Examine individual changes

'{{Short description|Central nervous system stimulant}} {{Pp-vandalism|small=yes}} {{hatnote group| {{redirect|Meth}} {{redirect|Hiropon|the sculpture|Hiropon (sculpture)}} }} {{Use dmy dates|date=August 2022}} {{Use American English|date=May 2018}} <!--READ THIS BEFORE EDITING THE LEAD! Every statement in the lead has a reference in the body of the article. Do not delete something because you think it's dubious; look for the statement ref in the body text first.--> {{Good article}} {{Infobox drug | verifiedrevid = 589084691 | INN = Metamfetamine<!--"Metamfetamine [INN]" from https://pubchem.ncbi.nlm.nih.gov/compound/Methamphetamine#section=Depositor-Supplied-Synonyms--> | IUPAC_name = (''RS'')-''N''-methyl-1-phenylpropan-2-amine | image = Racemic methamphetamine.svg | alt = A racemic image of the methamphetamine compound | imageL = (R)-methamphetamine-based-on-xtal-3D-bs-17.png | altL = A 3d image of the levo-methamphetamine compound | imageR = (S)-methamphetamine-based-on-xtal-3D-bs-17.png | altR = A 3d image of the dextro-methamphetamine compound <!-- Clinical data -->| pronounce = {{IPAc-en|ˌ|m|ɛ|θ|æ|m|ˈ|f|ɛ|t|əm|iː|n}}<br/>({{Respell|METH|am|FET|ə|meen}}), {{IPAc-en|ˌ|m|ɛ|θ|ə|m|ˈ|f|ɛ|t|əm|iː|n}}<br/>({{Respell|METH|əm|FET|ə|meen}}), {{IPAc-en|ˌ|m|ɛ|θ|ə|m|ˈ|f|ɛ|t|əm|ə|n}}<br/>({{Respell|METH|əm|FET|ə|mən}})<ref>{{cite encyclopedia |entry-url=https://www.lexico.com/en/definition/methamphetamine |entry=methamphetamine |dictionary=Lexico |access-date=22 April 2022 |title=Methamphetamine |archive-date=14 June 2021 |archive-url=https://web.archive.org/web/20210614004641/https://www.lexico.com/en/definition/methamphetamine |url-status=dead }}</ref> | tradename = Desoxyn, Methedrine | Drugs.com = {{Drugs.com|monograph|methamphetamine-hydrochloride}} | pregnancy_AU = | pregnancy_US = C | dependency_liability = Physical: None; Psychological: Very High | addiction_liability = Very High | legal_AU = S8 | legal_BR = F2 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-07-25}}</ref> | legal_CA = Schedule I | legal_NZ = Class A | legal_UK = Class A | legal_US = Schedule II | legal_UN = Psychotropic Schedule II | legal_DE = Anlage II | licence_US = Methamphetamine | routes_of_administration = Medical: [[Oral route|oral (ingestion)]]<br />Recreational: [[Oral route|oral]], [[intravenous administration|intravenous]], [[intramuscular administration|intramuscular]], [[subcutaneous administration|subcutaneous]], [[smoking|vapour inhalation]], [[Insufflation (medicine)|insufflation]], [[Suppository|rectal]], [[intravaginal administration|vaginal]] <!-- Pharmacokinetic data -->| bioavailability = [[Oral administration|Oral]]: 67%<ref name="pmid19426289" /><ref name="Schep" /><ref name="pmid25176528" /><ref name="Bioavailability">{{cite journal |vauthors = Rau T, Ziemniak J, Poulsen D |title = The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury |journal = Prog. Neuropsychopharmacol. Biol. Psychiatry |volume = 64 |pages = 231–6 |year = 2015 |pmid = 25724762 |doi = 10.1016/j.pnpbp.2015.02.013 |quote = In humans, the oral bioavailability of methamphetamine is approximately 70% but increases to 100% following intravenous (IV) delivery (Ares-Santos et al., 2013). |doi-access = free }}</ref><br />[[Intranasal administration|Intranasal]]: 79%<ref name="pmid19426289" /><ref name="Schep" /><br />[[Inhalational administration|Inhalation]]: 67–90%<ref name="pmid19426289" /><ref name="Schep" /><ref name="pmid25176528" /><br />[[Intravenous administration|Intravenous]]: 100%<ref name="pmid19426289" /><ref name="Bioavailability" /> | protein_bound = Varies widely<ref name="Pubchem1">{{cite encyclopedia |title = Methamphetamine |section-url = https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Toxicity |work = PubChem Compound |publisher = National Center for Biotechnology Information |section = Toxicity |access-date = 4 January 2015 |archive-date = 4 January 2015 |archive-url = https://web.archive.org/web/20150104182703/https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Toxicity |url-status = live }}</ref> | metabolism = [[CYP2D6]]<ref name="Methamphetamine – p-hydroxymethamphetamine CYP2D6 review">{{cite journal |vauthors = Sellers EM, Tyndale RF |title = Mimicking gene defects to treat drug dependence |journal = Ann. N. Y. Acad. Sci. |volume = 909 |issue = 1|pages = 233–246 |date = 2000 |pmid = 10911933 |doi = 10.1111/j.1749-6632.2000.tb06685.x |quote = Methamphetamine, a central nervous system stimulant drug, is p-hydroxylated by CYP2D6 to less active p-OH-methamphetamine. |bibcode = 2000NYASA.909..233S |s2cid = 27787938 }}</ref><ref name="FDA Pharmacokinetics" /> and [[Flavin-containing monooxygenase 3|FMO3]]<ref name="FMO" /><ref name="FMO3-Primary" /> | onset = [[Oral administration|Oral]]: 3{{nbsp}}hours (peak)<ref name="pmid19426289" /><br />[[Intranasal]]: <15{{nbsp}}minutes<ref name="pmid19426289" /><br />[[Inhalational administration|Inhalation]]: <18{{nbsp}}minutes<ref name="pmid19426289" /><ref name="Schep" /><br />[[Intravenous]]: <15{{nbsp}}minutes<ref name="pmid19426289" /> | elimination_half-life = 9–12{{nbsp}}hours (range 5–30{{nbsp}}hours) (irrespective of route)<ref name="Schep" /><ref name="pmid19426289" /> | duration_of_action = 8–12{{nbsp}}hours<ref name="pmid25176528">{{cite journal | vauthors = Courtney KE, Ray LA | title = Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature | journal = Drug Alcohol Depend | volume = 143 | issue = | pages = 11–21 | date = October 2014 | pmid = 25176528 | pmc = 4164186 | doi = 10.1016/j.drugalcdep.2014.08.003 | url = }}</ref> | excretion = Primarily [[kidney]] <!-- Identifiers -->| index2_label = (dl)-Methamphetamine hydrochloride | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 537-46-2 | CAS_number2_Ref = {{cascite|correct|CAS}} | CAS_number2 = 300-42-5 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 44RAL3456C | UNII2_Ref = {{fdacite|correct|FDA}} | UNII2 = 24GNZ56D62 | ATC_prefix = N06 | ATC_suffix = BA03 | ATC_supplemental = | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 6809 | IUPHAR_ligand = 4803 | PDB_ligand = B40 | PubChem = 1206 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB01577 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 1169 | NIAID_ChemDB = | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08187 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1201201 | synonyms = {{nowrap|''N''-[[methylamphetamine]]}}, {{nowrap|''N'',α-[[dimethylphenethylamine]]}}, desoxyephedrine <!-- Chemical data -->| C = 10 | H = 15 | N = 1 | chirality = [[Racemic mixture]] | SMILES = CNC(C)Cc1ccccc1 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C10H15N/c1-9(11-2)8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = MYWUZJCMWCOHBA-UHFFFAOYSA-N <!-- Physical data -->| boiling_point = 212 | boiling_notes = at 760&nbsp;[[mmHg]]<ref name="Pubchem2">{{cite encyclopedia |title = Methamphetamine |section-url = https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Chemical-and-Physical-Properties |work = PubChem Compound |publisher = National Center for Biotechnology Information |section = Chemical and Physical Properties |access-date = 4 January 2015 |archive-date = 4 January 2015 |archive-url = https://web.archive.org/web/20150104182703/https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Chemical-and-Physical-Properties |url-status = live }}</ref> | melting_point = 170 | melting_notes = <ref name="Pubchem2"/> }} <!-- READ THIS BEFORE EDITING: every medical statement in the lead has a reference in the body of the article. Please do not delete contested lead content without either looking for the statement's ref in the body of the article and/or asking about it on the talk page first. --> '''Methamphetamine'''{{#tag:ref|Synonyms and alternate spellings include: ''N''-methylamphetamine, desoxyephedrine, Syndrox, Methedrine, and Desoxyn.<ref name="EMCDDA profile">{{cite web |url = http://www.emcdda.europa.eu/publications/drug-profiles/methamphetamine |title = Methamphetamine |date = 8 January 2015 |website = Drug profiles |publisher = [[European Monitoring Centre for Drugs and Drug Addiction]] (EMCDDA) |access-date = 27 November 2018 |quote = The term metamfetamine (the International Non-Proprietary Name: INN) strictly relates to the specific enantiomer (S)-N,α-dimethylbenzeneethanamine. |archive-url = https://web.archive.org/web/20160415220149/http://www.emcdda.europa.eu/publications/drug-profiles/methamphetamine |archive-date = 15 April 2016 |url-status = live }}</ref><ref name="DB ID">{{cite encyclopedia |title = Methamphetamine |section-url = http://www.drugbank.ca/drugs/DB01577#identification |work = DrugBank |publisher = University of Alberta |date = 8 February 2013 |section = Identification |access-date = 1 January 2014 |archive-date = 28 December 2015 |archive-url = https://web.archive.org/web/20151228164940/http://www.drugbank.ca/drugs/DB01577#identification |url-status = live }}</ref><ref>{{cite web |url = http://addictionlibrary.org/prescription/methedrine.html |title = Methedrine (methamphetamine hydrochloride): Uses, Symptoms, Signs and Addiction Treatment |newspaper = Addictionlibrary.org |access-date = 16 January 2016 |archive-url = https://web.archive.org/web/20160304045442/http://addictionlibrary.org/prescription/methedrine.html |archive-date = 4 March 2016 |url-status = live }}</ref> Common slang terms for methamphetamine include: '''speed''', '''meth''', '''crank''' and '''shabu''' (also '''sabu''' and '''shabu-shabu''') in Indonesia and the Philippines,<ref>{{Cite web |last=Detik News|title=Polisi Tangkap Bandar Shabu-shabu |url=https://news.detik.com/berita/d-356478/polisi-tangkap-bandar-shabu-shabu |access-date=2023-07-29 |website=detiknews |language=id-ID}}</ref><ref>{{Cite web |title=P1-M shabu seized from 3 drug pushers |url=https://mb.com.ph/2023/7/26/p1-m-shabu-seized-from-3-drug-pushers |access-date=2023-07-29 |website=Manila Bulletin |language=en}}</ref><ref>{{Cite web |last=Agency |first=ANTARA News |title=Jadi pengedar sabu seorang IRT di Pidoli Dolok ditangkap Polisi - ANTARA News Sumatera Utara |url=https://sumut.antaranews.com/berita/538872/jadi-pengedar-sabu-seorang-irt-di-pidoli-dolok-ditangkap-polisi |access-date=2023-07-29 |website=Antara News}}</ref><ref>{{Cite web |last=Marantal |first=Romeo D. |title=E-bike driver nabbed in drug bust, shabu worth almost P1 million seized |url=https://www.philstar.com/the-freeman/cebu-news/2023/06/02/2270858/e-bike-driver-nabbed-drug-bust-shabu-worth-almost-p1-million-seized |access-date=2023-07-29 |website=Philstar.com}}</ref> and for the hydrochloride '''crystal''', '''crystal meth''', '''glass''', '''shards''', and '''ice''',<ref>{{cite web |title = Meth Slang Names |url = http://www.methhelponline.com/meth-slang.htm |website = MethhelpOnline |access-date = 1 January 2014 |archive-url = https://web.archive.org/web/20131207185806/http://www.methhelponline.com/meth-slang.htm |archive-date = 7 December 2013 |url-status = live }}</ref> and, in New Zealand, '''P'''.<ref>{{cite web |url = http://www.police.govt.nz/advice/drugs-and-alcohol/methamphetamine-and-law |title = Methamphetamine and the law |access-date = 30 December 2014 |archive-url = https://web.archive.org/web/20150128175632/http://www.police.govt.nz/advice/drugs-and-alcohol/methamphetamine-and-law |archive-date = 28 January 2015 |url-status = live }}</ref>| group="note" }} (contracted from {{nowrap|'''''N''-[[methylamphetamine]]'''}}) is a potent [[central nervous system]] (CNS) [[stimulant]] that is mainly used as a [[recreational drug use|recreational drug]] and less commonly as a [[second-line treatment]] for [[attention deficit hyperactivity disorder]] and [[obesity]].<ref name="Recent advances in methamphetamine neurotoxicity – 2015 review">{{cite journal |vauthors = Yu S, Zhu L, Shen Q, Bai X, Di X |title = Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology |journal = Behav. Neurol. |volume = 2015 |pages = 103969 |date = March 2015 |pmid = 25861156 |pmc = 4377385 |doi = 10.1155/2015/103969 |quote = In 1971, METH was restricted by US law, although oral METH (Ovation Pharmaceuticals) continues to be used today in the USA as a second-line treatment for a number of medical conditions, including attention deficit hyperactivity disorder (ADHD) and refractory obesity [3]. |doi-access = free }}</ref> Methamphetamine was discovered in 1893 and exists as two [[enantiomer]]s: [[levo-methamphetamine]] and dextro-methamphetamine.{{#tag:ref|Enantiomers are molecules that are ''mirror images'' of one another; they are structurally identical, but of the opposite orientation.<br />Levomethamphetamine and dextromethamphetamine are also known as {{nowrap|L-methamphetamine}}, {{nowrap|(''R'')-methamphetamine}}, or levmetamfetamine ([[International Nonproprietary Name]] [INN]) and {{nowrap|D-methamphetamine}}, {{nowrap|(''S'')-methamphetamine}}, or metamfetamine ([[International Nonproprietary Name|INN]]), respectively.<ref name="EMCDDA profile" /><ref>{{cite encyclopedia | title=Levomethamphetamine | url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604 | work=Pubchem Compound | publisher=National Center for Biotechnology Information | access-date=27 November 2018 | archive-url=https://web.archive.org/web/20141006215922/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604 | archive-date=6 October 2014 | url-status=live }}</ref>|group="note"}} ''Methamphetamine'' properly refers to a specific chemical substance, the [[racemic mixture|racemic]] [[free base]], which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms, but the [[hydrochloride]] salt, commonly called crystal meth, is widely used. Methamphetamine is rarely prescribed over concerns involving human [[neurotoxicity]] and potential for recreational use as an [[aphrodisiac]] and [[euphoriant]], among other concerns, as well as the availability of safer [[substitute good|substitute drugs]] with comparable treatment efficacy such as [[Adderall]] and [[Vyvanse]]. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine. Both racemic methamphetamine and dextromethamphetamine are illicitly trafficked and sold owing to their potential for recreational use. The highest prevalence of illegal methamphetamine use occurs in parts of Asia and Oceania, and in the United States, where racemic methamphetamine and dextromethamphetamine are classified as [[list of Schedule II drugs (US)|schedule II]] controlled substances. [[Levomethamphetamine]] is available as an [[over-the-counter]] (OTC) drug for use as an inhaled [[nasal decongestant]] in the United States.