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{{Short description|Central nervous system stimulant}}
{{Redirect4|Meth|Tik}}
{{Pp-vandalism|small=yes}}
{{About|the ] drug, methamphetamine, in both ] and ] forms|the CNS inactive ] nasal decongestant|levomethamphetamine}}
{{Use American English|date=May 2018}}
{{Drugbox
{{Use dmy dates|date=June 2024}}
| verifiedrevid = 398683476
{{cs1 config|name-list-style=vanc|display-authors=6}}
| IUPAC_name = ''N''-methyl-1-phenylpropan-2-amine
{{Good article}}
| image = Methamphetamine.svg
{{redirect|Meth}}
{{Redirect2|Hiropon|Philopon|the Takashi Murakami sculpture|Hiropon (sculpture)}}
{{Infobox drug
| verifiedrevid = 589084691
| INN = Metamfetamine<!-- "Metamfetamine " from https://pubchem.ncbi.nlm.nih.gov/compound/Methamphetamine#section=Depositor-Supplied-Synonyms -->
| 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
| chirality = ]


<!-- 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>
| image2 = Methamphetamine-3d-CPK.png | width=200
| tradename = Desoxyn, others
| CASNo_Ref = {{cascite|correct|CAS}}
| Drugs.com = {{Drugs.com|monograph|methamphetamine-hydrochloride}}
| MedlinePlus =
| DailyMedID = <!-- DailyMed may use generic or brand name (generic name preferred) -->
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment =
| pregnancy_category =
| dependency_liability = {{Ublist|]: None|]: Very high}}
| addiction_liability = Very high
| routes_of_administration = ], ], ], ], ], ], ], ]
| class =
| ATC_prefix = N06
| ATC_suffix = BA03
| ATC_supplemental = <!-- Legal status -->
| legal_AU = S8
| legal_AU_comment =
| legal_BR = F2
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=24 July 2023 |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=27 August 2023 |access-date=27 August 2023 |publisher=] |language=pt-BR |publication-date=25 July 2023}}</ref>
| legal_CA = Schedule I
| legal_CA_comment =
| legal_DE = Anlage II
| legal_DE_comment =
| legal_NZ = Class A
| legal_NZ_comment =
| legal_UK = Class A
| legal_UK_comment =
| legal_US = Schedule II
| legal_US_comment = <ref name=":USAS2">{{Cite web |last=Ingersoll |first=John |date=July 7, 1971 |title=Amphetamine, Methamphetamine, and Optical Isomers |url=https://archives.federalregister.gov/issue_slice/1971/7/7/12730-12734.pdf |url-status=live |archive-url=https://archive.today/20241127164332/https://archives.federalregister.gov/issue_slice/1971/7/7/12730-12734.pdf |archive-date=November 27, 2024 |access-date=November 27, 2024 |website=] |publisher=Bureau of Narcotics and Dangerous Drugs}}</ref>
| legal_EU =
| legal_EU_comment =
| legal_UN = Psychotropic Schedule II
| legal_UN_comment =
| legal_status = SE: Förteckning II

<!-- Pharmacokinetic data -->| bioavailability = ]: 67%<ref name="pmid19426289" /><ref name="Schep" /><ref name="pmid25176528" /><ref name="pmid25724762">{{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 = Progress in Neuro-psychopharmacology & Biological Psychiatry |volume = 64 |pages = 231–236 |date = January 2016 |pmid = 25724762 |doi = 10.1016/j.pnpbp.2015.02.013 |doi-access = free |issn=0278-5846 }}</ref><br />]: 79%<ref name="pmid19426289" /><ref name="Schep" /><br />]: 67–90%<ref name="pmid19426289" /><ref name="Schep" /><ref name="pmid25176528" /><br />]: 100%<ref name="pmid19426289" /><ref name="pmid25724762" />
| protein_bound = Varies widely<ref name="Pubchem1">{{cite web |title = Methamphetamine: Toxicity | url = https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Toxicity |work = PubChem Compound |publisher = National Center for Biotechnology Information |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 = ]<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 ]<ref name="FMO" /><ref name="FMO3-Primary" />
| metabolites = • ] <br>
• ] <br> • ]
| onset = ]: 3{{nbsp}}hours (peak)<ref name="pmid19426289" /><br />]: <15{{nbsp}}minutes<ref name="pmid19426289" /><br />]: <18{{nbsp}}minutes<ref name="pmid19426289" /><ref name="Schep" /><br />]: <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 ]

