /><ref name="FDA Interactions" /> Inhibitors of the enzymes that metabolize amphetamine (e.g., [[CYP2D6#Ligands|CYP2D6]] and [[Flavin-containing monooxygenase 3#Ligands|FMO3]]) will prolong its [[elimination half-life]], meaning that its effects will last longer.<ref name="FMO" /><ref name="FDA Interactions">{{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 [[blood plasma|plasma]] catecholamines (i.e., norepinephrine and dopamine);<ref name="FDA Interactions" /> therefore, concurrent use of both is dangerous.<ref name="FDA Interactions" /> Amphetamine modulates the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of [[sedative]]s and [[depressant]]s and increase the effects of [[stimulant]]s and [[antidepressant]]s.<ref name="FDA Interactions" /> Amphetamine may also decrease the effects of [[antihypertensives]] and [[antipsychotic]]s due to its effects on blood pressure and dopamine respectively.<ref name="FDA Interactions" /> [[Zinc supplementation]] may reduce the minimum [[Effective dose (pharmacology)|effective dose]] of amphetamine when it is used for the treatment of ADHD.{{#tag:ref|The human [[dopamine transporter]] contains a [[affinity (pharmacology)|high affinity]] extracellular zinc [[binding site]] which, upon zinc binding, inhibits dopamine [[reuptake]] and amplifies amphetamine-induced [[neurotransmitter efflux|dopamine efflux]] ''[[in vitro]]''.<ref name="Zinc binding sites + ADHD review">{{cite journal | vauthors = Krause J | title = SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder | journal = Expert Rev. Neurother. | volume = 8 | issue = 4 | pages = 611–625 | date = April 2008 | pmid = 18416663 | doi = 10.1586/14737175.8.4.611 | quote = Zinc binds at&nbsp;... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm.}}</ref><ref name="Review - cites 2002 amph-zinc primary study">{{cite journal | vauthors = Sulzer D | title = How addictive drugs disrupt presynaptic dopamine neurotransmission | journal = Neuron | volume = 69 | issue = 4 | pages = 628–649 | date = February 2011 | pmid = 21338876 | pmc = 3065181 | doi = 10.1016/j.neuron.2011.02.010 | quote = They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002).}}</ref><ref name="Primary 2002 amph-zinc study">{{cite journal | vauthors = Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH | title = The role of zinc ions in reverse transport mediated by monoamine transporters | journal = J. Biol. Chem. | volume = 277 | issue = 24 | pages = 21505–21513 | date = June 2002 | pmid = 11940571 | doi = 10.1074/jbc.M112265200 | quote = The human dopamine transporter (hDAT) contains an endogenous high affinity Zn<sup>2+</sup> binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396).&nbsp;... Although Zn<sup>2+</sup> inhibited uptake, Zn<sup>2+</sup> facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET).&nbsp;... Surprisingly, this amphetamine-elicited efflux was markedly enhanced, rather than inhibited, by the addition of 10&nbsp;μM Zn<sup>2+</sup> to the superfusion buffer (Fig. 2 A, open squares). We stress that Zn<sup>2+</sup> per se did not affect basal efflux (Fig. 2 A).&nbsp;... In many brain regions, Zn<sup>2+</sup> is stored in synaptic vesicles and co-released together with glutamate; under basal conditions, the extracellular levels of Zn<sup>2+</sup> are low (∼10&nbsp;nM; see Refs. 39, 40). Upon neuronal stimulation, however, Zn<sup>2+</sup> is co-released with the neurotransmitters and, consequently, the free Zn<sup>2+</sup> concentration may transiently reach values that range from 10–20&nbsp;μM (10) up to 300&nbsp;μM (11). The concentrations of Zn<sup>2+</sup> shown in this study, required for the stimulation of dopamine release (as well as inhibition of uptake), covered this physiologically relevant range, with maximum stimulation occurring at 3–30&nbsp;μM. It is therefore conceivable that the action of Zn<sup>2+</sup> on hDAT does not merely reflect a biochemical peculiarity but that it is physiologically relevant.&nbsp;... Thus, when Zn<sup>2+</sup> is co-released with glutamate, it may greatly augment the efflux of dopamine.}}</ref> The human [[serotonin transporter]] and [[norepinephrine transporter]] do not contain zinc binding sites.<ref name="Primary 2002 amph-zinc study" />|group="note"}}<ref name="Zinc and PEA">{{cite journal |vauthors=Scassellati C, Bonvicini C, Faraone SV, Gennarelli M | title = Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses | journal = J. Am. Acad. Child Adolesc. Psychiatry | volume = 51 | issue = 10 | pages = 1003–1019.e20 | date = October 2012 | pmid = 23021477 | doi = 10.1016/j.jaac.2012.08.015 | quote = Although we did not find a sufficient number of studies suitable for a meta-analysis of PEA and ADHD, three studies<sup>20,57,58</sup> confirmed that urinary levels of PEA were significantly lower in patients with ADHD compared with controls.&nbsp;... Administration of D-amphetamine and methylphenidate resulted in a markedly increased urinary excretion of PEA,<sup>20,60</sup> suggesting that ADHD treatments normalize PEA levels.&nbsp;... Similarly, urinary biogenic trace amine PEA levels could be a biomarker for the diagnosis of ADHD,<sup>20,57,58</sup> for treatment efficacy,<sup>20,60</sup> and associated with symptoms of inattentivenesss.<sup>59</sup>&nbsp;... With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30&nbsp;mg/day of zinc were safe for at least 8&nbsp;weeks, but the clinical effect was equivocal except for the finding of a 37%&nbsp;reduction in amphetamine optimal dose with 30&nbsp;mg per day of zinc.<sup>110</sup>}}</ref>
* <ref name="CRC-Fl">{{CRC90|strony=16-24}}</ref>

* <ref name="bazyl.karnet.waw">[http://bazyl.karnet.waw.pl/szukaj.php?nazwa=AMFETAMINA-STRIP Farmaceutyczna baza danych „Bazyl”]</ref>
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 (i.e., make it less acidic).<ref name="FDA Interactions" />
* <ref name="ess">{{cytuj książkę | autor = Stephen M. Stahl | tytuł = Essential Psychopharmacology, The Prescriber's Guide | wydawca = Cambridge University Press | rok = 2006}}</ref>

* <ref name="NIST1">{{NIST|nazwa= Dekstroamfetamina|51-64-9}}</ref>
==Pharmacology==
* <ref name="NIST2">{{NIST|300-62-9}}</ref>

* <ref name="psc">{{PSChem|strony=28}}</ref>
===Pharmacodynamics===
* <ref name="PubChemD">{{cytuj stronę | url = http://pubchem.ncbi.nlm.nih.gov/compound/5826 | tytuł = <small>D</small>-Amfetamina | opublikowany = PubChem | data dostępu = 2013-12-25}}</ref>
{{For|a simpler and less technical explanation of amphetamine's mechanism of action|Adderall#Mechanism of action}}
* <ref name="PubChemL">{{cytuj stronę | url = http://pubchem.ncbi.nlm.nih.gov/compound/32893 | tytuł = <small>L</small>-Amfetamina | opublikowany = PubChem | data dostępu = 2013-12-25}}</ref>
{{amphetamine pharmacodynamics}}<!--
* <ref name="SA-US">{{Sigma-Aldrich|MSDS=tak|A1263|Sigma|język=en|data dostępu=2015-06-22}}</ref>