{{#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 |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 every 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine. |access-date = 7 March 2016 |archive-date = 25 December 2019 |archive-url = https://web.archive.org/web/20191225081836/https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=341.80 |url-status = live }}</ref><ref>{{cite encyclopedia |title = Levomethamphetamine |section = Identification |section-url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604#section=Identification |work = Pubchem Compound |publisher = National Center for Biotechnology Information |access-date = 4 September 2017 |archive-date = 6 October 2014 |archive-url = https://web.archive.org/web/20141006215922/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604#section=Identification |url-status = live }}</ref>|name="OTC levmetamfetamine"|group="note"}} Internationally, the production, distribution, sale, and possession of methamphetamine is restricted or banned in many countries, owing to its placement in schedule II of the [[Convention on Psychotropic Substances|United Nations Convention on Psychotropic Substances]] treaty. While dextromethamphetamine is a more potent drug, racemic methamphetamine is illicitly produced more often, owing to the relative ease of [[#Synthesis|synthesis]] and regulatory limits of [[Precursor (chemistry)|chemical precursor]] availability. In low to moderate doses, methamphetamine can [[euphoria|elevate mood]], increase alertness, concentration and energy in fatigued individuals, reduce appetite, and promote weight loss. At very high doses, it can induce [[stimulant psychosis#Substituted amphetamines|psychosis]], [[rhabdomyolysis|breakdown of skeletal muscle]], [[Generalized seizures|seizures]] and [[cerebral hemorrhage|bleeding in the brain]]. Chronic high-dose use can precipitate unpredictable and rapid [[mood swing]]s, [[stimulant psychosis]] (e.g., [[paranoia]], [[hallucination]]s, [[delirium]], and [[delusion]]s) and [[Aggression|violent behavior]]. Recreationally, methamphetamine's ability to [[mental energy|increase energy]] has been reported to [[euphoria|lift mood]] and [[aphrodisiac|increase sexual desire]] to such an extent that users are able to engage in sexual activity continuously for several days while binging the drug.<ref name="AP-NBC 2004">{{cite web |title=Meth's aphrodisiac effect adds to drug's allure |url=http://www.nbcnews.com/id/6646180/ns/health-addictions/t/meths-aphrodisiac-effect-adds-drugs-allure/ |website=NBC News |publisher=Associated Press |access-date=12 September 2019 |archive-url=https://web.archive.org/web/20130812083225/http://www.nbcnews.com/id/6646180/ns/health-addictions/t/meths-aphrodisiac-effect-adds-drugs-allure/ |archive-date=12 August 2013 |date=3 December 2004}}</ref> Methamphetamine is known to possess a high [[addiction]] liability (i.e., a high likelihood that long-term or high dose use will lead to compulsive drug use) and high [[substance dependence|dependence]] liability (i.e. a high likelihood that [[drug withdrawal|withdrawal]] symptoms will occur when methamphetamine use ceases). Withdrawal from methamphetamine after heavy use may lead to a [[post-acute-withdrawal syndrome]], which can persist for months beyond the typical withdrawal period. Methamphetamine is [[neurotoxicity|neurotoxic]] to human [[midbrain]] [[Dopaminergic pathways|dopaminergic]] [[neuron]]s and, to a lesser extent, [[serotonin|serotonergic]] neurons at high doses.<ref name="Low dose Ntox">{{cite journal |vauthors = Yu S, Zhu L, Shen Q, Bai X, Di X |title = Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology |journal = Behav Neurol |volume = 2015 |pages = 1–11 |year = 2015 |pmid = 25861156 |pmc = 4377385 |doi = 10.1155/2015/103969 |doi-access = free }}</ref><ref name="pmid19328213" /> Methamphetamine neurotoxicity causes adverse changes in brain structure and function, such as reductions in [[grey matter]] volume in several brain regions, as well as adverse changes in markers of metabolic integrity.<ref name="pmid19328213" /> Methamphetamine belongs to the [[substituted phenethylamine]] and [[substituted amphetamine]] [[Chemical classification|chemical classes]]. It is related to the other [[dimethylphenethylamine]]s as a [[positional isomer]] of these compounds, which share the common [[chemical formula]] {{chem2|auto=1|C10H15N}}.<!-- READ THIS BEFORE EDITING: every medical statement in the lead has a reference in the body of the article. Please do not delete contested lead content without either looking for the statement's ref in the body of the article and/or asking about it on the talk page first. -->{{TOC limit|3}} == Uses == === Medical === [[File:Desoxyn Package of 100 Pills.jpg|thumb|Desoxyn (methamphetamine hydrochloride) 100 tablets]] In the United States, methamphetamine hydrochloride, under the trade name ''Desoxyn'', has been approved by the FDA for treating [[attention deficit hyperactivity disorder|ADHD]] and [[obesity]] in both adults and children;<ref name="Desoxyn" /><ref name="pmid22089317"/> however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use.<ref name="Desoxyn" /> To avoid toxicity and risk of side effects, FDA guidelines recommend an initial dose of methamphetamine at doses 5–10&nbsp;mg/day for ADHD in adults and children over six years of age, and may be increased at weekly intervals of 5&nbsp;mg, up to 25&nbsp;mg/day, until optimum clinical response is found; the usual effective dose is around 20–25&nbsp;mg/day.<ref name="Bioavailability" /><ref name="Desoxyn" /> Methamphetamine is sometimes prescribed [[off label]] for [[narcolepsy]] and [[idiopathic hypersomnia]].<ref name="pmid8341891">{{cite journal |vauthors = Mitler MM, Hajdukovic R, Erman MK |title = Treatment of narcolepsy with methamphetamine |journal = Sleep |volume = 16 |issue = 4 |pages = 306–317 |year = 1993 |pmid = 8341891 |pmc = 2267865 }}</ref><ref>{{cite journal |vauthors = Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, Boehlecke B, ((Chesson AL Jr)), Friedman L, Maganti R, Owens J, Pancer J, Zak R, ((Standards of Practice Committee of the American Academy of Sleep Medicine)) |title = Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin |journal = Sleep |volume = 30 |issue = 12|pages = 1705–11 |year = 2007 |pmid = 18246980 |pmc = 2276123 |doi = 10.1093/sleep/30.12.1705}}</ref> In the United States, [[levomethamphetamine|methamphetamine's levorotary form]] is available in some [[over-the-counter]] (OTC) [[nasal decongestant]] products.<ref name="OTC levmetamfetamine" group="note" /> As methamphetamine is associated with a high potential for misuse, the drug is regulated under the [[Controlled Substances Act]] and is [[List of Schedule II drugs (US)|listed under Schedule II]] in the United States.<ref name="Desoxyn" /> Methamphetamine hydrochloride dispensed in the United States is required to include a [[boxed warning]] regarding its potential for [[recreational drug use|recreational]] misuse and [[addiction]] liability.<ref name="Desoxyn" /> '''Desoxyn''' and '''Desoxyn Gradumet''' are both pharmaceutical forms of the drug. The latter is no longer produced and is a [[extended-release]] form of the drug, flattening the curve of the effect of the drug while extending it.<ref>{{Cite web |date=19 March 2022 |title=Desoxyn Gradumet Side Effects |url=https://www.drugs.com/sfx/desoxyn-gradumet-side-effects.html |url-status=live |access-date=18 October 2022 |website=Drugs.com |archive-date=18 October 2022 |archive-url=https://web.archive.org/web/20221018043550/https://www.drugs.com/sfx/desoxyn-gradumet-side-effects.html }}</ref> === Recreational === {{Hatnote|See also: [[Party and play]] and the [[History and culture of substituted amphetamines#Recreational routes of administration|Recreational routes of methamphetamine administration]]}} Methamphetamine is often used recreationally for its effects as a potent [[euphoriant]] and stimulant as well as [[aphrodisiac]] qualities.<ref name="SF Meth">{{cite AV media |date=August 2013 |title=San Francisco Meth Zombies |medium=TV documentary |url=http://channel.nationalgeographic.com/drugs-inc/episodes/san-francisco-meth-zombies/ |publisher=National Geographic Channel |asin=B00EHAOBAO |access-date=7 July 2016 |archive-url=https://web.archive.org/web/20160708142916/http://channel.nationalgeographic.com/drugs-inc/episodes/san-francisco-meth-zombies/ |archive-date=8 July 2016 |url-status=live }}</ref> According to a [[National Geographic Channel|National Geographic]] TV documentary on methamphetamine, an entire subculture known as [[party and play]] is based around sexual activity and methamphetamine use.<ref name="SF Meth" /> Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up through [[internet dating]] sites and have sex.<ref name="SF Meth" /> Because of its strong stimulant and aphrodisiac effects and inhibitory effect on [[ejaculation]], with repeated use, these sexual encounters will sometimes occur continuously for several days on end.<ref name="SF Meth" /> The crash following the use of methamphetamine in this manner is very often severe, with marked [[hypersomnia]] (excessive daytime sleepiness).<ref name="SF Meth" /> The party and play subculture is prevalent in major US cities such as San Francisco and New York City.<ref name="SF Meth" /><ref>{{cite book | vauthors = Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE |title = Goldfrank's toxicologic emergencies |date = 2011 |publisher = McGraw-Hill Medical |location = New York |isbn = 978-0-07-160593-9 |edition = 9th |page = 1080 }}</ref> {{multiple image <!-- Essential parameters --> | align = center | direction = horizontal | width = <!-- Extra parameters --> | header = | header_align = center | header_background = | footer = | footer_align = | footer_background = | background color = <!-- Images – the template can take up to 10 --> |image1=Desoxyn (methamphetamine) 5 mg tablets.jpg |image2=Blue Crystal Meth.jpg <!-- Image parameters – width is ignored if the "essential parameter" width is specified --> |width1=260 |caption1=Desoxyn tablets&nbsp;– pharmaceutical methamphetamine hydrochloride |alt1=Desoxyn tablet |width2=236 |caption2=Crystal meth&nbsp;– illicit methamphetamine hydrochloride |alt2=Crystal meth }} {{clear}} == Contraindications == Methamphetamine is [[contraindicated]] in individuals with a history of [[substance use disorder]], [[heart disease]], or severe [[Irritability|agitation]] or anxiety, or in individuals currently experiencing [[arteriosclerosis]], [[glaucoma]], [[hyperthyroidism]], or severe [[hypertension]].<ref name="Desoxyn" /> The FDA states that individuals who have experienced [[hypersensitivity]] reactions to other stimulants in the past or are currently taking [[monoamine oxidase inhibitor]]s should not take methamphetamine.<ref name="Desoxyn" /> The FDA also advises individuals with [[bipolar disorder]], [[Major depressive disorder|depression]], elevated [[blood pressure]], liver or kidney problems, [[mania]], [[psychosis]], [[Raynaud's phenomenon]], [[epileptic seizure|seizures]], [[thyroid]] problems, [[tic]]s, or [[Tourette syndrome]] to monitor their symptoms while taking methamphetamine.<ref name="Desoxyn" /> Owing to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.<ref name="Desoxyn" /> == Adverse effects == [[File:HarmCausedByDrugsTable.svg|thumb|right|upright=1.0|A 2010 study ranking various illegal and legal drugs based on statements by drug-harm experts. Methamphetamine was found to be the fourth most damaging to users.<ref>{{cite journal | vauthors = Nutt DJ, King LA, Phillips LD | title = Drug harms in the UK: a multicriteria decision analysis | journal = Lancet | volume = 376 | issue = 9752 | pages = 1558–65 | date = November 2010 | pmid = 21036393 | doi = 10.1016/S0140-6736(10)61462-6 | citeseerx = 10.1.1.690.1283 | s2cid = 5667719 }}</ref>]] === Physical === The physical effects of methamphetamine can include [[Anorexia (symptom)|loss of appetite]], hyperactivity, [[dilated pupils]], [[Flushing (physiology)|flushed skin]], [[diaphoresis|excessive sweating]], [[Psychomotor agitation|increased movement]], dry mouth and [[bruxism|teeth grinding]] (leading to "[[meth mouth]]"), headache, [[arrhythmias|irregular heartbeat]] (usually as [[tachycardia|accelerated heartbeat]] or [[bradycardia|slowed heartbeat]]), [[tachypnea|rapid breathing]], [[hypertension|high blood pressure]], [[hypotension|low blood pressure]], [[hyperthermia|high body temperature]], diarrhea, constipation, [[blurred vision]], [[dizziness]], [[Fasciculation|twitching]], [[numbness]], [[tremor]]s, dry skin, [[acne]], and [[pallor|pale appearance]].<ref name="Desoxyn" /><ref name="Westfall" /> Long-term meth users may have [[Ulcer (dermatology)|sores]] on their skin;<ref name=NIH-What>{{cite web | url = https://www.drugabuse.gov/publications/research-reports/methamphetamine/what-are-long-term-effects-methamphetamine-misuse | title = What are the long-term effects of methamphetamine misuse? | date = October 2019 | work = National Institute on Drug Abuse | publisher = [[National Institutes of Health]], U.S. Department of Health & Human Services | access-date = 15 March 2020 | archive-date = 29 March 2020 | archive-url = https://web.archive.org/web/20200329012502/https://www.drugabuse.gov/publications/research-reports/methamphetamine/what-are-long-term-effects-methamphetamine-misuse | url-status = live }}</ref><ref name=Elkins /> these may be caused by scratching due to [[itchiness]] or the belief that insects are crawling under their skin,<ref name=NIH-What/> and the damage is compounded by poor diet and hygiene.<ref name=Elkins>{{cite web | url = https://www.drugrehab.com/addiction/drugs/crystal-meth/sores/ | title = Meth Sores | vauthors = Elkins C | date = 27 February 2020 | work = DrugRehab.com | publisher = Advanced Recovery Systems | access-date = 15 March 2020 | archive-date = 14 August 2020 | archive-url = https://web.archive.org/web/20200814113224/https://www.drugrehab.com/addiction/drugs/crystal-meth/sores/ | url-status = live }}</ref> Numerous deaths related to methamphetamine overdoses have been reported.<ref>{{Cite web|url=https://www.bluecrestrc.com/can-you-overdose-on-meth/|title=Meth Overdose Symptoms, Effects & Treatment &#124; BlueCrest|date=17 June 2019|website=Bluecrest Recovery Center|access-date=8 October 2020|archive-date=16 January 2021|archive-url=https://web.archive.org/web/20210116171406/https://www.bluecrestrc.com/can-you-overdose-on-meth/|url-status=live}}</ref><ref>{{Cite web|url=https://www.drugabuse.gov/drug-topics/trends-statistics/overdose-death-rates|title=Overdose Death Rates|author=National Institute on Drug Abuse|date=29 January 2021|website=National Institute on Drug Abuse|access-date=8 October 2020|archive-date=25 January 2018|archive-url=https://web.archive.org/web/20180125182059/https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates|url-status=live}}</ref> ==== Meth mouth ==== {{Main|Meth mouth}} [[File:Suspectedmethmouth09-19-05.jpg|thumb|A suspected case of [[meth mouth]]]] Methamphetamine users and addicts may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as [[meth mouth]].