<!-- 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
| PubChem = 1206
| IUPHAR_ligand = 4803
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01577
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 1169
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 44RAL3456C | UNII = 44RAL3456C
| UNII2_Ref = {{fdacite|correct|FDA}}
| InChI = 1/C10H15N/c1-9(11-2)8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3
| UNII2 = 24GNZ56D62
| InChIKey = MYWUZJCMWCOHBA-UHFFFAOYAT
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08187
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 6809
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1201201
| NIAID_ChemDB =
| PDB_ligand = B40
| synonyms = {{nowrap|''N''-]}}, {{nowrap|''N'',α-]}}, desoxyephedrine

<!-- Chemical and physical data -->| IUPAC_name = (''RS'')-''N''-methyl-1-phenylpropan-2-amine
| C = 10
| H = 15
| N = 1
| 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 | 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 | StdInChIKey = MYWUZJCMWCOHBA-UHFFFAOYSA-N
| density =
| CAS_number=537-46-2
| density_notes =
| ATC_prefix=N06
| melting_point = 170
| ATC_suffix=BA03
| melting_notes = <ref name="Pubchem2"/>
| ATC_supplemental=
| boiling_point = 212
| PubChem=1206
| boiling_notes = at 760&nbsp;]<ref name="Pubchem2">{{cite web |title = Methamphetamine: Chemical and Physical Properties | url = https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Chemical-and-Physical-Properties |work = PubChem Compound |publisher = National Center for Biotechnology Information |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>
| ChemSpiderID = 1169
| solubility =
| DrugBank=DB01577
| C=10 | H=15 | N=1 | sol_units =
| specific_rotation =
| molecular_weight = 149.233 g/mol
| smiles = N(C(Cc1ccccc1)C)C
| synonyms = Desoxyephedrine<br>Pervitin<br>Anadrex<br>Methedrine<br>Methylamphetamine<br>Syndrox<br>Desoxyn
| bioavailability= 62.7% oral; 79% nasal; 90.3% smoked; 99% rectally; 100% IV
| metabolism = ]
| elimination_half-life= 9–12 hours<ref name="Schep"/>
| excretion = ]
| pregnancy_AU =
| pregnancy_US = C
| pregnancy_category =
| legal_AU = S8
| legal_CA = Schedule I
| legal_UK =
| legal_US = Schedule II
| legal_status = Class A<small>(])</small><br>Schedule 5<small>(])</small><br>Injectable:Class A, Oral: A<small>(])</small>
| routes_of_administration= Medical: Oral<br>Recreational: Oral, ], ], Insufflation, Inhalation, Rectal
}} }}
<!--


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''' ({{pron-en|ˌmɛθæmˈfɛtəmiːn}} <small></small>), also known as '''metamfetamine''' (]), '''methylamphetamine''', '''N-methylamphetamine''', '''desoxyephedrine''', and colloquially as '''meth''', is a ] of the ] and ] ]. It increases ], concentration, energy, and in high doses, can induce ], enhance ], and increase ].<ref name="isbn1-59385-174-X">{{Cite book|author=Mack, Avram H.; Frances, Richard J.; Miller, Sheldon I. |title=Clinical Textbook of Addictive Disorders, Third Edition |publisher=The Guilford Press |location=New York |year=2005 |pages= 207|isbn=1-59385-174-X}}</ref><ref name="Logan">B.K. Logan. ''Methamphetamine - Effects on Human Performance and Behavior''. Forensic Science Review, Vol. 14, no. 1/2 (2002), p. 142 {{Dead link|date=November 2010}}</ref> Methamphetamine has high potential for ] and ] by activating the psychological ] via triggering a ] of ], ] and ] in the brain. Methamphetamine is ] for the treatment of ] and ], marketed in the USA and Canada under the trademark name '''Desoxyn'''.<ref></ref>