* <ref name="Stahl2008-s7-14">{{cytuj książkę | nazwisko = Stahl | imię = Stephen M. | tytuł = Podstawy psychofarmakologii | data = 2008 | wydawca = Via Medica | miejsce = Gdańsk | isbn = 978-83-60945-73-5 | strony = 7-14}}</ref>
-->Amphetamine exerts its behavioral effects by altering the use of [[monoamines]] as neuronal signals in the brain, primarily in [[catecholamine]] neurons in the reward and executive function pathways of the brain.<ref name="Miller" /><ref name="cognition enhancers" /> The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine 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|vauthors=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 |vauthors=Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C | 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" /><ref name="Miller+Grandy 2016" /> Notably, amphetamine and [[trace amine]]s bind to TAAR1, but not monoamine autoreceptors.<ref name="Miller" /><ref name="Miller+Grandy 2016" /> Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 {{nowrap|co-localization}} in the associated monoamine neurons.<ref name="Miller" /> {{As of|2014|alt=As of 2010,}} {{nowrap|co-localization}} of TAAR1 and the [[dopamine transporter]] (DAT) has been visualized in rhesus monkeys, but {{nowrap|co-localization}} of TAAR1 with the [[norepinephrine transporter]] (NET) and the [[serotonin transporter]] (SERT) has only been evidenced by [[messenger RNA]] (mRNA) expression.<ref name="Miller" />

In addition to the neuronal monoamine [[Membrane transport protein|transporters]], amphetamine also inhibits both vesicular monoamine transporters, [[VMAT1]] and [[VMAT2]], as well as [[SLC1A1]], [[SLC22A3]], and [[SLC22A5]].{{#tag:ref|<ref name="E Weihe" /><ref name="EAAT3">{{cite journal |vauthors=Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG | title = Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons | journal = Neuron | volume = 83 | issue = 2 | pages = 404–416 | date = July 2014 | pmid = 25033183 | pmc = 4159050 | doi = 10.1016/j.neuron.2014.05.043 | quote = AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).&nbsp;... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate.&nbsp;... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH}}</ref><ref name="IUPHAR VMATs">{{cite web|title=SLC18 family of vesicular amine transporters|url=http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=193|website=IUPHAR database|publisher=International Union of Basic and Clinical Pharmacology|accessdate=13 November 2015}}</ref><ref name="SLC1A1">{{cite web | title=SLC1A1 solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 [ Homo sapiens (human) ] | url=http://www.ncbi.nlm.nih.gov/gene/6505 | website=NCBI Gene | publisher=United States National Library of Medicine&nbsp;– 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 |vauthors=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 |vauthors=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 |vauthors=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 |vauthors=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 DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB.}}</ref><ref name="PubChem Targets" /> a [[neuropeptide]] involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival ''[[in vitro]]''.<ref name="PubChem Targets">{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#section=Biomolecular-Interactions-and-Pathways | work=PubChem Compound | publisher = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=13 October 2013 | section=Biomolecular Interactions and Pathways }}</ref><ref name="CART functions">{{cite journal |vauthors=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 = Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. 3. In fact, little is known about the way in which CART peptide interacts with its receptors, initiates downstream cascades and finally exerts its neuroprotective effect under normal or pathological conditions. The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART}}</ref><ref name="CART">{{cite journal | vauthors = Rogge G, Jones D, Hubert GW, Lin Y, Kuhar MJ | title = CART peptides: regulators of body weight, reward and other functions | journal = Nat. Rev. Neurosci. | volume = 9 | issue = 10 | pages = 747–758 | date = October 2008 | pmid = 18802445 | pmc = 4418456 | doi = 10.1038/nrn2493 | quote = Several studies on CART (cocaine- and amphetamine-regulated transcript)-peptide-induced cell signalling have demonstrated that CART peptides activate at least three signalling mechanisms. First, CART 55–102 inhibited voltage-gated L-type Ca2+ channels&nbsp;...}}</ref> The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique {{nowrap|[[Gi alpha subunit|G<sub>i</sub>/G<sub>o</sub>-coupled]]}} {{abbr|GPCR|G protein-coupled receptor}}.<ref name="CART" /><ref name="pmid21855138">{{cite journal |vauthors=Lin Y, Hall RA, Kuhar MJ | title = CART peptide stimulation of G protein-mediated signaling in differentiated PC12 cells: identification of PACAP 6–38 as a CART receptor antagonist | journal = Neuropeptides | volume = 45 | issue = 5 | pages = 351–358 |date=October 2011 | pmid = 21855138 | pmc = 3170513 | doi = 10.1016/j.npep.2011.07.006 }}</ref> Amphetamine also inhibits [[monoamine oxidase]] 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 = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=17 April 2015 | date=11 April 2015 | section=Compound Summary }}</ref><ref name="BRENDA MAO Homo sapiens">{{cite encyclopedia | title=Monoamine oxidase (Homo sapiens)| url=http://www.brenda-enzymes.info/enzyme.php?ecno=1.4.3.4&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0 | work=BRENDA | publisher=Technische Universität Braunschweig | accessdate=4 May 2014 | date=1 January 2014}}</ref> In humans, the only post-synaptic receptor at which amphetamine is known to bind is the [[5-HT1A receptor|{{nowrap|5-HT1A}} receptor]], where it acts as an agonist with [[micromolar]] affinity.<ref name="5HT1A secondary" /><ref name="5HT1A Primary" />