<ref name="pmid22782046" /> The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.<ref name="pmid22782046">{{cite journal |vauthors = Hussain F, Frare RW, Py Berrios KL |title = Drug abuse identification and pain management in dental patients: a case study and literature review |journal = Gen. Dent. |volume = 60 |issue = 4 |pages = 334–345 |year = 2012 |pmid = 22782046 }}</ref> According to the [[American Dental Association]], meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in [[xerostomia]] (dry mouth), extended periods of poor [[oral hygiene]], frequent consumption of high-calorie, carbonated beverages and [[bruxism]] (teeth grinding and clenching)".<ref name="pmid22782046" /><ref name="ADA">{{cite web |url = http://www.ada.org/prof/resources/topics/methmouth.asp |title = Methamphetamine Use (Meth Mouth) |access-date = 15 December 2006 |publisher = American Dental Association |archive-url = https://web.archive.org/web/20080601035323/http://www.ada.org/prof/resources/topics/methmouth.asp |archive-date = 2008-06-01 }}</ref> As dry mouth is also a common side effect of other stimulants, which are not known to contribute severe tooth decay, many researchers suggest that methamphetamine-associated tooth decay is more due to users' other choices. They suggest the side effect has been exaggerated and stylized to create a stereotype of current users as a deterrence for new ones.<ref name="pmid22089317">{{cite journal |vauthors = Hart CL, Marvin CB, Silver R, Smith EE |title = Is cognitive functioning impaired in methamphetamine users? A critical review |journal = Neuropsychopharmacology |volume = 37 |issue = 3 |pages = 586–608 |date = February 2012 |pmid = 22089317 |pmc = 3260986 |doi = 10.1038/npp.2011.276 }}</ref> ==== Sexually transmitted infection ==== Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both [[HIV/AIDS|HIV-positive]] and unknown casual partners, an association more pronounced in HIV-positive participants.<ref name="STD" /> These findings suggest that methamphetamine use and engagement in unprotected anal intercourse are co-occurring risk behaviors, behaviors that potentially heighten the risk of HIV transmission among gay and bisexual men.<ref name="STD">{{cite journal |vauthors = Halkitis PN, Pandey Mukherjee P, Palamar JJ |title = Longitudinal Modeling of Methamphetamine Use and Sexual Risk Behaviors in Gay and Bisexual Men |journal = AIDS and Behavior |volume = 13 |issue = 4 |pages = 783–791 |year = 2008 |pmid = 18661225 |doi = 10.1007/s10461-008-9432-y |pmc = 4669892 }}</ref> Methamphetamine use allows users of both sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions as well as [[priapism]] in men.<ref name="Desoxyn" /><ref name="Patrick Moore">{{cite web | vauthors = Moore P |url = http://www.villagevoice.com/2005-06-14/people/we-are-not-ok/ |title = We Are Not OK |publisher = VillageVoice |date = June 2005 |access-date = 15 January 2011 |archive-url = https://web.archive.org/web/20110604154056/http://www.villagevoice.com/2005-06-14/people/we-are-not-ok/ |archive-date = 4 June 2011 |url-status = live }}</ref> Methamphetamine may also cause sores and abrasions in the mouth via [[bruxism]], increasing the risk of sexually transmitted infection.<ref name="Desoxyn" /><ref name="Patrick Moore" /> Besides the sexual transmission of HIV, it may also be transmitted between users who [[needle sharing|share a common needle]].<ref name="unsw" /> The level of needle sharing among methamphetamine users is similar to that among other drug injection users.<ref name="unsw">{{cite web |url = http://www.med.unsw.edu.au/NDARCWeb.nsf/resources/NDLERF_Methamphetamine/$file/NDLERF+USE+AND+HEALTH.pdf |archive-url = https://web.archive.org/web/20080816134234/http://www.med.unsw.edu.au/NDARCWeb.nsf/resources/NDLERF_Methamphetamine/%24file/NDLERF%2BUSE%2BAND%2BHEALTH.pdf |archive-date = 16 August 2008 |title = Methamphetamine Use and Health {{pipe}} UNSW: The University of New South Wales&nbsp;– Faculty of Medicine |access-date = 15 January 2011 |url-status=dead }}</ref> === Psychological === The psychological effects of methamphetamine can include [[euphoria]], [[dysphoria]], changes in [[libido]], [[alertness]], apprehension and [[concentration]], decreased sense of fatigue, [[insomnia]] or [[wakefulness]], [[self-confidence]], sociability, irritability, restlessness, [[grandiosity]] and [[Fixation (psychology)|repetitive and obsessive]] behaviors.<ref name="Desoxyn">{{cite web |title = Desoxyn Prescribing Information |url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/005378s028lbl.pdf |date = December 2013 |website = United States Food and Drug Administration |access-date = 6 January 2014 |archive-url = https://web.archive.org/web/20140102192621/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/005378s028lbl.pdf |archive-date = 2 January 2014 |url-status = live }}</ref><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 |isbn = 978-0-07-162442-8 |vauthors = Westfall DP, Westfall TC |section = Miscellaneous Sympathomimetic Agonists |section-url = http://www.accessmedicine.com/content.aspx?aID=16661601 |edition = 12th |access-date = 1 January 2014 |archive-date = 10 November 2013 |archive-url = https://web.archive.org/web/20131110094145/http://www.accessmedicine.com/content.aspx?aID=16661601 }}</ref><ref name="Merck_Manual_Amphetamines">{{cite web |url = http://www.merckmanuals.com/professional/special_subjects/drug_use_and_dependence/amphetamines.html | vauthors = O'Connor PG |title = Amphetamines |website = Merck Manual for Health Care Professionals |publisher = Merck |date = February 2012 |access-date = 8 May 2012 |archive-url = https://web.archive.org/web/20120506232123/http://www.merckmanuals.com/professional/special_subjects/drug_use_and_dependence/amphetamines.html |archive-date = 6 May 2012 |url-status = live }}</ref> Peculiar to methamphetamine and related stimulants is "[[punding]]", persistent non-goal-directed repetitive activity.<ref name="NeurClin">{{cite journal | vauthors = Rusinyak DE |title = Neurologic manifestations of chronic methamphetamine abuse |journal = Neurologic Clinics |date = 2011 |volume = 29 |issue = 3 |pages = 641–655 |doi = 10.1016/j.ncl.2011.05.004 |pmc = 3148451 |pmid = 21803215 }}</ref> Methamphetamine use also has a high association with [[anxiety]], [[Major depressive disorder|depression]], [[Stimulant psychosis#Substituted amphetamines|amphetamine psychosis]], [[suicide]], and violent behaviors.<ref name="Darke-2008">{{cite journal |vauthors = Darke S, Kaye S, McKetin R, Duflou J |title = Major physical and psychological harms of methamphetamine use |journal = Drug Alcohol Rev. |volume = 27 |issue = 3 |pages = 253–262 |date = May 2008 |pmid = 18368606 |doi = 10.1080/09595230801923702 }}</ref><ref name="Sword">{{cite news |vauthors=Raskin S |title=Missouri sword slay suspect smiles for mug shot after allegedly killing beau |url=https://nypost.com/2021/12/26/missouri-woman-grins-for-mug-shot-after-alleged-sword-slay/ |access-date=26 December 2021 |agency=New York Post |date=26 December 2021 |archive-date=26 December 2021 |archive-url=https://web.archive.org/web/20211226192534/https://nypost.com/2021/12/26/missouri-woman-grins-for-mug-shot-after-alleged-sword-slay/ |url-status=live }}</ref> === Neurotoxic and neuroimmunological === [[File:Glial ntox review.jpg|upright=1.5|thumb|right|This diagram depicts the [[Neuroimmune system|neuroimmune mechanisms]] that mediate methamphetamine-induced neurodegeneration in the human brain.<ref name="Glial tox review – Ntox diagram" /> The [[NF-κB]]-mediated neuroimmune response to methamphetamine use which results in the increased permeability of the [[blood–brain barrier]] arises through its binding at and activation of [[sigma receptor]]s, the increased production of [[reactive oxygen species]] (ROS), [[reactive nitrogen species]] (RNS), and [[damage-associated molecular pattern molecules]] (DAMPs), the dysregulation of [[glutamate transporter]]s (specifically, [[EAAT1]] and [[EAAT2]]) and [[glucose metabolism]], and excessive [[calcium in biology|Ca²⁺ ion]] influx in [[glial cell]]s and dopamine [[neuron]]s.<ref name="Glial tox review – Ntox diagram">{{Cite book |vauthors = Beardsley PM, Hauser KF |chapter = Glial Modulators as Potential Treatments of Psychostimulant Abuse |title = Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse |volume = 69 |pages = 1–69 |year = 2014 |pmid = 24484974 |pmc = 4103010 |doi = 10.1016/B978-0-12-420118-7.00001-9 |quote = Glia (including astrocytes, microglia, and oligodendrocytes), which constitute the majority of cells in the brain, have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants |series = Advances in Pharmacology |isbn = 9780124201187 }}</ref><ref name="Neuroimmune meth toxicity">{{Cite book |vauthors = Loftis JM, Janowsky A |title = Neuroimmune Signaling in Drug Actions and Addictions |chapter = Neuroimmune basis of methamphetamine toxicity |journal = Int. Rev. Neurobiol. |volume = 118 |pages = 165–197 |year = 2014 |pmid = 25175865 |pmc = 4418472 |doi = 10.1016/B978-0-12-801284-0.00007-5 |quote = Collectively, these pathological processes contribute to neurotoxicity (e.g., increased BBB permeability, inflammation, neuronal degeneration, cell death) and neuropsychiatric impairments (e.g., cognitive deficits, mood disorders) |series = International Review of Neurobiology |isbn = 9780128012840 }}<br />"[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418472/figure/F1/ Figure 7.1: Neuroimmune mechanisms of methamphetamine-induced CNS toxicity] {{Webarchive|url=https://web.archive.org/web/20180916144723/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418472/figure/F1/ |date=16 September 2018 }}"</ref><ref name="Sigma" />]] Methamphetamine is directly [[neurotoxic]] to dopaminergic neurons in both lab animals and humans.<ref name="Low dose Ntox" /><ref name="pmid19328213" /> [[Excitotoxicity]], [[oxidative stress]], metabolic compromise, UPS dysfunction, protein nitration, [[Endoplasmic reticulum stress in beta cells|endoplasmic reticulum stress]], [[p53 expression]] and other processes contributed to this neurotoxicity.<ref name="Neurotoxicity 2015">{{cite journal |vauthors = Yu S, Zhu L, Shen Q, Bai X, Di X |title = Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology |journal = Behavioural Neurology |volume = 2015 |date = 2015 |page = 103969 |pmid = 25861156 |pmc = 4377385 |doi = 10.1155/2015/103969 |doi-access = free }}</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 |s2cid = 2873101 }}</ref><ref name="Cruickshank-2009">{{cite journal |vauthors = Cruickshank CC, Dyer KR |title = A review of the clinical pharmacology of methamphetamine |journal = Addiction |volume = 104 |issue = 7 |pages = 1085–1099 |date = July 2009 |pmid = 19426289 |doi = 10.1111/j.1360-0443.2009.02564.x |s2cid = 37079117 |doi-access = free }}</ref> In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of [[Parkinson's disease]].<ref name="Cisneros_2014 and review" /> In addition to its dopaminergic neurotoxicity, a review of evidence in humans indicated that high-dose methamphetamine use can also be neurotoxic to [[serotonin|serotonergic]] neurons.<ref name="pmid19328213">{{cite journal |vauthors = Krasnova IN, Cadet JL |title = Methamphetamine toxicity and messengers of death |journal = Brain Res. Rev. |volume = 60 |issue = 2 |pages = 379–407 |date = May 2009 |pmid = 19328213 |pmc = 2731235 |doi = 10.1016/j.brainresrev.2009.03.002 |quote = Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006)&nbsp;...<br />Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts&nbsp;...<br /> There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals&nbsp;...<br /> Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007). }}</ref> It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.<ref>{{cite journal |vauthors = Yuan J, Hatzidimitriou G, Suthar P, Mueller M, McCann U, Ricaurte G |title = Relationship between temperature, dopaminergic neurotoxicity, and plasma drug concentrations in methamphetamine-treated squirrel monkeys |journal = The Journal of Pharmacology and Experimental Therapeutics |volume = 316 |issue = 3 |pages = 1210–1218 |date = March 2006 |pmid = 16293712 |doi = 10.1124/jpet.105.096503 |s2cid = 11909155 |url = https://semanticscholar.org/paper/8ee9ad283b3c02b201346ce8e3dafff98655245c |access-date = 28 December 2019 |archive-date = 31 October 2021 |archive-url = https://web.archive.org/web/20211031105430/https://www.semanticscholar.org/paper/Relationship-between-Temperature%2C-Dopaminergic-and-Yuan-Hatzidimitriou/8ee9ad283b3c02b201346ce8e3dafff98655245c |url-status = live }}</ref> Withdrawal of methamphetamine in dependent persons may lead to [[post-acute-withdrawal syndrome|post-acute withdrawal]] which persists months beyond the typical withdrawal period.<ref name="Cruickshank-2009" /> [[Magnetic resonance imaging]] studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse [[neuroplastic]] changes in brain structure and function.<ref name="pmid19328213" /> In particular, methamphetamine appears to cause [[hyperintensity]] and [[hypertrophy]] of [[white matter]], marked shrinkage of [[Hippocampus|hippocampi]], and reduced [[gray matter]] in the [[cingulate cortex]], [[limbic cortex]], and [[paralimbic cortex]] in recreational methamphetamine users.<ref name="pmid19328213" /> Moreover, evidence suggests that adverse changes in the level of [[biomarker]]s of metabolic integrity and synthesis occur in recreational users, such as a reduction in [[N-acetylaspartate|''N''-acetylaspartate]] and [[creatine]] levels and elevated levels of [[choline]] and [[myoinositol]].<ref name="pmid19328213" /> Methamphetamine has been shown to activate [[TAAR1]] in human [[astrocytes]] and generate [[cyclic AMP|cAMP]] as a result.<ref name="Cisneros_2014 and review" /> Activation of astrocyte-localized TAAR1 appears to function as a mechanism by which methamphetamine attenuates membrane-bound [[EAAT2]] (SLC1A2) levels and function in these cells.<ref name="Cisneros_2014 and review"><!--Primary ref-->{{bull}}{{cite journal |vauthors = Cisneros IE, Ghorpade A |title = Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes |journal = Neuropharmacology |volume = 85 |pages = 499–507 |date = October 2014 |pmid = 24950453 |doi = 10.1016/j.neuropharm.2014.06.011 |quote = TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance&nbsp;... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. |pmc = 4315503 }}<br /><!