-->
Methamphetamine abuse can lead to ] and prolonged psychiatric disorders, cognitive impairment, as well as increasing the risk of developing ]. Following a period of heavy use, also known as "binging", which typically last days or even weeks, a severe ] lasting up to 10 days can occur, primarily consisting of depression, fatigue, excessive sleeping and an increased appetite. Following chronic methamphetamine abuse, symptoms can persist beyond the withdrawal period for months and even up to a year, as the brain regenerates ] sites which were previously hyperstimulated and subsequently ].<ref name="Cruickshank-2009">{{Cite journal | last1 = Cruickshank | first1 = CC. | last2 = Dyer | first2 = KR. | title = A review of the clinical pharmacology of methamphetamine. | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2009.02564.x/full | journal = Addiction | volume = 104 | issue = 7 | pages = 1085-99 | month = Jul | year = 2009 | doi = 10.1111/j.1360-0443.2009.02564.x | PMID = 19426289 }}</ref> Research has found that 20 percent of methamphetamine addicts experience a ] resembling ] which persists for longer than six months post-methamphetamine use; this ] can be resistant to traditional treatment.<ref name="Barr-2006"/> In addition to the psychological harm of methamphetamine abuse, physical harm, primarily consisting of ] damage, can often occur with chronic abuse or acute overdose.<ref name="Darke-2008"/>