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or [[neurotransmission]] of [[dopamine]],<ref name="Miller">{{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 |vauthors=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 DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR)&nbsp;... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).--> | pmc=4183197}}</ref> [[histamine]],<ref name="E Weihe" /> [[cocaine and amphetamine regulated transcript|CART peptides]],<ref name="CART NAcc" /><ref name="PubChem Targets" /> [[endogenous opioid]]s,<ref name="Amphetamine-induced endogenous opioid release review">{{cite journal | vauthors = Finnema SJ, Scheinin M, Shahid M, Lehto J, Borroni E, Bang-Andersen B, Sallinen J, Wong E, Farde L, Halldin C, Grimwood S | title = Application of cross-species PET imaging to assess neurotransmitter release in brain | journal = Psychopharmacology (Berl.) | volume = 232 | issue = 21-22 | pages = 4129–4157 | date = November 2015 | pmid = 25921033 | pmc = 4600473 | doi = 10.1007/s00213-015-3938-6 | quote = More recently, Colasanti and colleagues reported that a pharmacologically induced elevation in endogenous opioid release reduced [<sup>11</sup>C]carfentanil binding in several regions of the human brain, including the basal ganglia, frontal cortex, and thalamus (Colasanti et al. 2012). Oral administration of d-amphetamine, 0.5&nbsp;mg/kg, 3&nbsp;h before [<sup>11</sup>C]carfentanil injection, reduced BPND values by 2–10&nbsp;%. The results were confirmed in another group of subjects (Mick et al. 2014). However, Guterstam and colleagues observed no change in [<sup>11</sup>C]carfentanil binding when d-amphetamine, 0.3&nbsp;mg/kg, was administered intravenously directly before injection of [<sup>11</sup>C]carfentanil (Guterstam et al. 2013). It has been hypothesized that this discrepancy may be related to delayed increases in extracellular opioid peptide concentrations following amphetamine-evoked monoamine release (Colasanti et al. 2012; Mick et al. 2014).}}</ref><ref name="Opioids">{{cite journal | vauthors = Loseth GE, Ellingsen DM, Leknes S | title = State-dependent μ-opioid modulation of social motivation | journal = Front. Behav. Neurosci. | volume = 8 | issue = | pages = 1–15 | date = December 2014 | pmid = 25565999 | pmc = 4264475 | doi = 10.3389/fnbeh.2014.00430 | quote = Similar MOR activation patterns were reported during positive mood induced by an amusing video clip (Koepp et al., 2009) and following amphetamine administration in humans (Colasanti et al., 2012). }}</ref><ref name="Opioids cited primary source">{{cite journal | vauthors = Colasanti A, Searle GE, Long CJ, Hill SP, Reiley RR, Quelch D, Erritzoe D, Tziortzi AC, Reed LJ, Lingford-Hughes AR, Waldman AD, Schruers KR, Matthews PM, Gunn RN, Nutt DJ, Rabiner EA | title = Endogenous opioid release in the human brain reward system induced by acute amphetamine administration | journal = Biol. Psychiatry | volume = 72 | issue = 5 | pages = 371–377 | date = September 2012 | pmid = 22386378 | doi = 10.1016/j.biopsych.2012.01.027 | quote = }}</ref> [[adrenocorticotropic hormone]],<ref name="Human amph effects" /><ref name="Primary: Human HPA axis" /> [[corticosteroid]]s,<ref name="Human amph effects" /><ref name="Primary: Human HPA axis" /> and [[glutamate]],<ref name="EAAT3" /><ref name="SLC1A1" /> which it effects through interactions with {{abbr|CART|cocaine- and amphetamine-regulated transcript}}, {{nowrap|{{abbr|5-HT1A|serotonin receptor 1A}}}}, {{abbr|EAAT3|excitatory amino acid transporter 3}}, {{abbr|TAAR1|trace amine-associated receptor 1}}, {{abbr|VMAT1|vesicular monoamine transporter 1}}, {{abbr|VMAT2|vesicular monoamine transporter 2}}, and possibly other [[biological target]]s.{{#tag:ref|<ref name="Miller" /><ref name="E Weihe" /><ref name="IUPHAR VMATs" /><ref name="SLC1A1" /><ref name="CART NAcc" /><ref name="5HT1A secondary" />|group="sources"}}

Dextroamphetamine is a more potent agonist of {{abbr|TAAR1|trace amine-associated receptor 1}} than levoamphetamine.<ref name="TAAR1 stereoselective" /> Consequently, dextroamphetamine produces greater {{abbr|CNS|central nervous system}} stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.<ref name="Westfall" /><ref name="TAAR1 stereoselective">{{cite journal |vauthors=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 |vauthors=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, an effect which is associated with DAT phosphorylation through an unidentified [[Ca2+/calmodulin-dependent protein kinase]] (CAMK)-dependent pathway, in turn producing dopamine efflux.<ref name="TAAR1 IUPHAR" /><ref name="EAAT3" /><ref name="DAT regulation review">{{cite journal |vauthors=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, {{abbr|TAAR1|trace amine associated receptor 1}} reduces the [[action potential|firing rate]] of postsynaptic dopamine neurons, preventing a hyper-dopaminergic state.<ref name="GIRK">{{cite journal |vauthors=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 | date = July 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 />{{•}} tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA) }}</ref><ref name="TAAR1-Paradoxical">{{cite journal |vauthors=Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC |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>

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" /> Like dopamine, amphetamine has low, micromolar affinity at the human [[5-HT1A receptor]].<ref name="5HT1A secondary">{{cite encyclopedia | title=Amphetamine | url=http://www.t3db.ca/toxins/T3D2706 | website=T3DB | publisher=University of Alberta | accessdate=24 February 2015 | section=Targets}}</ref><ref name="5HT1A Primary">{{cite journal | vauthors = Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS | title = Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications | journal = NIDA Res. Monogr. | volume = 178 | issue = | pages = 440–466 | date = March 1998 | pmid = 9686407 | doi = | url = }}</ref>

====Other neurotransmitters, peptides, and hormones====
<!--Amphetamine has no direct effect on [[acetylcholine]] neurotransmission, but several studies have noted that acetylcholine release increases after its use.<ref name="Acetylcholine">{{cite journal |vauthors=Hutson PH, Tarazi FI, Madhoo M, Slawecki C, Patkar AA | title = Preclinical pharmacology of amphetamine: implications for the treatment of neuropsychiatric disorders | journal = Pharmacol. Ther. | volume = 143 | issue = 3 | pages = 253–264 | date = September 2014 | pmid = 24657455 | doi = 10.1016/j.pharmthera.2014.03.005 | url = }}</ref> In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream effect.<ref name="Acetylcholine" />-->
Acute amphetamine administration in humans increases [[endogenous opioid]] release in several brain structures in the [[reward system]].<ref name="Amphetamine-induced endogenous opioid release review" /><ref name="Opioids" /><ref name="Opioids cited primary source" /> Extracellular levels of [[Glutamate (neurotransmitter)|glutamate]], the primary [[Neurotransmitter#Excitatory and inhibitory|excitatory neurotransmitter]] in the brain, have been shown to increase in the striatum following exposure to amphetamine.<ref name="EAAT3" /> This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of [[EAAT3]], a glutamate reuptake transporter, in dopamine neurons.<ref name="EAAT3" /><ref name="SLC1A1" /> Amphetamine also induces the selective release of [[histamine]] from [[mast cell]]s and efflux from [[Tuberomammillary nucleus|histaminergic neurons]] through {{abbr|VMAT2|vesicular monoamine transporter 2}}.<ref name="E Weihe" /> Acute amphetamine administration can also increase [[adrenocorticotropic hormone]] and [[corticosteroid]] levels in [[blood plasma]] by stimulating the [[hypothalamic–pituitary–adrenal axis]].<ref name="Evekeo" /><ref name="Human amph effects">{{cite book | author=Gunne LM | title=Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence | date=2013 | publisher=Springer | location=Berlin, Germany; Heidelberg, Germany | isbn=9783642667091 | pages=247–260 | accessdate=4 December 2015 | chapter=Effects of Amphetamines in Humans | chapter-url=https://books.google.com/books?id=gb_uCAAAQBAJ&pg=PA247#v=onepage&q&f=false | quote = }}</ref><ref name="Primary: Human HPA axis">{{cite journal | vauthors = Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L, Brasic J, Wand GS | title = Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine | journal = Neuropsychopharmacology | volume = 30 | issue = 4 | pages = 821–832 | date = April 2005 | pmid = 15702139 | doi = 10.1038/sj.npp.1300667 | quote = Findings from several prior investigations have shown that plasma levels of glucocorticoids and ACTH are increased by acute administration of AMPH in both rodents and humans}}</ref>

===Pharmacokinetics===
<onlyinclude>{{#ifeq:{{{transcludesection|Pharmacokinetics}}}|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">{{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> Amphetamine is a weak base with a [[Acid dissociation constant|p''K''<sub>a</sub>]] of 9.9;<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> consequently, when the pH is basic, more of the drug is in its [[lipid]] soluble [[free base]] form, and more is absorbed through the lipid-rich [[cell membranes]] of the gut [[epithelium]].<ref name="FDA Pharmacokinetics" /><ref name="FDA Interactions" /> Conversely, an acidic pH means the drug is predominantly in a water-soluble [[cation]]ic (salt) form, and less is absorbed.<ref name="FDA Pharmacokinetics" /> Approximately {{nowrap|15–40%}} of amphetamine circulating in the bloodstream is bound to [[plasma protein]]s.<ref name="Drugbank-amph">{{cite encyclopedia | 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>