--Review: cites ref above-->{{bull}}{{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 |pages = 345–352 |date = August 2015 |pmid = 26092759 |doi = 10.1016/j.ejphar.2015.06.019 |quote = TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007) |pmc = 4532615 }}</ref> Methamphetamine binds to and activates both [[sigma receptor]] subtypes, [[Sigma-1 receptor|σ₁]] and [[Sigma-2 receptor|σ₂]], with micromolar affinity.<ref name="Sigma" /><ref name="SigmaB" /> Sigma receptor activation may promote methamphetamine-induced neurotoxicity by facilitating [[hyperthermia]], increasing dopamine synthesis and release, influencing microglial activation, and modulating [[apoptotic]] signaling cascades and the formation of reactive oxygen species.<ref name="Sigma" /><ref name="SigmaB" /> === Addictive === {{Addiction glossary|collapse=yes|width=610px}} {{Psychostimulant addiction|align=right}} 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 |pages = 565–598 |date = July 2006 |pmid = 16776597 |doi = 10.1146/annurev.neuro.29.051605.113009 |s2cid = 15139406 |url = https://pdfs.semanticscholar.org/fc1e/144037cd3c08aaf32d0a92b8c55a6ae451a5.pdf |archive-url = https://web.archive.org/web/20180919115435/https://pdfs.semanticscholar.org/fc1e/144037cd3c08aaf32d0a92b8c55a6ae451a5.pdf |archive-date = 19 September 2018 }}</ref><ref name="Nestler" /> 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 = 978-0-07-148127-4 |page = 94 |edition = 2nd |chapter = Chapter 4: Signal Transduction in the Brain |quote = <!-- All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug. --> }}</ref>|group="note"}} that produce these alterations are [[ΔFosB]], [[Cyclic adenosine monophosphate|cAMP]] response element binding protein ([[cAMP response element binding protein|CREB]]), and nuclear factor kappa B ([[nuclear factor kappa B|NFκB]]).<ref name="Nestler" /> ΔFosB 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="Cellular basis" /><ref name="Nestler" /><ref name="What the ΔFosB?" /> Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /> It has been implicated in addictions to [[alcoholism|alcohol]], [[cannabinoid]]s, [[cocaine]], [[methylphenidate]], [[nicotine]], [[opioid]]s, [[phencyclidine]], [[propofol]], and [[substituted amphetamines]], among others.<ref name="Nestler" /><ref name="What the ΔFosB?">{{cite journal | vauthors = 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 |s2cid = 19157711 |quote = ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. }}</ref><!--Preceding review covers ΔFosB in propofol addiction--><ref name="Natural and drug addictions">{{cite journal | vauthors = 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><ref name="Alcoholism ΔFosB">{{cite web |title = Alcoholism – Homo sapiens (human) |url = http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 |website = KEGG Pathway |access-date = 31 October 2014 |author = Kanehisa Laboratories |date = 29 October 2014 |archive-url = https://web.archive.org/web/20141013072800/http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 |archive-date = 13 October 2014 |url-status = live }}</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 misuse and addiction (3, 6–10). Thus, although oral administration of clinical doses of methylphenidate is not associated with euphoria or with misuse problems, nontherapeutic use of high doses or i.v. administration may lead to addiction (39, 40).--> |bibcode = 2009PNAS..106.2915K |doi-access = free }}</ref> [[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 |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 an 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 use (i.e., the alterations mediated by ΔFosB).<ref name="Nestler" /> ΔFosB also plays an important role in regulating behavioral responses to [[natural reward]]s, such as palatable food, sex, and exercise.<ref name="Nestler" /><ref name="Natural and drug addictions" /><ref name="ΔFosB reward">{{cite journal |vauthors = Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M |title = Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms |journal = Journal of Psychoactive Drugs |volume = 44 |issue = 1 |pages = 38–55 |date = March 2012 |pmid = 22641964 |pmc = 4040958 |doi = 10.1080/02791072.2012.662112 |quote = It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus.&nbsp;... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance.&nbsp;... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. }}</ref> Since both natural rewards and addictive drugs [[inducible gene|induce 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="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^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high-fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. }}</ref><ref name="Natural and drug addictions" /> 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.{{#tag:ref|The associated research only involved amphetamine, not methamphetamine; however, this statement is included here due to the similarity between the pharmacodynamics and aphrodisiac effects of amphetamine and methamphetamine.|group="note"}}<ref name="Natural and drug addictions" /><ref name="Amph and sex addiction" /> These sex addictions (i.e., drug-induced compulsive sexual behaviors) are associated with a [[dopamine dysregulation syndrome]] which occurs in some patients taking [[dopaminergic#Supplements and drugs|dopaminergic drugs]], such as amphetamine or methamphetamine.<ref name="Natural and drug addictions" /><ref name="ΔFosB reward" /><ref name="Amph and sex addiction"><!--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 = Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior.&nbsp;... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.&nbsp;... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity }}</ref> ====Epigenetic factors==== Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year.<ref name="pmid24685563">{{cite journal |vauthors=Brecht ML, Herbeck D |title=Time to relapse following treatment for methamphetamine use: a long-term perspective on patterns and predictors |journal=Drug Alcohol Depend |volume=139 |pages=18–25 |date=June 2014 |pmid=24685563 |pmc=4550209 |doi=10.1016/j.drugalcdep.2014.02.702 }}</ref> About half of those with methamphetamine addiction continue with use over a ten-year period, while the other half reduce use starting at about one to four years after initial use.<ref name="pmid23313146">{{cite journal |vauthors=Brecht ML, Lovinger K, Herbeck DM, Urada D |title=Patterns of treatment utilization and methamphetamine use during first 10 years after methamphetamine initiation |journal=J Subst Abuse Treat |volume=44 |issue=5 |pages=548–56 |date=2013 |pmid=23313146 |pmc=3602162 |doi=10.1016/j.jsat.2012.12.006 }}</ref> The frequent persistence of addiction suggests that long-lasting changes in [[Regulation of gene expression#Regulation of transcription in addiction|gene expression]] may occur in particular regions of the brain, and may contribute importantly to the addiction phenotype. In 2014, a crucial role was found for [[epigenetics|epigenetic]] mechanisms in driving lasting changes in gene expression in the brain.<ref name="pmid23643695">{{cite journal |vauthors=Nestler EJ |title=Epigenetic mechanisms of drug addiction |journal=Neuropharmacology |volume=76 Pt B |pages=259–68 |date=January 2014 |pmid=23643695 |pmc=3766384 |doi=10.1016/j.neuropharm.2013.04.004 }}</ref> A review in 2015<ref name=Godino>{{cite journal |vauthors=Godino A, Jayanthi S, Cadet JL |title=Epigenetic landscape of amphetamine and methamphetamine addiction in rodents |journal=Epigenetics |volume=10 |issue=7 |pages=574–80 |date=2015 |pmid=26023847 |pmc=4622560 |doi=10.1080/15592294.2015.1055441 }}</ref> summarized a number of studies involving chronic methamphetamine use in rodents. Epigenetic alterations were observed in the brain [[Mesolimbic pathway|reward pathways]], including areas like [[ventral tegmental area]], [[nucleus accumbens]], and dorsal [[striatum]], the [[hippocampus]], and the [[prefrontal cortex]]. Chronic methamphetamine use caused gene-specific [[histone acetylation and deacetylation|histone acetylations, deacetylations]] and [[Histone methylation|methylations]]. Gene-specific DNA methylations in particular regions of the brain were also observed. The various epigenetic alterations caused [[downregulation and upregulation|downregulations or upregulations]] of specific genes important in addiction. For instance, chronic methamphetamine use caused [[Histone methylation#Function|methylation of the lysine]] in position 4 of histone 3 located at the [[Promoter (genetics)|promoters]] of the ''[[c-fos]]'' and the ''[[CCR2|C-C chemokine receptor 2]] (ccr2)'' genes, activating those genes in the nucleus accumbens (NAc).<ref name=Godino /> c-fos is well known to be important in [[addiction]].<ref name="pmid25446457">{{cite journal |vauthors=Cruz FC, Javier Rubio F, Hope BT |title=Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction |journal=Brain Res. |volume=1628 |issue=Pt A |pages=157–73 |date=December 2015 |pmid=25446457 |pmc=4427550 |doi=10.1016/j.brainres.2014.11.005 }}</ref> The ''ccr2'' gene is also important in addiction, since mutational inactivation of this gene impairs addiction.<ref name=Godino /> In methamphetamine addicted rats, epigenetic regulation through reduced [[acetylation]] of histones, in brain striatal neurons, caused reduced transcription of [[glutamate receptor#Conditions with demonstrated associations to glutamate receptors|glutamate receptors]].<ref name="pmid24239129">{{cite journal |vauthors=Jayanthi S, McCoy MT, Chen B, Britt JP, Kourrich S, Yau HJ, Ladenheim B, Krasnova IN, Bonci A, Cadet JL |title=Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms |journal=Biol. Psychiatry |volume=76 |issue=1 |pages=47–56 |date=July 2014 |pmid=24239129 |pmc=3989474 |doi=10.1016/j.biopsych.2013.09.034 }}</ref> Glutamate receptors play an important role in regulating the reinforcing effects of misused illicit drugs.<ref name="pmid15120493">{{cite journal |vauthors=Kenny PJ, Markou A |title=The ups and downs of addiction: role of metabotropic glutamate receptors |journal=Trends Pharmacol. Sci. |volume=25 |issue=5 |pages=265–72 |date=May 2004 |pmid=15120493 |doi=10.1016/j.tips.2004.03.009 }}</ref> Administration of methamphetamine to rodents causes [[DNA damage (naturally occurring)|DNA damage]] in their brain, particularly in the [[nucleus accumbens]] region.<ref>{{cite journal | vauthors = Tokunaga I, Ishigami A, Kubo S, Gotohda T, Kitamura O | title = The peroxidative DNA damage and apoptosis in methamphetamine-treated rat brain | journal = The Journal of Medical Investigation | volume = 55 | issue = 3–4 | pages = 241–245 | date = August 2008 | pmid = 18797138 | doi = 10.2152/jmi.55.241 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Johnson Z, Venters J, Guarraci FA, Zewail-Foote M | title = Methamphetamine induces DNA damage in specific regions of the female rat brain | journal = Clinical and Experimental Pharmacology & Physiology | volume = 42 | issue = 6 | pages = 570–575 | date = June 2015 | pmid = 25867833 | doi = 10.1111/1440-1681.12404 | s2cid = 24182756 }}</ref> During repair of such DNA damages, persistent chromatin alterations may occur such as in the [[DNA methylation|methylation of DNA]] or the acetylation or [[histone methylation|methylation of histones]] at the sites of repair.<ref>{{cite journal | vauthors = Dabin J, Fortuny A, Polo SE | title = Epigenome Maintenance in Response to DNA Damage | journal = Molecular Cell | volume = 62 | issue = 5 | pages = 712–727 | date = June 2016 | pmid = 27259203 | pmc = 5476208 | doi = 10.1016/j.molcel.2016.04.006 }}</ref> These alterations can be [[epigenetics|epigenetic scars]] in the [[chromatin]] that contribute to the persistent epigenetic changes found in methamphetamine addiction. ==== Treatment and management ==== {{Further|Addiction#Research}} A 2018 systematic review and [[network meta-analysis]] of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that [[combination therapy]] with both [[contingency management]] and [[community reinforcement approach]] had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).<ref name="Psychosocial interventions network meta-analysis">{{cite journal | vauthors = De Crescenzo F, Ciabattini M, D'Alò GL, De Giorgi R, Del Giovane C, Cassar C, Janiri L, Clark N, Ostacher MJ, Cipriani A | title = Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis | journal = PLOS Medicine | volume = 15 | issue = 12 | pages = e1002715 | date = December 2018 | pmid = 30586362 | pmc = 6306153 | doi = 10.1371/journal.pmed.1002715 | doi-access = free }}</ref> Other treatment modalities examined in the analysis included [[monotherapy]] with contingency management or community reinforcement approach, [[cognitive behavioral therapy]], [[12-step program]]s, non-contingent reward-based therapies, [[psychodynamic therapy]], and other combination therapies involving these.<ref name="Psychosocial interventions network meta-analysis" /> {{As of|December 2019}}, there is no effective [[pharmacotherapy]] for methamphetamine 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. |pmc = 4017926 }}</ref><ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" /><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> A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in [[randomized controlled trial]]s (RCTs) for amphetamine and methamphetamine addiction;<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" /> it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy">{{cite journal | vauthors = Chan B, Freeman M, Kondo K, Ayers C, Montgomery J, Paynter R, Kansagara D | title = Pharmacotherapy for methamphetamine/amphetamine use disorder-a systematic review and meta-analysis | journal = Addiction | volume = 114 | issue = 12 | pages = 2122–2136 | date = December 2019 | pmid = 31328345 | doi = 10.1111/add.14755 | s2cid = 198136436 }}</ref> There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, [[mirtazapine]], [[sertraline]]), antipsychotics ([[aripiprazole]]), anticonvulsants ([[topiramate]], [[baclofen]], [[gabapentin]]), [[naltrexone]], [[varenicline]], [[citicoline]], [[ondansetron]], [[prometa]], [[riluzole]], [[atomoxetine]], dextroamphetamine, and [[modafinil]].<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" />{{verify source|date=June 2023|reason=Although the abstract says &quot;Studies of anticonvulsants, ... provided either low-strength or insufficient evidence of no effect on the outcomes of interest&quot;, this sounds like a misprint for &quot;of any effect...&quot;.<!--I can't read the main text to check-->}} ==== Dependence and withdrawal ==== [[Drug tolerance|Tolerance]] is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.<ref>{{cite web | vauthors = O'Connor P |title = Amphetamines: Drug Use and Abuse |url = http://www.merckmanuals.com/home/special_subjects/drug_use_and_abuse/amphetamines.html |website = Merck Manual Home Health Handbook |publisher = Merck |access-date = 26 September 2013 |archive-url = https://web.archive.org/web/20070217053619/http://www.merck.com/mmhe/sec07/ch108/ch108g.html |archive-date = 17 February 2007 |url-status = live }}</ref><ref name="Cochrane Abuse">{{cite journal |vauthors=Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M |title = Efficacy of psychostimulant drugs for amphetamine abuse or dependence |journal = Cochrane Database Syst. Rev. |volume = 9 |issue = 9 |pages = CD009695 |year = 2013 |pmid = 23996457 |doi = 10.1002/14651858.CD009695.pub2 | veditors = Pérez-Mañá C |doi-access = free }}</ref> In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.<ref name="Cochrane Withdrawal" /> [[Depression (mood)|Depression]] from methamphetamine withdrawal lasts longer and is more severe than that of [[cocaine]] withdrawal.<ref name="pmid17990840">{{cite journal |vauthors = Winslow BT, Voorhees KI, Pehl KA |title = Methamphetamine abuse |journal = American Family Physician |volume = 76 |issue = 8 |pages = 1169–1174 |year = 2007 |pmid = 17990840 }}</ref> According to the current Cochrane review on [[drug dependence]] and [[drug withdrawal|withdrawal]] in recreational users of methamphetamine, "when chronic heavy users abruptly discontinue [methamphetamine] 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. |issue = 2 |pages = CD003021 |year = 2009 |volume = 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;... Withdrawal symptoms typically present within 24&nbsp;hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) |pmc = 7138250 }}</ref> 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" /> Methamphetamine withdrawal symptoms can include anxiety, [[Craving (withdrawal)|drug craving]], [[Dysphoria|dysphoric mood]], [[Fatigue (medical)|fatigue]], [[hyperphagia|increased appetite]], [[Psychomotor agitation|increased movement]] or [[psychomotor retardation|decreased movement]], [[anhedonia|lack of motivation]], [[insomnia|sleeplessness]] or [[hypersomnia|sleepiness]], and [[Lucid dream|vivid or lucid dreams]].<ref name="Cochrane Withdrawal" /> Methamphetamine that is present in a mother's [[bloodstream]] can pass through the [[placenta]] to a [[fetus]] and be secreted into [[breast milk]].<ref name="pmid17990840" /> Infants born to methamphetamine-abusing mothers may experience a [[neonatal withdrawal]] syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and [[hypertonia]].<ref name="pmid17990840" /> This withdrawal syndrome is relatively mild and only requires medical intervention in approximately&nbsp;4% of cases.<ref name="pmid17990840" /> {{clear right}} {{Addiction-related plasticity|Table title=Summary of addiction-related plasticity}} ===Neonatal=== Unlike other drugs, babies with prenatal exposure to methamphetamine do not show immediate signs of withdrawal. Instead, cognitive and behavioral problems start emerging when the children reach school age.<ref name="2020-01-03_ABC">[https://www.abc.net.au/news/2020-01-03/the-hidden-problem-of-babies-born-to-meth-affected-mothers/11829668 Babies born to meth-affected mothers seem well behaved, but their passive nature masks a serious problem] {{Webarchive|url=https://web.archive.org/web/20211024113948/https://www.abc.net.au/news/2020-01-03/the-hidden-problem-of-babies-born-to-meth-affected-mothers/11829668 |date=24 October 2021 }}, Elicia Kennedy, [[ABC News Online]], 3 January 2020</ref> A [[prospective cohort study]] of 330 children showed that at the age of 3, children with methamphetamine exposure showed increased emotional reactivity, as well as more signs of anxiety and depression; and at the age of 5, children showed higher rates of [[externalizing disorders|externalizing]] and [[attention deficit hyperactivity disorder|attention deficit/hyperactivity]] disorders.<ref name="LaGasse_2012">{{cite journal | vauthors = LaGasse LL, Derauf C, Smith LM, Newman E, Shah R, Neal C, Arria A, Huestis MA, DellaGrotta S, Lin H, Dansereau LM, Lester BM | display-authors = 6 | title = Prenatal methamphetamine exposure and childhood behavior problems at 3 and 5 years of age | journal = Pediatrics | volume = 129 | issue = 4 | pages = 681–8 | date = April 2012 | pmid = 22430455 | pmc = 3313637 | doi = 10.1542/peds.2011-2209 | publisher=American Academy of Pediatrics }}</ref> == Overdose == A methamphetamine overdose may result in a wide range of symptoms.<ref name="Schep" /><ref name="Desoxyn" /> A moderate overdose of methamphetamine may induce symptoms such as: [[Cardiac dysrhythmia|abnormal heart rhythm]], confusion, [[dysuria|difficult and/or painful urination]], high or low blood pressure, [[hyperthermia|high body temperature]], [[hyperreflexia|over-active and/or over-responsive reflexes]], [[myalgia|muscle aches]], severe [[Psychomotor agitation|agitation]], [[tachypnea|rapid breathing]], [[tremor]], [[urinary hesitancy]], and [[urinary retention|an inability to pass urine]].<ref name="Schep" /><ref name="Westfall" /> An extremely large overdose may produce symptoms such as [[adrenergic storm]], [[methamphetamine psychosis]], [[anuria|substantially reduced or no urine output]], [[cardiogenic shock]], [[cerebral hemorrhage|bleeding in the brain]], [[circulatory collapse]], [[hyperpyrexia]] (i.e., dangerously high body temperature), [[pulmonary hypertension]], [[kidney failure]], [[rhabdomyolysis|rapid muscle breakdown]], [[serotonin syndrome]], and a form of [[stereotypy#Associated terms|stereotypy]] ("tweaking").{{#tag:ref|<ref name="Schep" /><ref name="Desoxyn" /><ref name="Westfall" /><ref name="Merck_Manual_Amphetamines" /><ref name="Albertson_2011">{{cite book |veditors = Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AH |title = Poisoning & Drug Overdose | vauthors = Albertson TE |year = 2011 |publisher = McGraw-Hill Medical |location = New York |isbn = 978-0-07-166833-0 |chapter = Amphetamines |pages = 77–79 |edition = 6th }}</ref><ref>{{cite web |title = Amphetamine Poisoning |url = http://emergency.unboundmedicine.com/emergency/ub/view/5-Minute_Emergency_Consult/307063/all/Amphetamine_Poisoning |website = Emergency Central |publisher = Unbound Medicine |date = 11 February 2011 |access-date = 11 June 2013 |vauthors = Oskie SM, Rhee JW |archive-url = https://web.archive.org/web/20130926150016/http://emergency.unboundmedicine.com/emergency/ub/view/5-Minute_Emergency_Consult/307063/all/Amphetamine_Poisoning |archive-date = 26 September 2013 |url-status = live }}</ref><ref name="pmid17874986">{{cite journal |vauthors = Isbister GK, Buckley NA, Whyte IM |title = Serotonin toxicity: a practical approach to diagnosis and treatment |journal = Med. J. Aust. |volume = 187 |issue = 6 |pages = 361–365 |date = September 2007 |pmid = 17874986 |doi = 10.5694/j.1326-5377.2007.tb01282.x|s2cid = 13108173 |url = https://www.mja.com.au/system/files/issues/187_06_170907/isb10375_fm.pdf |access-date = 2 January 2014 |archive-url = https://web.archive.org/web/20140704062057/https://www.mja.com.au/system/files/issues/187_06_170907/isb10375_fm.pdf |archive-date = 4 July 2014 |url-status = live }}</ref>| group="sources" }} A methamphetamine overdose will likely also result in mild [[brain damage]] owing to [[dopaminergic]] and [[Serotonin|serotonergic]] neurotoxicity.<ref name="Malenka">{{cite book|title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience|vauthors=Malenka RC, Nestler EJ, Hyman SE|publisher=McGraw-Hill Medical|year=2009|isbn=978-0-07-148127-4|veditors=Sydor A, Brown RY|edition=2nd|location=New York|page=370|chapter=15|quote=Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.}}</ref><ref name="pmid19328213" /> Death from methamphetamine poisoning is typically preceded by convulsions and [[coma]].<ref name="Desoxyn" /> === Psychosis === {{hatnote|Main section: {{section link|Stimulant psychosis|Substituted amphetamines}}}} Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g., [[paranoia]], [[hallucination]]s, [[delirium]], and [[delusion]]s).<ref name="Schep" /><ref name="Cochrane" /> A [[Cochrane Collaboration]] review on treatment for amphetamine, dextroamphetamine, and methamphetamine use-induced psychosis states that about&nbsp;5–15% of users fail to recover completely.<ref name="Cochrane">{{cite journal |veditors = Shoptaw SJ, Ali R |vauthors = Shoptaw SJ, Kao U, Ling W |title = Treatment for amphetamine psychosis |journal = Cochrane Database Syst. Rev. |issue = 1 |pages = CD003026 |year = 2009 |volume = 2009 |pmid = 19160215 |doi = 10.1002/14651858.CD003026.pub3 |pmc = 7004251 |quote = A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention&nbsp;...<br />About&nbsp;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 | vauthors = Hofmann FG |title = A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects |publisher = Oxford University Press |isbn = 978-0-19-503057-0 |location = New York |year = 1983 |page = [https://archive.org/details/handbookondrugal0002hofm/page/329 329] |edition = 2nd |url = https://archive.org/details/handbookondrugal0002hofm/page/329 }}</ref> The same review asserts that, based upon at least one trial, [[antipsychotic]] medications effectively resolve the symptoms of acute amphetamine psychosis.<ref name="Cochrane" /> [[Stimulant psychosis#Substituted amphetamines|Amphetamine psychosis]] may also develop occasionally as a treatment-emergent side effect.<ref name="Berman-2009">{{cite journal |vauthors = Berman SM, Kuczenski R, McCracken JT, London ED |title = Potential adverse effects of amphetamine treatment on brain and behavior: a review |journal = Mol. Psychiatry |volume = 14 |issue = 2 |pages = 123–142 |date = February 2009 |pmid = 18698321 |pmc = 2670101 |doi = 10.1038/mp.2008.90 }}</ref> === Emergency treatment === Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of [[activated charcoal]] and [[sedation]].<ref name="Schep" /> There is not enough evidence on [[hemodialysis]] or [[peritoneal dialysis]] in cases of methamphetamine intoxication to determine their usefulness.<ref name="Desoxyn" /> [[Forced acid diuresis]] (e.g., with [[vitamin C]]) will increase methamphetamine excretion but is not recommended as it may increase the risk of aggravating acidosis, or cause seizures or rhabdomyolysis.<ref name="Schep" /> Hypertension presents a risk for [[intracranial hemorrhage]] (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous [[phentolamine]] or [[nitroprusside]].<ref name="Schep" /> Blood pressure often drops gradually following sufficient sedation with a [[benzodiazepine]] and providing a calming environment.<ref name="Schep" /> Antipsychotics such as [[haloperidol]] are useful in treating agitation and psychosis from methamphetamine overdose.<ref name="Richards 2015 review" /><ref>{{cite journal |vauthors = Richards JR, Derlet RW, Duncan DR |title = Methamphetamine toxicity: treatment with a benzodiazepine versus a butyrophenone |journal = Eur. J. Emerg. Med. |date = September 1997 |volume = 4 |issue = 3 |pages = 130–135 |pmid = 9426992 |doi = 10.1097/00063110-199709000-00003 }}</ref> [[Beta blocker]]s with lipophilic properties and CNS penetration such as [[metoprolol]] and [[labetalol]] may be useful for treating CNS and cardiovascular toxicity.<ref name="Medscape meth toxicity">{{cite encyclopedia |url = http://emedicine.medscape.com/article/820918-overview#showall |title = Methamphetamine Toxicity |section-url = http://emedicine.medscape.com/article/820918-treatment#showall |section = Treatment & Management |vauthors = Richards JR, Derlet RW, Albertson TE |website = Medscape |publisher = WebMD |access-date = 20 April 2016 |archive-url = https://web.archive.org/web/20160409114830/http://emedicine.medscape.com/article/820918-overview#showall |archive-date = 9 April 2016 |url-status = live }}</ref>{{Failed verification | reason = I cannot find a mention of "beta blockers" or metoprolol and labetalol on the cited link for methamphetamine intoxication| date = May 2023}} The mixed [[alpha blocker|alpha-]] and [[beta-blocker]] labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.<ref name="Richards 2015 review">{{cite journal |vauthors = Richards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ |title = Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review |journal = Drug Alcohol Depend. |date = May 2015 |volume = 150 |pages = 1–13 |doi = 10.1016/j.drugalcdep.2015.01.040 |pmid = 25724076 }}</ref> The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.<ref name="Richards 2015 review" /> == Interactions == Methamphetamine is metabolized by the liver enzyme [[CYP2D6]], so [[CYP2D6#Ligands|CYP2D6 inhibitors]] will prolong the [[elimination half-life]] of methamphetamine.<ref name="DrugBank Enzymes">{{cite encyclopedia |title = Methamphetamine |section-url = http://www.drugbank.ca/drugs/DB01577#enzymes |work = DrugBank |publisher = University of Alberta |date = 8 February 2013 |section = Enzymes |access-date = 2 January 2014 |archive-date = 28 December 2015 |archive-url = https://web.archive.org/web/20151228164940/http://www.drugbank.ca/drugs/DB01577#enzymes |url-status = live }}</ref> Methamphetamine also interacts with [[monoamine oxidase inhibitors]] (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.<ref name="Desoxyn" /> Methamphetamine may decrease the effects of [[sedative]]s and [[depressant]]s and increase the effects of [[antidepressant]]s and other [[stimulant]]s as well.<ref name="Desoxyn" /> Methamphetamine may counteract the effects of [[antihypertensives]] and [[antipsychotic]]s owing to its effects on the cardiovascular system and cognition respectively.<ref name="Desoxyn" /> The [[pH]] of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.<ref name="Desoxyn" /> Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.<ref name="Desoxyn" /> Owing to the effect pH has on absorption, [[proton pump inhibitor]]s, which reduce [[gastric acid]], are known to interact with methamphetamine.<ref name="Desoxyn" /> == Pharmacology == [[File:Amphetamine mechanism of action.svg|upright=1.2|right|thumb|This illustration depicts the normal operation of the [[dopaminergic]] terminal to the left, and the dopaminergic terminal in the presence of methamphetamine to the right. Methamphetamine reverses the action of the dopamine transporter (DAT) by activating [[TAAR1]] (not shown). TAAR1 activation also causes some of the dopamine transporters to move into the presynaptic neuron and cease transport (not shown). At VMAT2 (labeled VMAT), methamphetamine causes dopamine efflux (release).|alt=An image of methamphetamine pharmacodynamics]] === Pharmacodynamics === Methamphetamine has been identified as a potent [[full agonist]] of [[TAAR1|trace amine-associated receptor 1]] (TAAR1), a [[G protein-coupled receptor]] (GPCR) that regulates brain [[catecholamine]] systems.