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

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

[[CYP2D6]], [[dopamine β-hydroxylase]] (DBH), [[flavin-containing monooxygenase 3]] (FMO3), [[butyrate-CoA ligase]] (XM-ligase), and [[glycine N-acyltransferase]] (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans.{{#tag:ref|<ref name="FDA Pharmacokinetics" /><ref name="Substituted amphetamines, FMO, and DBH">{{cite book | author = Glennon RA |veditors=Lemke TL, Williams DA, Roche VF, Zito W | title=Foye's principles of medicinal chemistry | date=2013 | publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins | location=Philadelphia, USA | isbn=9781609133450 | pages=646–648 | edition=7th | section-url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646&q=substituted%20derivatives%20substituents%20hydroxyamphetamine%20flavin%20monooxygenase#v=onepage | accessdate=11 September 2015 | section=Phenylisopropylamine stimulants: amphetamine-related agents | quote=The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39).&nbsp;... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase.&nbsp;... Amphetamine can also undergo aromatic hydroxylation to ''p''-hydroxyamphetamine.&nbsp;... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords ''p''-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.}}</ref><ref name="DBH amph primary">{{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 |vauthors=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><ref name="FMO">{{cite journal |vauthors=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}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ Table 5: N-containing drugs and xenobiotics oxygenated by FMO]</ref><ref name="FMO3-Primary">{{cite journal |vauthors=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="Metabolites" /><ref name="Benzoic1" /><ref name="Benzoic2" />| name="amphetamine metabolism" |group = "sources" }} Amphetamine has a variety of excreted metabolic products, including {{nowrap|[[4-hydroxyamphetamine]]}}, {{nowrap|[[4-hydroxynorephedrine]]}}, {{nowrap|[[4-hydroxyphenylacetone]]}}, [[benzoic acid]], [[hippuric acid]], [[norephedrine]], and [[phenylacetone]].<ref name="FDA Pharmacokinetics" /><ref name="Pubchem Kinetics">{{cite encyclopedia | title=Amphetamine | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#section=Pharmacology-and-Biochemistry | work=Pubchem Compound | publisher = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=12 October 2013 | section=Pharmacology and Biochemistry }}</ref><ref name="Metabolites">{{cite journal |vauthors=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 = United States National Library of Medicine&nbsp;– 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 = United States National Library of Medicine&nbsp;– 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 = United States National Library of Medicine&nbsp;– 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 metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:
{{Amphetamine Pharmacokinetics|header=Metabolic pathways of amphetamine in humans<ref name="amphetamine metabolism" group = "sources" />|caption=The primary active metabolites of amphetamine are {{nowrap|4-hydroxyamphetamine}} and norephedrine;<ref name="Metabolites" /> at normal urine pH, about {{nowrap|30–40%}} of amphetamine is excreted unchanged and roughly&nbsp;50% is excreted as the inactive metabolites (bottom row).<ref name="FDA Pharmacokinetics" /> The remaining {{nowrap|10–20%}} is excreted as the active metabolites.<ref name="FDA Pharmacokinetics" /> Benzoic acid is metabolized by {{abbr|XM-ligase|butyrate-CoA ligase}} into an intermediate product, [[benzoyl-CoA]],<ref name="Benzoic1">{{cite encyclopedia| title=butyrate-CoA ligase| section-url=http://www.brenda-enzymes.info/enzyme.php?ecno=6.2.1.2&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0 | work=BRENDA| publisher=Technische Universität Braunschweig.| accessdate=7 May 2014| section=Substrate/Product}}</ref> which is then metabolized by {{abbr|GLYAT|glycine N-acyltransferase}} into hippuric acid.<ref name="Benzoic2">{{cite encyclopedia | title=glycine N-acyltransferase| section-url=http://www.brenda-enzymes.info/enzyme.php?ecno=2.3.1.13&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0 | work=BRENDA| publisher=Technische Universität Braunschweig.| accessdate=7 May 2014| section=Substrate/Product}}</ref>}}
{{clear}}<!--

-->}}</onlyinclude>

===Related endogenous compounds===
<onlyinclude>{{#ifeq:{{{transcludesection|Related endogenous compounds}}}|Related endogenous compounds|
{{details|topic=related compounds|Trace amine}}

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 |vauthors=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>

==Chemistry==
{{Annotated image 4
| caption = The [[skeletal structure]]s of {{abbr|L-amph|Levoamphetamine}} and {{abbr|D-amph|Dextroamphetamine}}
| header = Racemic amphetamine
| header_align = center
| header_background = aliceblue
| alt = Graphical representation of Amphetamine stereoisomers
| image = Racemic_amphetamine.svg
| align = right
| image-width = 300
| image-left = 0
| image-top = 0
| width = 300
| height = 76
| annot-font-size = 14
| annot-text-align = left
| annotations =
{{Annotation|5|60|[[Levoamphetamine]]}}
{{Annotation|170|60|[[Dextroamphetamine]]}}
}}
{{multiple image
<!-- Essential parameters -->
| align = right
| direction = vertical
| width = 300
<!-- Extra parameters -->
| image1=Amphetamine Freebase.png
| caption1=A vial of the colorless amphetamine free base
| alt1=An image of amphetamine free base
| image2=Amphetamine and P2P.png
| caption2=Amphetamine hydrochloride (left bowl)<br />[[Phenyl-2-nitropropene]] (right cups)
| alt2=An image of phenyl-2-nitropropene and amphetamine hydrochloride
}}
}}


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


===Substituted derivatives===
{{Klasyfikacja ATC|N06}}
{{Main list|Substituted amphetamine}}
{{Stymulanty}}

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

===Synthesis===
{{Details|topic=illicit amphetamine synthesis|History and culture of substituted amphetamines#Illegal synthesis}}

Since the first preparation was reported in 1887,<ref name="Vermont"/> numerous synthetic routes to amphetamine have been developed.<ref name="Allen_Ely_2009">{{cite journal | url = http://www.nwafs.org/newsletters/2011_Spring.pdf | title = Review: Synthetic Methods for Amphetamine |vauthors=Allen A, Ely R | format = PDF | work = | publisher = Northwest Association of Forensic Scientists | volume = 37 | issue = 2 | date = April 2009 | pages = 15–25 | journal = Crime Scene | accessdate = 6 December 2014}}</ref><ref name="Allen_Cantrell_1989">{{cite journal |vauthors=Allen A, Cantrell TS | title = Synthetic reductions in clandestine amphetamine and methamphetamine laboratories: A review | journal = Forensic Science International | date = August 1989 | volume = 42 | issue = 3 | pages = 183–199 | doi = 10.1016/0379-0738(89)90086-8 }}</ref> The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the [[Leuckart reaction]] (method 1).<ref name="EMC"/><ref name="Amph Synth" /> In the first step, a reaction between phenylacetone and [[formamide]], either using additional [[formic acid]] or formamide itself as a reducing agent, yields {{nowrap|[[N-formylamphetamine|''N''-formylamphetamine]]}}. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.<ref name="Amph Synth" /><ref>{{cite journal | doi = 10.1021/jo01145a001 | title = The Mechanism of the Leuckart Reaction |date=May 1951 |vauthors=Pollard CB, Young DC | journal = 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 |veditors=Johnson DS, Li JJ | author = Gray DL | title = The Art of Drug Synthesis | chapter = Approved Treatments for Attention Deficit Hyperactivity Disorder: Amphetamine (Adderall), Methylphenidate (Ritalin), and Atomoxetine (Straterra) | chapterurl = https://books.google.com/books?id=zvruBDAulWEC&lpg=PP1&dq=The%20Art%20of%20Drug%20Synthesis%20(Wiley%20Series%20on%20Drug%20Synthesis)&pg=SA17-PA4#v=onepage&q=amphetamine&f=false | year = 2007 | publisher = Wiley-Interscience | location = New York, USA | isbn = 9780471752158 | page = 247 }}</ref>