<ref name="Miller">{{cite journal | vauthors = Miller GM |title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity |journal = 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><ref name="Meth Targets">{{cite encyclopedia |title = Methamphetamine |section-url = http://www.drugbank.ca/drugs/DB01577#targets |work = DrugBank |publisher = University of Alberta |date = 8 February 2013 |section = Targets |access-date = 4 January 2014 |archive-date = 28 December 2015 |archive-url = https://web.archive.org/web/20151228164940/http://www.drugbank.ca/drugs/DB01577#targets |url-status = live }}</ref> Activation of TAAR1 increases [[cyclic adenosine monophosphate]] (cAMP) production and either completely inhibits or reverses the transport direction of the [[dopamine transporter]] (DAT), [[norepinephrine transporter]] (NET), and [[serotonin transporter]] (SERT).<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 |bibcode = 2001PNAS...98.8966B |doi-access = free }}</ref> When methamphetamine binds to TAAR1, it triggers transporter [[phosphorylation]] via [[protein kinase A]] (PKA) and [[protein kinase C]] (PKC) signaling, ultimately resulting in the [[endocytosis|internalization]] or reverse function of [[monoamine transporter]]s.<ref name="Miller" /><ref name="Xie and Miller 2009">{{cite journal |vauthors = Xie Z, Miller GM |title = A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain |journal = J. Pharmacol. Exp. Ther. |volume = 330 |issue = 1 |pages = 316–325 |date = July 2009 |pmid = 19364908 |pmc = 2700171 |doi = 10.1124/jpet.109.153775 }}</ref> Methamphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a [[Ca2+/calmodulin-dependent protein kinase]] (CAMK)-dependent signaling pathway, in turn producing dopamine efflux.<ref name="TAAR1 IUPHAR">{{cite web |title = TA₁ receptor |url = http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=364 |website = IUPHAR database |publisher = International Union of Basic and Clinical Pharmacology |access-date = 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]. --> |archive-url = https://web.archive.org/web/20150629065449/http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=364 |archive-date = 29 June 2015 |url-status = live }}</ref><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). }}</ref><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> TAAR1 has been shown to reduce the [[action potential|firing rate]] of neurons through direct activation of [[G protein-coupled inwardly-rectifying potassium channel]]s.<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 |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. |doi-access = free }}</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 | website = GenAtlas | publisher = University of Paris | access-date = 29 May 2014 | quote = <br />{{bull}} tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA) | archive-url = https://web.archive.org/web/20140529150342/http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=TAAR1 | archive-date = 29 May 2014 | url-status = live }}</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 |bibcode = 2011PNAS..108.8485R |doi-access = free }}</ref> TAAR1 activation by methamphetamine in [[astrocytes]] appears to negatively modulate the membrane expression and function of [[EAAT2]], a type of [[glutamate transporter]].<ref name="Cisneros_2014 and review" /> In addition to its effect on the plasma membrane monoamine transporters, methamphetamine inhibits synaptic vesicle function by inhibiting [[VMAT2]], which prevents monoamine uptake into the vesicles and promotes their release.<ref name="Meth Transporters" /> This results in the outflow of monoamines from [[synaptic vesicle]]s into the [[cytosol]] (intracellular fluid) of the [[presynaptic neuron]], and their subsequent release into the synaptic cleft by the phosphorylated transporters.<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 = 1|pages = 86–98 |date = January 2011 |pmid = 21272013 |doi = 10.1111/j.1749-6632.2010.05906.x |pmc = 4183197 |bibcode = 2011NYASA1216...86E }}</ref> Other [[Membrane transport protein|transporters]] that methamphetamine is known to inhibit are [[SLC22A3]] and [[SLC22A5]].<ref name="Meth Transporters">{{cite encyclopedia |title = Methamphetamine |section-url = http://www.drugbank.ca/drugs/DB01577#transporters |work = DrugBank |publisher = University of Alberta |date = 8 February 2013 |section = Transporters |access-date = 4 January 2014 |archive-date = 28 December 2015 |archive-url = https://web.archive.org/web/20151228164940/http://www.drugbank.ca/drugs/DB01577#transporters |url-status = live }}</ref> SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity [[carnitine]] transporter.<ref name="Meth Targets" /><ref name="pmid13677912">{{cite journal |vauthors = Inazu M, Takeda H, Matsumiya T |title = [The role of glial monoamine transporters in the central nervous system] |language = ja |journal = Nihon Shinkei Seishin Yakurigaku Zasshi |volume = 23 |issue = 4 |pages = 171–178 |date = August 2003 |pmid = 13677912 }}</ref> Methamphetamine is also an [[agonist]] of the [[alpha-2 adrenergic receptor]]s and [[sigma receptor]]s with a greater [[binding affinity|affinity]] for [[Sigma-1 receptor|σ₁]] than [[Sigma-2 receptor|σ₂]], and inhibits [[monoamine oxidase A]] (MAO-A) and [[monoamine oxidase B]] (MAO-B).<ref name="Sigma">{{cite journal |vauthors = Kaushal N, Matsumoto RR |title = Role of sigma receptors in methamphetamine-induced neurotoxicity |journal = Curr Neuropharmacol |volume = 9 |issue = 1 |pages = 54–57 |date = March 2011 |pmid = 21886562 |pmc = 3137201 |doi = 10.2174/157015911795016930 |quote = σ Receptors seem to play an important role in many of the effects of METH. They are present in the organs that mediate the actions of METH (e.g. brain, heart, lungs) [5]. In the brain, METH acts primarily on the dopaminergic system to cause acute locomotor stimulant, subchronic sensitized, and neurotoxic effects. σ Receptors are present on dopaminergic neurons and their activation stimulates dopamine synthesis and release [11–13]. σ-2 Receptors modulate DAT and the release of dopamine via protein kinase C (PKC) and Ca2+-calmodulin systems [14].<br />σ-1 Receptor antisense and antagonists have been shown to block the acute locomotor stimulant effects of METH [4]. Repeated administration or self administration of METH has been shown to upregulate σ-1 receptor protein and mRNA in various brain regions including the substantia nigra, frontal cortex, cerebellum, midbrain, and hippocampus [15, 16]. Additionally, σ receptor antagonists&nbsp;... prevent the development of behavioral sensitization to METH [17, 18].&nbsp;...<br /> σ Receptor agonists have been shown to facilitate dopamine release, through both σ-1 and σ-2 receptors [11–14]. }}</ref><ref name="Meth Targets" /><ref name="SigmaB">{{cite journal |vauthors = Rodvelt KR, Miller DK |title = Could sigma receptor ligands be a treatment for methamphetamine addiction? |journal = Curr Drug Abuse Rev |volume = 3 |issue = 3 |pages = 156–162 |date = September 2010 |pmid = 21054260 |doi = 10.2174/1874473711003030156 }}</ref> Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain.<ref name="Sigma" /><ref name="SigmaB" /> [[Dextromethamphetamine]] is a stronger [[psychostimulant]], but [[levomethamphetamine]] has stronger [[Peripheral nervous system|peripheral]] effects, a longer half-life, and longer perceived effects among addicts.<ref name="Melega">{{cite journal |vauthors = Melega WP, Cho AK, Schmitz D, Kuczenski R, Segal DS |title = l-methamphetamine pharmacokinetics and pharmacodynamics for assessment of in vivo deprenyl-derived l-methamphetamine |journal = J. Pharmacol. Exp. Ther. |volume = 288 |issue = 2 |pages = 752–758 |date = February 1999 |pmid = 9918585 }}</ref><ref name="Kuczenski">{{cite journal |vauthors = Kuczenski R, Segal DS, Cho AK, Melega W |title = Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine |journal = J. Neurosci. |volume = 15 |issue = 2 |pages = 1308–1317 |date = February 1995 |pmid = 7869099 |pmc = 6577819 |doi = 10.1523/jneurosci.15-02-01308.1995}}</ref><ref name="Mendelson">{{cite journal |vauthors = Mendelson J, Uemura N, Harris D, Nath RP, Fernandez E, Jacob P, Everhart ET, Jones RT |title = Human pharmacology of the methamphetamine stereoisomers |journal = Clin. Pharmacol. Ther. |volume = 80 |issue = 4 |pages = 403–420 |date = October 2006 |pmid = 17015058 |doi = 10.1016/j.clpt.2006.06.013 |s2cid = 19072636 }}</ref> At high doses, both enantiomers of methamphetamine can induce similar [[stereotypy]] and [[methamphetamine psychosis]],<ref name="Kuczenski" /> but levomethamphetamine has shorter psychodynamic effects.<ref name="Mendelson" /> === Pharmacokinetics === The [[bioavailability]] of methamphetamine is 67% [[oral administration|orally]], 79% [[intranasal administration|intranasally]], 67 to 90% via [[inhalational administration|inhalation]] ([[smoking]]), and 100% [[intravenous administration|intravenously]].<ref name="pmid19426289" /><ref name="Schep" /><ref name="pmid25176528" /> Following oral administration, methamphetamine is well-absorbed into the bloodstream, with peak plasma methamphetamine concentrations achieved in approximately 3.13–6.3&nbsp;hours post ingestion.<ref name="DrugBank methamphetamine metabolism" /> Methamphetamine is also well absorbed following inhalation and following intranasal administration.<ref name="Schep" /> Because of the high lipophilicity of methamphetamine, it can readily move through the [[blood–brain barrier]] faster than other stimulants, where it is more resistant to degradation by [[monoamine oxidase]].<ref name="Schep" /><ref name="DrugBank methamphetamine metabolism" /> The amphetamine metabolite peaks at 10–24&nbsp;hours.<ref name="Schep" /> Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH.<ref name="Desoxyn" /><ref name="DrugBank methamphetamine metabolism" /> When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.<ref name="DrugBank methamphetamine metabolism" /> Following IV doses, about&nbsp;45% is excreted as methamphetamine and 7% as amphetamine.<ref name="DrugBank methamphetamine metabolism" /> The [[elimination half-life]] of methamphetamine varies with a range of 5–30{{nbsp}}hours, but it is on average 9 to 12{{nbsp}}hours in most studies.<ref name="Schep">{{cite journal |vauthors = Schep LJ, Slaughter RJ, Beasley DM |title = The clinical toxicology of metamfetamine |journal = Clinical Toxicology |volume = 48 |issue = 7 |pages = 675–694 |date = August 2010 |pmid = 20849327 |doi = 10.3109/15563650.2010.516752 |s2cid = 42588722 |issn = 1556-3650 }}</ref><ref name="pmid19426289" /> The elimination half-life of methamphetamine does not vary by [[route of administration]], but is subject to substantial [[interindividual variability]].<ref name="pmid19426289">{{cite journal | vauthors = Cruickshank CC, Dyer KR | title = A review of the clinical pharmacology of methamphetamine | journal = Addiction | volume = 104 | issue = 7 | pages = 1085–99 | date = July 2009 | pmid = 19426289 | doi = 10.1111/j.1360-0443.2009.02564.x | s2cid = 37079117 | url = | doi-access = free }}</ref> [[CYP2D6]], [[dopamine β-hydroxylase]], [[flavin-containing monooxygenase 3]], [[butyrate-CoA ligase]], and [[glycine N-acyltransferase]] are the enzymes known to metabolize methamphetamine or its metabolites in humans.{{#tag:ref|<ref name="Methamphetamine – p-hydroxymethamphetamine CYP2D6 review" /><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 |website = United States Food and Drug Administration |date = December 2013 |access-date = 30 December 2013 |archive-url = https://web.archive.org/web/20131230233702/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf |archive-date = 30 December 2013 |url-status = live }}</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] {{Webarchive| url=https://web.archive.org/web/20180916144516/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ |date=16 September 2018 }}</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="DrugBank methamphetamine metabolism" /><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><ref name="Substituted amphetamines, FMO, and DBH">{{cite book |vauthors = 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 = 978-1-60913-345-0 |pages = 646–648 |edition = 7th |section-url = https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646 |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. |access-date = 5 October 2017 |archive-date = 13 January 2023 |archive-url = https://web.archive.org/web/20230113011526/https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646 |url-status = live }}</ref><ref name="DBH amph primary">{{cite journal | vauthors = 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 |doi = 10.1016/S0021-9258(19)43051-2 |pmid = 4809526 |access-date = 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. |archive-url = https://web.archive.org/web/20181007182156/http://www.jbc.org/content/249/2/454.full.pdf |archive-date = 7 October 2018 |url-status = live |doi-access = free }}</ref><ref name="pmid13977820">{{cite journal |vauthors = Sjoerdsma A, von Studnitz W |title = Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate |journal = Br. J. Pharmacol. Chemother. |volume = 20 |issue = 2|pages = 278–284 |date = April 1963 |pmid = 13977820 |pmc = 1703637 |doi = 10.1111/j.1476-5381.1963.tb01467.x |quote = Hydroxyamphetamine was administered orally to five human subjects&nbsp;... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man.&nbsp;... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues.&nbsp;... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline. }}</ref><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. |section = Substrate/Product |access-date = 5 October 2017 |archive-date = 22 June 2017 |archive-url = https://web.archive.org/web/20170622234353/http://www.brenda-enzymes.info/enzyme.php?ecno=6.2.1.2&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0 |url-status = live }}</ref><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. |section = Substrate/Product |access-date = 5 October 2017 |archive-date = 23 June 2017 |archive-url = https://web.archive.org/web/20170623000309/http://www.brenda-enzymes.info/enzyme.php?ecno=2.3.1.13&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0 |url-status = live }}</ref>| name="methamphetamine metabolism" |group="sources" }} The primary metabolites are amphetamine and [[pholedrine|4-hydroxymethamphetamine]];<ref name="DrugBank methamphetamine metabolism">{{cite encyclopedia |title = Methamphetamine |section = Pharmacology |section-url = https://www.drugbank.ca/drugs/DB01577#pharmacology |work = DrugBank |publisher = University of Alberta |access-date = 5 October 2017 |date = 2 October 2017 |quote = Methamphetamine is rapidly absorbed from the gastrointestinal tract with peak methamphetamine concentrations occurring in 3.13 to 6.3 hours post ingestion. Methamphetamine is also well absorbed following inhalation and following intranasal administration. It is distributed to most parts of the body. Because methamphetamine has a high lipophilicity it is distributed across the blood brain barrier and crosses the placenta.