A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.<ref name="Allen_Ely_2009"/><ref name="Allen_Cantrell_1989"/> One example is the [[Friedel–Crafts reaction#Friedel–Crafts alkylation|Friedel–Crafts]] alkylation of [[chlorobenzene]] by [[allyl chloride]] to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2).<ref name="pmid20985610">{{cite journal |vauthors=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 3). In this route, [[allylbenzene]] is reacted [[acetonitrile]] in sulfuric acid to yield an [[organosulfate]] which in turn is treated with sodium hydroxide to give amphetamine via an [[acetamide]] intermediate.<ref name="pmid18105933">{{cite journal |vauthors=Ritter JJ, Kalish J | title = A new reaction of nitriles; synthesis of t-carbinamines | journal = 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 |title=The Ritter Reaction|vauthors=Krimen LI, Cota DJ | journal = Organic Reactions | date = March 2011 | 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 4).<ref name = "US2413493">{{ cite patent | country = US | number = 2413493 | status = patent | title = Synthesis of isomer-free benzyl methyl acetoacetic methyl ester | pubdate = 31 December 1946 | fdate = 3 June 1943 | pridate = 3 June 1943 | inventor = Bitler WP, Flisik AC, Leonard N | assign1 = Kay Fries Chemicals Inc }}</ref>

A significant number of amphetamine syntheses feature a [[Organic redox reaction#Organic reductions|reduction]] of a [[nitro group|nitro]], [[imine]], [[oxime]] or other nitrogen-containing [[functional group]]s.<ref name = "Allen_Cantrell_1989"/> In one such example, a [[Knoevenagel condensation]] of [[benzaldehyde]] with [[nitroethane]] yields {{nowrap|[[phenyl-2-nitropropene]]}}. The double bond and nitro group of this intermediate is [[organic redox reaction|reduced]] using either catalytic [[hydrogenation]] or by treatment with [[lithium aluminium hydride]] (method 5).<ref name="Amph Synth">{{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><ref name="Delta Isotope">{{cite journal |vauthors=Collins M, Salouros H, Cawley AT, Robertson J, Heagney AC, Arenas-Queralt A | title = δ<sup>13</sup>C and δ<sup>2</sup>H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane | journal = Rapid Commun. Mass Spectrom. | volume = 24 | issue = 11 | pages = 1653–1658 |date=June 2010 | pmid = 20486262 | doi = 10.1002/rcm.4563 }}</ref> Another method is the reaction of [[phenylacetone]] with [[ammonia]], producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6).<ref name="Amph Synth" />

{| style="margin: 1em auto;"
|- style="vertical-align: top;"
|+'''Amphetamine synthetic routes'''
|<!--Left cell: nested table-->
{|
|{{multiple image
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| align = center
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| header =
| header_align = center
| header_background =
| footer =
| footer_align =
| footer_background =
| background color =

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

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

|image3=Amphetamine Friedel-Crafts alkylation.svg
|caption3=Method 2: Synthesis by Friedel–Crafts alkylation
|alt3=Diagram of amphetamine synthesis by Friedel–Crafts alkylation
}}
|}
|<!--Right cell: nested table-->
{|
|{{multiple image
<!-- Essential parameters -->
| align = center
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| header =
| header_align = center
| header_background =
| footer =
| footer_align =
| footer_background =
| background color =
|image1=Amphetamine Ritter Synthesis.svg
|caption1=Method 3: Ritter synthesis
|alt1=Diagram of amphetamine via Ritter synthesis
|image2=Amphetamine Hofmann Curtius Synthesis.svg
|caption2=Method 4: Synthesis via Hofmann and Curtius rearrangements
|alt2=Diagram of amphetamine synthesis via Hofmann and Curtius rearrangements
|image3=Amphetamine Knoevenagel synthesis.svg
|caption3=Method 5: Synthesis by Knoevenagel condensation
|alt3=Diagram of amphetamine synthesis by Knoevenagel condensation
|image4=Amphetamine p2p ammonia synthesis.svg
|caption4=Method 6: Synthesis using phenylacetone and ammonia
|alt4=Diagram of amphetamine synthesis from phenylacetone and ammonia
}}
|}
|}
{{clear}}

===Detection in body fluids===
Amphetamine is frequently measured in urine or blood as part of a [[drug test]] for sports, employment, poisoning diagnostics, and forensics.{{#tag:ref|<ref name="Ergogenics" /><ref name="pmid9700558">{{cite journal |vauthors=Kraemer T, Maurer HH | title = Determination of amphetamine, methamphetamine and amphetamine-derived designer drugs or medicaments in blood and urine | journal = 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 |vauthors=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 |vauthors=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 that contain [[levomethamphetamine]],{{#tag:ref|The active ingredient in some OTC inhalers in the United States is listed as ''levmetamfetamine'', the [[International Nonproprietary Name|INN]] and [[United States Adopted Name|USAN]] of levomethamphetamine.<ref name="FDA levmetamfetamine">{{cite encyclopedia | title=Code of Federal Regulations Title 21: Subchapter D – Drugs for human use | section = Part 341 – cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use | section-url=https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=341.80 | website=United States Food and Drug Administration | accessdate=7 March 2016 | date=April 2015 | quote=Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in each 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.}}</ref><ref>{{cite encyclopedia | title=Levomethamphetamine| section=Identification | section-url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604#section=Identification | work=Pubchem Compound| publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | accessdate=2 January 2014}}</ref>|name="OTC levmetamfetamine"|group = "note"}} or illicitly obtained substituted amphetamines.<ref name="pmid15516295">{{cite journal |vauthors=Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA | title = Enantiomeric separation and quantitation of (±)-amphetamine, (±)-methamphetamine, (±)-MDA, (±)-MDMA, and (±)-MDEA in urine specimens by GC-EI-MS after derivatization with (''R'')-(−)- or (''S'')-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (MTPA) | journal = 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 |vauthors=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 | date = August 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 article|History and culture of substituted amphetamines}}
{{Global estimates of illegal drug users}}

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist [[Lazăr Edeleanu]] who named it ''phenylisopropylamine'';<ref name="Vermont">{{cite web | url=http://healthvermont.gov/adap/meth/brief_history.aspx | 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 |vauthors=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 [[History of Benzedrine|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> Benzedrine sulfate was introduced three years later and found a wide variety of medical applications, including narcolepsy.<ref name="Benzedrine" /><ref name="pmid20997404">{{cite journal | vauthors = Bett WR | title = Benzedrine sulphate in clinical medicine; a survey of the literature | journal = Postgrad. Med. J. | volume = 22 | issue = | pages = 205–218 | date = August 1946 | pmid = 20997404 | pmc = 2478360 | doi = 10.1136/pgmj.22.250.205| url = }}</ref> During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.<ref name="Vermont" /><ref>{{cite journal | author = Rasmussen N | title=Medical science and the military: the Allies' use of amphetamine during World War II | journal=J. Interdiscip. Hist. | date=August 2011 | volume=42 | issue=2 | pages=205–233 | pmid=22073434 | doi=10.1162/JINH_a_00212 }}</ref><ref name="pmid22849208">{{cite journal |vauthors=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 = 10.1016/s1522-8649(11)50016-2}}</ref> As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.<ref name="Vermont" /> For example, during the early 1970s in the United States, amphetamine became a [[Schedule II (US)|schedule II controlled substance]] under the [[Controlled Substances Act]].<ref>{{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 = https://web.archive.org/web/20080214171739/http://www.wordsareimportant.com/ontheroad.htm | archivedate = 14 February 2008}}</ref> musicians,<ref>{{cite web | 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 | publisher = Internet Journal of Criminology | year = 2008 | accessdate=25 May 2013 }}</ref> mathematicians,<ref>{{cite web | title = Paul Erdos, Mathematical Genius, Human (In That Order) |url = http://www.untruth.org/~josh/math/Paul%20Erd%F6s%20bio-rev2.pdf | author = Hill J | 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">{{cite web | title = World Drug Report 2014 | editor = Mohan J | date = June 2014 | page = 3 | 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> 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 [[Euro|€]]6–38&nbsp;per gram during the same period.<ref name="EMCDDA 2014" /> Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.<ref name="WDR2014" />

===Legal status===
As a result of the [[United Nations]] 1971 [[Convention on Psychotropic Substances]], amphetamine became a schedule II controlled substance, as defined in the treaty, in all (183) state parties.<ref name="UN Convention">{{cite web|title=Convention on psychotropic substances |url=http://treaties.un.org/Pages/ViewDetails.aspx?src=TREATY&mtdsg_no=VI-16&chapter=6&lang=en |archive-url=https://web.archive.org/web/20160331074842/https://treaties.un.org/pages/ViewDetails.aspx?src=TREATY&mtdsg_no=VI-16&chapter=6&lang=en |archive-date=31 March 2016 |work=United Nations Treaty Collection |publisher=United Nations |accessdate=11 November 2013 |deadurl=no |df=dmy }}</ref> Consequently, it is heavily regulated in most countries.<ref name="UNODC2007">{{cite book | author = United Nations Office on Drugs and Crime | title = Preventing Amphetamine-type Stimulant Use Among Young People: A Policy and Programming Guide | publisher = United Nations | location = New York, 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 = https://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 = https://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 |deadurl=yes |archiveurl=https://web.archive.org/web/20131122143804/http://laws-lois.justice.gc.ca/eng/acts/C%2D38.8/page-24.html |archivedate=22 November 2013 }}</ref> the Netherlands ([[Opium Law|List I drug]]),<ref name="Opiumwet">{{cite web | url = http://wetten.overheid.nl/BWBR0001941/geldigheidsdatum_03-08-2009 | title = Opiumwet | publisher = Government of the Netherlands | accessdate = 3 April 2015 }}</ref> the United States ([[List of Schedule II drugs (US)|schedule II drug]]),<ref name="FDA Abuse & OD" /> Australia ([[Standard for the Uniform Scheduling of Medicines and Poisons#Schedule 8 Controlled Drug|schedule 8]]),<ref>{{cite encyclopedia | title = Poisons Standard | section = Schedule 8 | section-url = https://www.comlaw.gov.au/Details/F2015L01534/Html/Text#_Toc420496378 | url = https://www.comlaw.gov.au/Details/F2015L01534/Html/Text | publisher = Australian Government Department of Health | accessdate = 15 December 2015 | date = October 2015}}</ref> Thailand ([[Law of Thailand#Criminal Law|category 1 narcotic]]),<ref>{{cite web | url = http://narcotic.fda.moph.go.th/faq/upload/Thai%20Narcotic%20Act%202012.doc._37ef.pdf | archiveurl=https://web.archive.org/web/20140308001155/http://narcotic.fda.moph.go.th/faq/upload/Thai%20Narcotic%20Act%202012.doc._37ef.pdf | 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 | archivedate=8 March 2014 }}</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 = https://web.archive.org/web/20070804233232/http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/ | archivedate = 4 August 2007 }}</ref> amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.<ref name="WDR2014" /><ref name="Nonmedical">{{cite journal |vauthors=Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S | title = Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature | journal = 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>

===Pharmaceutical products===
Several currently prescribed amphetamine formulations contain both enantiomers, including Adderall, Dyanavel XR, and Evekeo, the last of which is racemic amphetamine sulfate.<ref name="Amph Uses" /><ref name="Evekeo" /><ref name="Dyanavel" /> 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="Amph Uses" /> Levoamphetamine was previously available as Cydril.<ref name="Amph Uses" /> Many current amphetamine pharmaceuticals are [[salt (chemistry)|salts]] due to the comparatively high volatility of the free base.<ref name="Amph Uses" /><ref name="NDCD" /><ref name="EMC" /> However, oral suspension and [[orally disintegrating tablet]] (ODT) [[dosage form]]s composed of the free base were introduced in 2015 and 2016.<ref name="Dyanavel" /><ref name="FDA Dyanavel approval date" /><ref name="Adzenys" /> Some of the current brands and their generic equivalents are listed below.
<!--This is a simple 1x2 matrix of nested tables-->
{| style="width: 100%"
|<!--Left cell: nested table-->
{| class="wikitable sortable" style="text-align:center; width:500px;"
|+ Amphetamine pharmaceuticals
! scope="col" | Brand<br />name
! scope="col" | [[United States Adopted Name|United&nbsp;States<br />Adopted&nbsp;Name]]
! scope="col" class="unsortable" style="text-align:center" | [[wikt:enantiomeric ratio|(D:L)&nbsp;ratio]]<br />
! scope="col"| Dosage<br />form
! scope="col" class="unsortable" | Marketing<br />start&nbsp;date
! scope="col" class="unsortable" | <small>Sources</small>
|-
| Adderall || – || 3:1&nbsp;<small>(salts)</small> <!--DO NOT CHANGE THIS RATIO: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666194/table/table1-0269881113482532/ -->|| tablet || 1996 || <ref name="Amph Uses" /><ref name="NDCD" />
|-
| Adderall&nbsp;XR || – || 3:1&nbsp;<small>(salts)</small> || capsule || 2001 || <ref name="Amph Uses" /><ref name="NDCD" />
|-
| Adzenys XR || amphetamine || 3:1&nbsp;<small>(base)</small> || [[Orally disintegrating tablet|ODT]] || 2016 || <ref name="Adzenys">{{cite web | title=Adzenys XR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204326s000lbl.pdf | website = United States Food and Drug Administration | publisher=Neos Therapeutics, Inc. | accessdate=7 March 2016 | page=15 | date=January 2016 | quote = ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.}}</ref><ref name="FDA Adzenys approval date">{{cite web | title=Adzenys XR | url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Adzenys&SearchType=BasicSearch | website=United States Food and Drug Administration | accessdate=7 March 2016}}</ref>
|-
| Dyanavel&nbsp;XR || amphetamine || 3.2:1&nbsp;<small>(base)</small> || suspension || 2015 || <ref name="Dyanavel" /><ref name="FDA Dyanavel approval date">{{cite web | title=Dyanavel XR| url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Dyanavel&SearchType=BasicSearch | website=United States Food and Drug Administration | accessdate=1 January 2016}}</ref>
|-
| Evekeo || amphetamine&nbsp;sulfate || 1:1&nbsp;<small>(salts)</small> || tablet || 2012 || <ref name="Evekeo">{{cite web | title=Evekeo Prescribing Information | url=https://www.evekeo.com/assets/evekeo-pi.pdf | publisher=Arbor Pharmaceuticals LLC | accessdate=11 August 2015 | pages=1–2 | date=April 2014}}</ref><ref name="Racemic amph - FDA Evekeo status">{{cite web | title=Evekeo | url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Evekeo&SearchType=BasicSearch | website=United States Food and Drug Administration | accessdate=11 August 2015}}</ref>
|-
| Dexedrine || dextroamphetamine&nbsp;sulfate || 1:0&nbsp;<small>(salts)</small> || capsule || 1976 || <ref name="Amph Uses" /><ref name="NDCD" />
|-
| ProCentra || dextroamphetamine&nbsp;sulfate || 1:0&nbsp;<small>(salts)</small> || liquid || 2010 || <ref name="NDCD" />
|-
| Zenzedi || dextroamphetamine&nbsp;sulfate || 1:0&nbsp;<small>(salts)</small> || tablet || 2013 || <ref name="NDCD" />
|-
| Vyvanse || lisdexamfetamine&nbsp;dimesylate || 1:0&nbsp;<small>(prodrug)</small> || capsule || 2007 || <ref name="Amph Uses">{{cite journal |vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–496 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 | quote = The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation.&nbsp;... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).}}</ref><ref name="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>
|}
|<!--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 lisdexamfetamine compound]]
|}
|}