&nbsp;...<br />The primary site of metabolism is in the liver by aromatic hydroxylation, N-dealkylation and deamination. At least seven metabolites have been identified in the urine, with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine. Other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine. |archive-date = 6 October 2017 |archive-url = https://web.archive.org/web/20171006012111/https://www.drugbank.ca/drugs/DB01577#pharmacology |url-status = live }}</ref> other minor metabolites include: {{nowrap|[[4-hydroxyamphetamine]]}}, {{nowrap|[[4-hydroxynorephedrine]]}}, {{nowrap|[[4-hydroxyphenylacetone]]}}, [[benzoic acid]], [[hippuric acid]], [[norephedrine]], and [[phenylacetone]], the metabolites of amphetamine.<ref name="FDA Pharmacokinetics" /><ref name="DrugBank methamphetamine metabolism" /><ref name="Metabolites" /> Among these metabolites, the active [[sympathomimetics]] are amphetamine, {{nowrap|4‑hydroxyamphetamine}},<ref>{{cite encyclopedia |title = p-Hydroxyamphetamine |section-url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3651 |work = PubChem Compound |publisher = National Center for Biotechnology Information |section = Compound Summary |access-date = 4 September 2017 |archive-date = 7 June 2013 |archive-url = https://web.archive.org/web/20130607202440/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3651 |url-status = live }}</ref> {{nowrap|4‑hydroxynorephedrine}},<ref>{{cite encyclopedia |title = p-Hydroxynorephedrine |section-url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11099 |work = PubChem Compound |publisher = National Center for Biotechnology Information |section = Compound Summary |access-date = 4 September 2017 |archive-date = 15 October 2013 |archive-url = https://web.archive.org/web/20131015073126/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11099 |url-status = live }}</ref> {{nowrap|4-hydroxymethamphetamine}},<ref name="DrugBank methamphetamine metabolism" /> and norephedrine.<ref>{{cite encyclopedia |title = Phenylpropanolamine |section-url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=26934 |work = PubChem Compound |publisher = National Center for Biotechnology Information |section = Compound Summary |access-date = 4 September 2017 |archive-date = 29 September 2013 |archive-url = https://web.archive.org/web/20130929154657/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=26934 |url-status = live }}</ref> Methamphetamine is a CYP2D6 inhibitor.<ref name="DrugBank Enzymes" /> 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="DrugBank methamphetamine metabolism" /><ref name="Pubchem Kinetics">{{cite encyclopedia |title = Amphetamine |url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007 |work = Pubchem Compound |publisher = National Center for Biotechnology Information |access-date = 12 October 2013 |archive-url = https://web.archive.org/web/20131013122604/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007 |archive-date = 13 October 2013 |url-status = live }}</ref> The known metabolic pathways include: {{Methamphetamine pharmacokinetics|header=Metabolic pathways of methamphetamine in humans<ref name="methamphetamine metabolism" group="sources" />|caption=The primary metabolites of methamphetamine are amphetamine and 4-hydroxymethamphetamine.<ref name="DrugBank methamphetamine metabolism" /> [[Human microbiota]], particularly ''[[Lactobacillus]]'', ''[[Enterococcus]]'', and ''[[Clostridium]]'' species, contribute to the metabolism of methamphetamine via an enzyme which N-demethylates methamphetamine and 4-hydroxymethamphetamine into amphetamine and 4-hydroxyamphetamine respectively.<ref name="Meth demethylation review">{{cite journal |vauthors = Haiser HJ, Turnbaugh PJ |title = Developing a metagenomic view of xenobiotic metabolism |journal = Pharmacol. Res. |volume = 69 |issue = 1 |pages = 21–31 |date = March 2013 |pmid = 22902524 |pmc = 3526672 |doi = 10.1016/j.phrs.2012.07.009 }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526672/table/T2/ Table 2: Xenobiotics metabolized by the human gut microbiota] {{Webarchive|url=https://web.archive.org/web/20211031105429/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526672/table/T2/ |date=31 October 2021 }}</ref><ref name="Meth demethylation primary">{{cite journal |vauthors = Caldwell J, Hawksworth GM |title = The demethylation of methamphetamine by intestinal microflora |journal = J. Pharm. Pharmacol. |volume = 25 |issue = 5 |pages = 422–424 |date = May 1973 |pmid = 4146404 |doi = 10.1111/j.2042-7158.1973.tb10043.x |s2cid = 34050001 }}</ref>}} {{clear}} ==== Detection in biological fluids ==== Methamphetamine and amphetamine are often measured in urine or blood as part of a [[drug test]] for sports, employment, poisoning diagnostics, and forensics.<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 }}</ref><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 |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 |s2cid = 32917584 }}</ref><ref name="pmid8075776">{{cite journal |vauthors = Goldberger BA, Cone EJ |title = Confirmatory tests for drugs in the workplace by gas chromatography-mass spectrometry |journal = 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> Chiral techniques may be employed to help distinguish the source of the drug to determine whether it was obtained illicitly or legally via prescription or prodrug.<ref name="pmid15516295" /> Chiral separation is needed to assess the possible contribution of [[levomethamphetamine]], which is an active ingredients in some OTC nasal decongestants,<ref name="OTC levmetamfetamine" group="note" /> toward a positive test result.<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)-(+)-alpha-methoxy-alpha-(trifluoromethy)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 |doi-access = free }}</ref><ref name="pmid14871155">{{cite journal |vauthors = de la Torre R, Farré M, Navarro M, Pacifici R, Zuccaro P, Pichini S |title = Clinical pharmacokinetics of amfetamine and related substances: monitoring in conventional and non-conventional matrices |journal = Clin Pharmacokinet |volume = 43 |issue = 3 |pages = 157–185 |year = 2004 |pmid = 14871155 |doi = 10.2165/00003088-200443030-00002 |s2cid = 44731289 }}</ref><ref>{{cite book | vauthors = Baselt RC |title = Disposition of toxic drugs and chemicals in man |year = 2020 |publisher = Biomedical Publications |location = Seal Beach, Ca. |isbn = 978-0-578-57749-4 |pages = 1277–1280}}</ref> Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.<ref name="pmid21740689">{{cite journal |vauthors = Venkatratnam A, Lents NH |title = Zinc reduces the detection of cocaine, methamphetamine, and THC by ELISA urine testing |journal = J. Anal. Toxicol. |volume = 35 |issue = 6 |pages = 333–340 |date = July 2011 |pmid = 21740689 |doi = 10.1093/anatox/35.6.333 |doi-access = }}</ref> == Chemistry == [[File:Crystal Meth.jpg|thumb|Shards of pure methamphetamine hydrochloride, also known as crystal meth|alt=Methamphetamine hydrochloride]] Methamphetamine is a [[chirality (chemistry)|chiral]] compound with two enantiomers, [[dextromethamphetamine]] and [[levomethamphetamine]]. At room temperature, the [[free base]] of methamphetamine is a clear and colorless liquid with an odor characteristic of [[geranium]] leaves.<ref name="Pubchem2" /> It is [[soluble]] in [[diethyl ether]] and [[ethanol]] as well as [[miscible]] with [[chloroform]].<ref name="Pubchem2" /> In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.<ref name="Pubchem2" /> It has a melting point between {{convert|170|and|175|C|F}} and, at room temperature, occurs as white crystals or a white [[Crystallinity|crystalline]] powder.<ref name="Pubchem2" /> The hydrochloride salt is also freely soluble in ethanol and water.<ref name="Pubchem2" /> The crystal structure of either enantiomer is [[monoclinic]] with P2₁ [[space group]]; at {{convert|90|K|C F}}, it has [[lattice parameter]]s ''a'' = 7.10&nbsp;[[Angstrom|Å]], ''b'' = 7.29&nbsp;Å, ''c'' = 10.81&nbsp;Å, and ''β'' = 97.29°.<ref>{{cite journal | vauthors = Hakey P, Ouellette W, Zubieta J, Korter T | title = Redetermination of (+)-methamphetamine hydro-chloride at 90 K | journal = Acta Crystallographica Section E | volume = 64 | issue = Pt 5 | pages = o940 | date = April 2008 | pmid = 21202421 | pmc = 2961146 | doi = 10.1107/S1600536808011550 }}</ref> === Degradation === A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration.<ref>{{cite web | vauthors = Nakayama MT |title = Chemical Interaction of Bleach and Methamphetamine: A Study of Degradation and Transformation Effects |url = http://gradworks.umi.com/14/93/1493688.html |website = gradworks |publisher = UNIVERSITY OF CALIFORNIA, DAVIS |access-date = 17 October 2014 |archive-url = https://web.archive.org/web/20141019005517/http://gradworks.umi.com/14/93/1493688.html |archive-date = 19 October 2014 |url-status = live }}</ref> A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant.<ref name="pmid21777940">{{cite journal |vauthors = Pal R, Megharaj M, Kirkbride KP, Heinrich T, Naidu R |title = Biotic and abiotic degradation of illicit drugs, their precursor, and by-products in soil |journal = Chemosphere |volume = 85 |issue = 6 |pages = 1002–9 |date = October 2011 |pmid = 21777940 |doi = 10.1016/j.chemosphere.2011.06.102 |bibcode = 2011Chmsp..85.1002P }}</ref> In a 2013 study of bioreactors in [[wastewater]], methamphetamine was found to be largely degraded within 30&nbsp;days under exposure to light.<ref name="pmid23886544">{{cite journal |vauthors = Bagnall J, Malia L, Lubben A, Kasprzyk-Hordern B |title = Stereoselective biodegradation of amphetamine and methamphetamine in river microcosms |journal = Water Res. |volume = 47 |issue = 15 |pages = 5708–18 |date = October 2013 |pmid = 23886544 |doi = 10.1016/j.watres.2013.06.057 |bibcode = 2013WatRe..47.5708B |doi-access = free }}</ref> === Synthesis === {{further|topic=illicit amphetamine synthesis|History and culture of substituted amphetamines#Illegal synthesis}} [[Racemic]] methamphetamine may be prepared starting from [[phenylacetone]] by either the [[Leuckart reaction|Leuckart]]<ref name=Crossley_1944>{{cite journal |vauthors = Crossley FS, Moore ML |title = Studies on the Leuckart reaction |journal = The Journal of Organic Chemistry |date = November 1944 |volume = 9 |issue = 6 |pages = 529–536 |doi = 10.1021/jo01188a006 }}</ref> or [[reductive amination]] methods.<ref name="pmid19637924">{{cite journal |vauthors = Kunalan V, Nic Daéid N, Kerr WJ, Buchanan HA, McPherson AR |title = Characterization of route specific impurities found in methamphetamine synthesized by the Leuckart and reductive amination methods |journal = Anal. Chem. |volume = 81 |issue = 17 |pages = 7342–7348 |date = September 2009 |pmid = 19637924 |pmc = 3662403 |doi = 10.1021/ac9005588 }}</ref> In the Leuckart reaction, one equivalent of phenylacetone is reacted with two equivalents of {{nowrap|[[N-methylformamide|''N''-methylformamide]]}} to produce the formyl [[amide]] of methamphetamine plus carbon dioxide and [[methylamine]] as side products.<ref name="pmid19637924" /> In this reaction, an [[iminium]] cation is formed as an intermediate which is [[Redox|reduced]] by the second equivalent of {{nowrap|''N''-methylformamide}}.<ref name="pmid19637924" /> The intermediate formyl amide is then [[hydrolyzed]] under acidic aqueous conditions to yield methamphetamine as the final product.<ref name="pmid19637924" /> Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.<ref name="pmid19637924" /> {{multiple image <!-- Essential parameters --> | align = center | direction = vertical | width = 500 <!-- Extra parameters --> | header = Methamphetamine synthesis | header_align = center | header_background = <!-- Image 1--> |image1=Methamphetamine reductive amination.png |caption1=Method of methamphetamine synthesis of methamphetamine via [[reductive amination]] |alt1=Diagram of methamphetamine synthesis by reductive amination <!-- Image 2--> |image2=Methamphetamine leuckart synthesis.png |caption2=Methods of methamphetamine synthesis via the [[Leuckart reaction]] |alt2=Diagram of methamphetamine synthesis by Leuckart reaction <!-- Image 3--> |image3= |caption3= |alt3= }} {{clear}} == History, society, and culture == {{Main|History and culture of substituted amphetamines}} [[File:Pervitindose.jpg|alt=A methamphetamine tablet container|thumb|Pervitin, a methamphetamine brand used by German soldiers during [[World War II]], was dispensed in these tablet containers.]] [[File:US timeline. Drugs involved in overdose deaths.jpg|thumb|U.S. [[drug overdose]] related fatalities in 2017 were 70,200, including 10,333 of those related to psychostimulants (including methamphetamine).<ref name=NIDA-deaths>[https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates "Overdose Death Rates"]. {{Webarchive|url=https://web.archive.org/web/20171213234138/https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates |date=13 December 2017 }}. [[National Institute on Drug Abuse]] (NIDA).</ref><ref>{{cite news |title=US overdose deaths from fentanyl and synthetic opioids doubled in 2016 |url=https://www.theguardian.com/us-news/2017/sep/03/fentanyl-synthetic-opioids-deaths-doubled-us |work=The Guardian |date=3 September 2017 |access-date=17 August 2018 |archive-url=https://web.archive.org/web/20180817225855/https://www.theguardian.com/us-news/2017/sep/03/fentanyl-synthetic-opioids-deaths-doubled-us |archive-date=17 August 2018 |url-status=live }}</ref>]] Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist [[Lazăr Edeleanu]] who named it ''phenylisopropylamine''.<ref>{{cite book | vauthors = Rassool GH |title = Alcohol and Drug Misuse: A Handbook for Students and Health Professionals |year = 2009 |publisher = Routledge |location = London |isbn = 978-0-203-87117-1 |page = 113 }}</ref><ref name="Vermont">{{cite web |url = http://healthvermont.gov/adap/meth/brief_history.aspx |title = Historical overview of methamphetamine |website = Vermont Department of Health |publisher = Government of Vermont |access-date = 29 January 2012 |archive-url = https://web.archive.org/web/20120620083221/http://healthvermont.gov/adap/meth/brief_history.aspx |archive-date = 20 June 2012 |url-status = live }}</ref> Shortly after, methamphetamine was synthesized from [[ephedrine]] in 1893 by Japanese [[chemist]] [[Nagai Nagayoshi]].<ref name="Grobler et al 2011">{{cite journal |vauthors = Grobler SR, Chikte U, Westraat J |title = The pH Levels of Different Methamphetamine Drug Samples on the Street Market in Cape Town |journal = ISRN Dentistry |volume = 2011 |pages = 1–4 |year = 2011 |pmid = 21991491 |pmc = 3189445 |doi = 10.5402/2011/974768 |doi-access = free }}</ref> Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist [[Akira Ogata]] via [[redox|reduction]] of ephedrine using red [[phosphorus]] and [[iodine]].<ref name="history">{{cite web |url = http://healthvermont.gov/adap/meth/brief_history.aspx |title = Historical overview of methamphetamine |publisher = Vermont Department of Health |access-date = 15 January 2012 |archive-url = https://web.archive.org/web/20120620083221/http://healthvermont.gov/adap/meth/brief_history.aspx |archive-date = 20 June 2012 |url-status = live }}</ref> From 1938, methamphetamine was marketed on a large scale in Germany as a nonprescription drug under the brand name ''Pervitin'', produced by the Berlin-based [[Temmler]] pharmaceutical company.<ref name="CISP">{{Citation|title=Pervitin|url=http://www.chemie.de/lexikon/Pervitin.html|publisher=CHEMIE.DE Information Service GmbH|location=Berlin|language=de|access-date=16 September 2015|archive-date=18 December 2019|archive-url=https://web.archive.org/web/20191218224238/https://www.chemie.de/lexikon/Pervitin.html|url-status=live}}</ref><ref>{{cite book | vauthors = Freye E |title= Pharmacology and Abuse of Cocaine, Amphetamines, Ecstasy and Related Designer Drugs |year=2009 |publisher=Springer |location=University Düsseldorf, Germany |isbn=978-90-481-2447-3 |page=110 }}</ref> It was used by all branches of the combined [[Wehrmacht|armed forces]] of the [[Third Reich]], for its stimulant effects and to induce extended [[wakefulness]].<ref>{{Cite news |title = The Nazi Death Machine: Hitler's Drugged Soldiers |url = http://www.spiegel.de/international/the-nazi-death-machine-hitler-s-drugged-soldiers-a-354606.html |publisher = Der Spiegel, 6 May 2005 |newspaper = Spiegel Online |date = 6 May 2005 | vauthors = Ulrich A |access-date = 12 August 2014 |archive-url = https://web.archive.org/web/20171219062055/http://www.spiegel.de/international/the-nazi-death-machine-hitler-s-drugged-soldiers-a-354606.html |archive-date = 19 December 2017 |url-status = live }}</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> Pervitin became colloquially known among the German troops as "[[Stuka]]-Tablets" (''Stuka-Tabletten'') and "[[Hermann Göring|Herman-Göring]]-Pills" (''Hermann-Göring-Pillen''), as a snide allusion to Göring's widely-known addiction to drugs. However, the side effects, particularly the withdrawal symptoms, were so serious that the army sharply cut back its usage in 1940.<ref name="shooting up">{{cite book | vauthors = Kamieński Ł |title = Shooting Up: A Short History of Drugs and War |url = https://books.google.com/books?id=NAVCCwAAQBAJ&pg=PA112 |year = 2016 |publisher = Oxford University Press |pages = 111–13 |isbn = 9780190263478 |access-date = 23 October 2016 |archive-url = https://web.archive.org/web/20170323182238/https://books.google.com/books?id=NAVCCwAAQBAJ&pg=PA112 |archive-date = 23 March 2017 |url-status = live }}</ref> By 1941, usage was restricted to a doctor's prescription, and the military tightly controlled its distribution. Soldiers would only receive a couple of tablets at a time, and were discouraged from using them in combat. Historian Łukasz Kamieński says, {{blockquote|A soldier going to battle on Pervitin usually found himself unable to perform effectively for the next day or two. Suffering from a drug hangover and looking more like a zombie than a great warrior, he had to recover from the side effects.}} Some soldiers turned violent, committing war crimes against civilians; others attacked their own officers.<ref name="shooting up" /> At the end of the war, it was used as part of a new drug: [[D-IX]]. [[Obetrol]], patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of [[obesity]], was one of the first brands of pharmaceutical methamphetamine products.<ref name="Real_Obetrol_Ad">{{cite book | vauthors = Rasmussen N |title = On Speed: The Many Lives of Amphetamine |date = March 2008 |publisher = New York University Press |edition = 1 |isbn = 978-0-8147-7601-8 |page = 148 }}</ref> Because of the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.<ref name="Real_Obetrol_Ad" /> Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.<ref name="Vermont" /> For example, during the early 1970s in the United States, methamphetamine became a [[Controlled Substances Act#Schedule II controlled substances|schedule II controlled substance]] under the [[Controlled Substances Act]].<ref>{{cite web |title = Controlled Substances Act |url = https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/ucm148726.htm |website = United States Food and Drug Administration |date = 11 June 2009 |access-date = 4 November 2013 |archive-url = https://web.archive.org/web/20170405002905/https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/ucm148726.htm |archive-date = 5 April 2017 |url-status = live }}</ref> Currently, methamphetamine is sold under the trade name ''Desoxyn'', [[trademark]]ed by the Danish pharmaceutical company [[Lundbeck]].<ref name="Desoxyn (Lundbeck)">{{cite web |url = http://www.lundbeck.com/us/products/cns-products/desoxyn |title = Desoxyn |publisher = Lundbeck: Desoxyn |access-date = 15 December 2012 |archive-url = https://web.archive.org/web/20121130095007/http://www.lundbeck.com/us/products/cns-products/desoxyn |archive-date = 30 November 2012 |df = dmy-all }}</ref> As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.<ref>{{cite web |url = http://www.recordatirarediseases.com/products/us-product/desoxyn%C2%AE-cii-methamphetamine-hydrochloride-tablets-usp |title = Recordati: Desoxyn |publisher = Recordati SP |access-date = 15 May 2013 |archive-url = https://web.archive.org/web/20130707013757/http://www.recordatirarediseases.com/products/us-product/desoxyn%C2%AE-cii-methamphetamine-hydrochloride-tablets-usp |archive-date = 7 July 2013 |df = dmy-all }}</ref> == Trafficking == The [[Golden Triangle (Southeast Asia)]], specifically [[Shan State]], Myanmar, is the world's leading producer of methamphetamine as production has shifted to [[Yaba (drug)|Yaba]] and crystalline methamphetamine, including for export to the United States and across East and Southeast Asia and the Pacific.<ref>{{Cite web|url=https://www.unodc.org/documents/southeastasiaandpacific/Publications/2019/SEA_TOCTA_2019_web.pdf/|title=Transnational Organized Crime in Southeast Asia: Evolution, Growth and Challenges|date=June 2019|access-date=30 July 2020|archive-date=22 January 2021|archive-url=https://web.archive.org/web/20210122015018/https://www.unodc.org/documents/southeastasiaandpacific/Publications/2019/SEA_TOCTA_2019_web.pdf}}</ref> Concerning the accelerating synthetic drug production in the region, the Cantonese Chinese syndicate [[Sam Gor]], also known as The Company, is understood to be the main international crime syndicate responsible for this shift.<ref>{{Cite web |url=https://edition.cnn.com/2019/10/23/opinions/tse-chi-lop-revealed-opinion-intl-hnk/index.html |title=The Man Accused of Running the Biggest Drug Trafficking Syndicate in Asia's History has Been Revealed: Here's What Needs To Happen Next |publisher=[[CNN]] |date=24 October 2019 |access-date=30 July 2020 |archive-date=22 October 2021 |archive-url=https://web.archive.org/web/20211022232716/https://edition.cnn.com/2019/10/23/opinions/tse-chi-lop-revealed-opinion-intl-hnk/index.html |url-status=live }}</ref> It is made up of members of five different triads. Sam Gor is primarily involved in drug trafficking, earning at least $8 billion per year.<ref>{{cite news | vauthors = Smith N |title=Drugs investigators close in on Asian 'El Chapo' at centre of vast meth ring |url=https://www.telegraph.co.uk/news/2019/10/14/drugs-investigators-close-asian-el-chapo-centre-vast-meth-ring/ |archive-url=https://ghostarchive.org/archive/20220110/https://www.telegraph.co.uk/news/2019/10/14/drugs-investigators-close-asian-el-chapo-centre-vast-meth-ring/ |archive-date=10 January 2022 |url-access=subscription |url-status=live |work=The Telegraph |date=14 October 2019}}{{cbignore}}</ref> Sam Gor is alleged to control 40% of the Asia-Pacific methamphetamine market, while also trafficking [[heroin]] and [[ketamine]]. The organization is active in a variety of countries, including Myanmar, Thailand, New Zealand, Australia, Japan, China, and Taiwan. Sam Gor previously produced meth in Southern China and is now believed to manufacture mainly in the [[Golden Triangle (Southeast Asia)|Golden Triangle]], specifically Shan State, Myanmar, responsible for much of the massive surge of crystal meth in circa 2019.<ref>{{Cite web|url=https://nypost.com/2019/10/14/inside-the-hunt-for-the-man-known-as-asias-el-chapo/|title=Inside the hunt for the man known as 'Asia's El Chapo'|work=[[New York Post]]|date=14 October 2019|access-date=30 July 2020|archive-date=19 January 2021|archive-url=https://web.archive.org/web/20210119003851/https://nypost.com/2019/10/14/inside-the-hunt-for-the-man-known-as-asias-el-chapo/|url-status=live}}</ref> The group is understood to be headed by [[Tse Chi Lop]], a gangster born in [[Guangzhou]], [[China]] who also holds a Canadian passport. [[Liu Zhaohua]] was another individual involved in the production and trafficking of methamphetamine until his arrest in 2005.<ref name=":0">{{Cite web |date=16 September 2009 |title=Notorious drug kingpin executed for trafficking |url=https://www.scmp.com/article/692604/notorious-drug-kingpin-executed-trafficking |access-date=3 June 2022 |website=South China Morning Post |language=en |archive-date=3 June 2022 |archive-url=https://web.archive.org/web/20220603092530/https://www.scmp.com/article/692604/notorious-drug-kingpin-executed-trafficking |url-status=live }}</ref> It was estimated over 18 tonnes of methamphetamine were produced under his watch.<ref name=":0" /> == Legal status == {{Main|Legal status of methamphetamine}} The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many [[jurisdiction]]s.<ref>{{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 |year = 2007 |isbn = 978-92-1-148223-2 |url = http://www.unodc.org/pdf/youthnet/ATS.pdf |access-date = 11 November 2013 |archive-url = https://web.archive.org/web/20131016082310/http://www.unodc.org/pdf/youthnet/ATS.pdf |archive-date = 16 October 2013 |url-status = live }}</ref><ref name="incb">{{cite web |title = List of psychotropic substances under international control |website = International Narcotics Control Board |publisher = United Nations |url = http://www.incb.org/pdf/e/list/green.pdf |access-date = 19 November 2005 |archive-url = https://web.archive.org/web/20051205125434/http://www.incb.org/pdf/e/list/green.pdf |archive-date = 5 December 2005 |date = August 2003 }}</ref> Methamphetamine has been placed in schedule II of the [[United Nations]] [[Convention on Psychotropic Substances]] treaty.<ref name=incb /> == Research == It has been suggested, based on animal research, that calcitriol, the active metabolite of [[vitamin D]], can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of methamphetamine.<ref>{{cite journal |vauthors = Cass WA, Smith MP, Peters LE |title = Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine |journal = Annals of the New York Academy of Sciences |volume = 1074 |issue = 1|pages = 261–71 |year = 2006 |pmid = 17105922 |doi = 10.1196/annals.1369.023 |bibcode = |s2cid = 8537458 }}</ref> == See also == *[[18-Methoxycoronaridine|18-MC]] * ''[[Breaking Bad]]'', a TV drama series centered on illicit methamphetamine synthesis * [[Drug checking]] * [[Faces of Meth]], a drug prevention project * [[Harm reduction]] * [[Methamphetamine and Native Americans]] * [[Methamphetamine use in Australia|Methamphetamine in Australia]] * [[Methamphetamine in Bangladesh]] * [[Illegal drug trade in the Philippines#Methamphetamine production|Methamphetamine in the Philippines]] * [[Methamphetamine in the United States]] * [[Montana Meth Project]], a Montana-based organization aiming to reduce meth use among teenagers * [[Recreational drug use]] * [[Rolling meth lab]], a transportable laboratory that is used to illegally produce methamphetamine * [[Ya ba]], Southeast Asian tablets containing a mixture of methamphetamine and caffeine == Explanatory notes == <references group="note" /> '''Image legend''' <references group="Color legend" /> == Reference notes == <references group="sources" /> {{clear}} == References == {{Reflist|3}} == Further reading == * {{cite news| vauthors = Szalavitz M |title=Why the Myth of the Meth-Damaged Brain May Hinder Recovery|url=http://healthland.time.com/2011/11/21/why-the-myth-of-the-meth-damaged-brain-may-hinder-recovery/|work=Time.com|publisher=Time USA, LLC}} * {{cite journal|vauthors=Hart CL, Marvin CB, Silver R, Smith EE|title=Is cognitive functioning impaired in methamphetamine users? A critical review|journal=Neuropsychopharmacology|date=February 2012|volume=37|issue=3|pages=586–608|doi=10.1038/npp.2011.276|pmid=22089317|issn=0893-133X|pmc=3260986}} **{{cite magazine | vauthors = Szalavitz M |date=21 November 2011 |title=Why the Myth of the Meth-Damaged Brain May Hinder Recovery |magazine=Time |url=http://healthland.time.com/2011/11/21/why-the-myth-of-the-meth-damaged-brain-may-hinder-recovery/}} == External links == {{Commons category}} * [http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+537-46-2 Methamphetamine Toxnet entry] * [http://www.inchem.org/documents/pims/pharm/pim334.htm Methamphetamine Poison Information Monograph] * [https://www.fbi.gov/news/stories/aryan-brotherhood-methamphetamine-operation-dismantled Drug Trafficking: Aryan Brotherhood Methamphetamine Operation Dismantled], [[FBI]] * [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148451 Neurologic manifestations of chronic methamphetamine abuse] {{Amphetamine}} {{Methamphetamine}} {{Drug use}} {{Stimulants}} {{ADHD pharmacotherapies}} {{Navboxes | title = [[Pharmacodynamics]] | titlestyle = background:#ccccff | list1 = {{Monoamine releasing agents}} {{TAAR ligands}} {{Sigma receptor modulators}} {{Monoamine neurotoxins}} }} {{Phenethylamines}} {{Authority control}} [[Category:Methamphetamine| ]] [[Category:1893 introductions]] [[Category:Anorectics]] [[Category:Aphrodisiacs]] [[Category:Attention deficit hyperactivity disorder management]] [[Category:Carbonic anhydrase activators]] [[Category:Cardiac stimulants]] [[Category:Euphoriants]] [[Category:Excitatory amino acid reuptake inhibitors]] [[Category:Japanese inventions]] [[Category:Management of obesity]] [[Category:Norepinephrine-dopamine releasing agents]] [[Category:Phenethylamines]] [[Category:Sigma agonists]] [[Category:Stimulants]] [[Category:Substituted amphetamines]] [[Category:Sympathomimetics]] [[Category:TAAR1 agonists]] [[Category:VMAT inhibitors]]'