{{Przypisy}}
[[Kategoria:Agonisty receptorów serotoninowych]]
[[Kategoria:Amfetaminy| ]]
[[Kategoria:ATC-N06]]
[[Kategoria:Leki anorektyczne]]
[[Kategoria:Leki psychostymulujące i nootropowe]]

Wersja z 19:34, 22 gru 2016

Szablon:Infobox drug

Amphetamine[note 1] (contracted from alphamethylphenethylamine) is a potent central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered in 1887 and exists as two enantiomers:[note 2] levoamphetamine and dextroamphetamine. 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 and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.[sources 1]

The first pharmaceutical amphetamine was Benzedrine, a brand which was used to treat a variety of conditions. Currently, pharmaceutical amphetamine is prescribed as racemic amphetamine, Adderall,[note 3] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases monoamine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine.[sources 2]

At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk with large recreational doses but is unlikely to arise from typical long-term medical use at therapeutic doses. 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 belongs to the phenethylamine class. It 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. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a constitutional isomer that differs only in the placement of the methyl group.[sources 4]

Szablon:TOC limit

Uses

Medical

Szablon:If pagename Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[32][33] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[34][35][36] Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.[34][35][36]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[37][38][39] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning two years have demonstrated treatment effectiveness and safety.[37][39] Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes[note 5] across nine outcome categories related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.[38][39] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[37] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.[39]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[40] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[40] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[7][40][41] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[42] 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][44] The Cochrane Collaboration's reviews[note 6] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[46][47] A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[48]

Enhancing performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;[49][50] the cognition-enhancing effects of amphetamine are known to occur through its indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex.[7][49] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[51] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[7][52] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[7][53][54] Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.[7][54][55] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs.[56][57][58] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[7][54]

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[8][22] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[59][60] In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction time.[8][61][62] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[61][62][63] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch" that allows the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[62][64][65] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[8][61] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[9][21][61]

Contraindications

Szablon:See also 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,[note 8] cardiovascular disease, severe agitation, or severe anxiety.[67][68] It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension.[67][68][69] People who have experienced allergic reactions to other stimulants in the past or who are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine,[67][68] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[70][71] These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine.[67][68] 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.[68] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[67][68] Due to the potential for reversible growth impairments,[note 9] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[67]

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.[9][21][22] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[17][21] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.[22]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[21] Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to extremities), and tachycardia (increased heart rate).[21][22][72] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[21] Abdominal side effects may include abdominal pain, appetite loss, nausea, and weight loss.[21][73] Other potential side effects include blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, and tics (a type of movement disorder).[sources 5] Dangerous physical side effects are rare at typical pharmaceutical doses.[22]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[22] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[22] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[22] This effect can be useful in treating bed wetting and loss of bladder control.[22] The effects of amphetamine on the gastrointestinal tract are unpredictable.[22] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[22] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[22] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[22]

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 6] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.[sources 7]

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.[21][22] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 8] these effects depend on the user's personality and current mental state.[22] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[9][21][23] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[9][21][24] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[21]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[46][80] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[80][81]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[68][82] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[22][68] Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose.[68] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[9][22] In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence).[note 10][83]

Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction.[84][85] Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since repeated overdoses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.[86][87][88] Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression.[86][89] While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction.[90][91] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[sources 9] exercise therapy improves clinical treatment outcomes and may be used as a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.[90][92][93] Szablon:Amphetamine overdose

Addiction

Szablon:Addiction glossary Szablon:Psychostimulant addiction Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical long-term medical use at therapeutic doses.[25][26][27] Szablon:If pagename Drug tolerance develops rapidly in amphetamine abuse (i.e., a recreational amphetamine overdose), so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[94][95]

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.[96][97][98] The most important transcription factors[note 11] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[97] ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 12] for most of the behavioral and neural adaptations that arise from addiction.[86][87][97] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[86][87] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 10]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression).[87][97][102] Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[97] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[89][97][103] Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.[89][97] Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[89][104][105] These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[89][103]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[98] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[98] 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.[98] This suggests that medical use of amphetamine does not significantly affect gene regulation.[98]

Pharmacological treatments

Szablon:Further information Szablon:As of, there is no effective pharmacotherapy for amphetamine addiction.[106][107][108] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[20][109] however, Szablon:As of, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[20][109] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 13] in the nucleus accumbens;[85] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[85][110] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[85] Supplemental magnesium[note 14] treatment has been shown to reduce amphetamine self-administration (i.e., doses given to oneself) in humans, but it is not an effective monotherapy for amphetamine addiction.[85]

Behavioral treatments

Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addictions.[93] Additionally, research on the neurobiological effects of physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct therapy (i.e., a supplemental treatment) for amphetamine addiction.[sources 9] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[90][92][111] In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D2 (DRD2) density in the striatum.[89][111] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[89] One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system.[91] Szablon:FOSB addiction table

Dependence and withdrawal

According to another Cochrane Collaboration review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[112] 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.[112] 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.[112] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[112] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[69][113][114]

Toxicity and psychosis

Szablon:See also

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminal degeneration and reduced transporter and receptor function.[115][116] There is no evidence that amphetamine is directly neurotoxic in humans.[117][118] However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia, the excessive formation of reactive oxygen species, and increased autoxidation of dopamine.[sources 11] Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity.[116] Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability.[116]

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as paranoia and delusions.[23] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[23][121] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[23] Psychosis very rarely arises from therapeutic use.[24][67]

Interactions

Szablon:See also Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.[122][123] Inhibitors of the enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer.[124][123] Amphetamine also interacts with Szablon:Abbr, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[123] therefore, concurrent use of both is dangerous.[123] Amphetamine modulates 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.[123] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[123] Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 15][128]

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.[123] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[123] 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 (i.e., make it less acidic).[123]

Pharmacology

Pharmacodynamics

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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.[19][130] Activation of Szablon:Abbr increases Szablon:Abbrlink production via adenylyl cyclase activation and inhibits monoamine transporter function.[19][131] 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.[19][20] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.[19][20] 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.[19] Szablon:As of 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.[19]

In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5.[sources 12] 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 12] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[138][139] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[139][140][141] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled Szablon:Abbr.[141][142] Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.[1][143] In humans, the only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with micromolar affinity.[144][145]

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine,[19] serotonin,[19] norepinephrine,[19] epinephrine,[129] histamine,[129] CART peptides,[138][139] endogenous opioids,[146][147][148] adrenocorticotropic hormone,[149][150] corticosteroids,[149][150] and glutamate,[132][134] which it effects through interactions with Szablon:Abbr, Szablon:Abbr, Szablon:Abbr, Szablon:Abbr, Szablon:Abbr, Szablon:Abbr, and possibly other biological targets.[sources 13]

Dextroamphetamine is a more potent agonist of Szablon:Abbr than levoamphetamine.[151] Consequently, dextroamphetamine produces greater Szablon:Abbr stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[22][151]

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[19] Amphetamine can enter the presynaptic neuron either through Szablon:Abbr or by diffusing across the neuronal membrane directly.[19] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[19] Upon entering the presynaptic neuron, amphetamine activates Szablon:Abbr which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[19] 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).[19][152] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux.[130][132][153] Through direct activation of G protein-coupled inwardly-rectifying potassium channels, Szablon:Abbr reduces the firing rate of postsynaptic dopamine neurons, preventing a hyper-dopaminergic state.[154][155][156]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, Szablon:Abbr.[129] Following amphetamine uptake at VMAT2, the synaptic vesicle releases dopamine molecules into the cytosol in exchange.[129] Subsequently, the cytosolic dopamine molecules exit the presynaptic neuron via reverse transport at Szablon:Abbr.[19][129]

Norepinephrine

Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[29][41] Based upon neuronal Szablon:Abbr Szablon:Abbr expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[19][129][152] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated Szablon:Abbr, competitive NET reuptake inhibition, and norepinephrine release from Szablon:Abbr.[19][129]

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[19][41] Amphetamine affects serotonin via Szablon:Abbr and, like norepinephrine, is thought to phosphorylate Szablon:Abbr via Szablon:Abbr.[19][129] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[144][145]

Other neurotransmitters, peptides, and hormones

Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system.[146][147][148] Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine.[132] This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons.[132][134] Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through Szablon:Abbr.[129] Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.[16][149][150]

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;[123] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[157] Amphetamine is a weak base with a pKa of 9.9;[122] 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.[122][123] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[122] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[158]

The half-life of amphetamine enantiomers differ and vary with urine pH.[122] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[122] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[159][160] The biological half-life is longer and distribution volumes are larger in amphetamine dependent individuals.[160] 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.[122] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[122] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[122] 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.[122] Amphetamine is usually eliminated within two days of the last oral dose.[159]Szablon:If pagename

CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans.[sources 14] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[122][159][164] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[167] 4‑hydroxynorephedrine,[168] and norephedrine.[169] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[122][159] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following: Szablon:Amphetamine Pharmacokinetics

Related endogenous compounds

Szablon:Details

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.[19][29] 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).[19][29][170] 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.[29][170] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[29][170] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via Szablon:Abbr;[19][170] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[29][170]

Chemistry

Szablon:Annotated image 4 Szablon:Multiple image

Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula Szablon: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.[2] This racemic mixture can be separated into its optical isomers:[note 16] levoamphetamine and dextroamphetamine.[2] 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.[171] Frequently prepared solid salts of amphetamine include amphetamine aspartate,[9] hydrochloride,[172] phosphate,[173] saccharate,[9] and sulfate,[9] the last of which is the most common amphetamine salt.[30] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[28][2] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[174]

Substituted derivatives

Szablon:Main list

The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";[28][31][175] specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents.[28][31][176] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[28][31][175]

Synthesis

Szablon:Details

Since the first preparation was reported in 1887,[177] numerous synthetic routes to amphetamine have been developed.[178][179] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1).[30][180] 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.[180][181]

A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[178] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[182] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[183] 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.[183]

A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.[178][179] One 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 2).[184] Another example employs the Ritter reaction (method 3). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate.[185][186] 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 4).[187]

A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime or other nitrogen-containing functional groups.[179] 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 5).[180][188] Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6).[180]

Amphetamine synthetic routes
Szablon:Multiple image
Szablon:Multiple image


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 15] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[192] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[193] Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products that contain levomethamphetamine,[note 17] or illicitly obtained substituted amphetamines.[193][196][197] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[5][198][199] These compounds may produce positive results for amphetamine on drug tests.[198][199] 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.[192]

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.[196] 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.[193] 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.[193] 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.[193]

History, society, and culture

Szablon:Main article Szablon:Global estimates of illegal drug users

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[177][200][201] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[201] 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.[10] Benzedrine sulfate was introduced three years later and found a wide variety of medical applications, including narcolepsy.[10][202] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[177][203][204] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[177] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[205] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[206] musicians,[207] mathematicians,[208] and athletes.[8]

Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[209] Among European Union (EU) member states, 1.2 million young adults used illicit amphetamine or methamphetamine in 2013.[210] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[210] the "street price" of illicit amphetamine within the EU ranged from 6–38 per gram during the same period.[210] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[209]

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.[11] Consequently, it is heavily regulated in most countries.[211][212] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[213][214] In other nations, such as Canada (schedule I drug),[215] the Netherlands (List I drug),[216] the United States (schedule II drug),[9] Australia (schedule 8),[217] Thailand (category 1 narcotic),[218] and United Kingdom (class B drug),[219] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[209][12]

Pharmaceutical products

Several currently prescribed amphetamine formulations contain both enantiomers, including Adderall, Dyanavel XR, and Evekeo, the last of which is racemic amphetamine sulfate.[5][16][73] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[17][220] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[220] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[5] Levoamphetamine was previously available as Cydril.[5] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[5][17][30] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016.[73][221][222] Some of the current brands and their generic equivalents are listed below.

Amphetamine pharmaceuticals
Brand
name
United States
Adopted Name
(D:L) ratio
Dosage
form
Marketing
start date
Sources
Adderall 3:1 (salts) tablet 1996 [5][17]
Adderall XR 3:1 (salts) capsule 2001 [5][17]
Adzenys XR amphetamine 3:1 (base) ODT 2016 [222][223]
Dyanavel XR amphetamine 3.2:1 (base) suspension 2015 [73][221]
Evekeo amphetamine sulfate 1:1 (salts) tablet 2012 [16][224]
Dexedrine dextroamphetamine sulfate 1:0 (salts) capsule 1976 [5][17]
ProCentra dextroamphetamine sulfate 1:0 (salts) liquid 2010 [17]
Zenzedi dextroamphetamine sulfate 1:0 (salts) tablet 2013 [17]
Vyvanse lisdexamfetamine dimesylate 1:0 (prodrug) capsule 2007 [5][220]
 
An image of the lisdexamfetamine compound
The skeletal structure of lisdexamfetamine
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    Figure 3: Treatment benefit by treatment type and outcome group
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    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
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Błąd w przypisach: Istnieje znacznik <ref> dla grupy o nazwie „note”, ale nie odnaleziono odpowiedniego znacznika <references group="note"/>
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