'''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 = ] (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 web |title = Methamphetamine: Identification | url = http://www.drugbank.ca/drugs/DB01577#identification |work = DrugBank |publisher = University of Alberta |date = 8 February 2013 |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: '''meth''', '''speed''', '''crank''' and '''shabu''' (also '''sabu''' and '''shabu-shabu''') in Indonesia and the Philippines,<ref>{{Cite web |work=Detik News |title=Polisi Tangkap Bandar Shabu-shabu |url=https://news.detik.com/berita/d-356478/polisi-tangkap-bandar-shabu-shabu |access-date=29 July 2023 |language=id-ID |archive-date=29 July 2023 |archive-url=https://web.archive.org/web/20230729143513/https://news.detik.com/berita/d-356478/polisi-tangkap-bandar-shabu-shabu |url-status=live }}</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=29 July 2023 |website=Manila Bulletin |language=en}}</ref><ref>{{Cite web |work=ANTARA News Agency |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=29 July 2023 |archive-date=22 September 2024 |archive-url=https://web.archive.org/web/20240922021108/https://sumut.antaranews.com/berita/538872/jadi-pengedar-sabu-seorang-irt-di-pidoli-dolok-ditangkap-polisi |url-status=live }}</ref><ref>{{Cite web |vauthors=Marantal RD |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=29 July 2023 |website=Philstar.com |archive-date=29 July 2023 |archive-url=https://web.archive.org/web/20230729143513/https://www.philstar.com/the-freeman/cebu-news/2023/06/02/2270858/e-bike-driver-nabbed-drug-bust-shabu-worth-almost-p1-million-seized |url-status=live }}</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 ] (CNS) ] that is mainly used as a ] or ] drug and less commonly as a ] for ] (ADHD).<ref name="d-meth review" /> It has also been researched as a potential treatment for ].<ref name="pmid25724762" /> Methamphetamine was discovered in 1893 and exists as two ]s: ] 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 (] ) and {{nowrap|D-methamphetamine}}, {{nowrap|(''S'')-methamphetamine}}, or metamfetamine (]), respectively.<ref name="EMCDDA profile" /><ref>{{cite web | 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 ] ], which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms, but the ] salt, commonly called crystal meth, is widely used. Methamphetamine is rarely prescribed over concerns involving its potential for recreational use as an ] and ], among other concerns, as well as the availability of safer ] with comparable treatment efficacy such as ] and ].<ref name="d-meth review">{{cite journal |vauthors=Moszczynska A, Callan SP |date=September 2017 |title=Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=362 |issue=3 |pages=474–488 |doi=10.1124/jpet.116.238501 |pmc=11047030 |pmid=28630283 |quote=METH is a schedule II drug, which can only be prescribed for attention deficit hyperactivity disorder (ADHD), extreme obesity, or narcolepsy (as Desoxyn; Recordati Rare Diseases LLC, Lebanon, NJ), with amphetamine being prescribed more often for these conditions due to amphetamine having lower reinforcing potential than METH (Lile et al., 2013).&nbsp;...<br /> As discussed earlier, the d-enantiomer has stronger CNS effects but is metabolized more quickly than the l-enantiomer, which is longer lasting due to the slower breakdown.&nbsp;...<br /> l-METH, a vasoconstrictor, is the active constituent of the Vicks Inhaler decongestant (Proctor & Gamble, Cincinnati, OH), an over-the-counter product containing about 50 mg of the drug (Smith et al., 2014). Desoxyn, which is d-METH, is rarely medically prescribed due to its strong reinforcing properties. Therapeutic doses of Desoxyn are 20–25 mg daily, taken every 12 hours, with dosing not exceeding 60 mg/day}}</ref> While pharmaceutical formulations of methamphetamine in the United States are labeled as methamphetamine hydrochloride, they contain dextromethamphetamine as the ].<ref name="d-meth review" />{{#tag:ref|The ] for Desoxyn lists the chemical name '''(S)-N,α-dimethylbenzeneethanamine hydrochloride''', which explicitly identifies the compound as dextromethamphetamine (the S-enantiomer) with no ] ambiguity.<ref name="Desoxyn FDA label" />|name="D-meth FDA label"|group="note"}} Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.<ref name="d-meth review" />
==History==
] methamphetamine was first ] in 1919 by ].]]
Methamphetamine was first synthesized from ] in Japan in 1893 by chemist ].<ref>{{Cite journal| url = http://ci.nii.ac.jp/naid/110003609935/|author =Nagai N.|title = Kanyaku maou seibun kenkyuu seiseki (zoku)|journal= Yakugaku Zasshi |year=1893|volume= 127|pages= 832–860}}</ref> In 1919, crystallized methamphetamine was synthesized by ] via ] of ] using red ] and ]. In 1943, ] requested for its approval from the ] (FDA) for the treatment of ], mild ], ], chronic ], cerebral ], and ]. Methamphetamine was approved for all of these indications in December, 1944.{{Citation needed|date=January 2010}} All of these indication approvals were eventually removed.{{Citation needed|date=January 2010}} The only two approved marketing indications remaining for methamphetamine are for ] (ADHD) and the short-term management of ], although the drug is clinically established as effective in the treatment of ].<ref name="Mitler MM, Hajdukovic R, Erman MK 1993 306–17">{{Cite journal|author=Mitler MM, Hajdukovic R, Erman MK |title=Treatment of narcolepsy with methamphetamine |journal=Sleep |volume=16 |issue=4 |pages=306–17 |year=1993 |month=June |pmid=8341891 |pmc=2267865}}</ref>


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 ] controlled substances. ] is available as an ] (OTC) drug for use as an inhaled ] in the United States.{{#tag:ref|The active ingredient in some OTC inhalers in the United States is listed as ''levmetamfetamine'', the ] and ] of levomethamphetamine.<ref name="FDA levmetamfetamine">{{cite web |title = Code of Federal Regulations Title 21: Subchapter D – Drugs for human use, Part 341 – cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use | 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 web |title = Levomethamphetamine: Identification | 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 ] treaty. While dextromethamphetamine is a more potent drug, racemic methamphetamine is illicitly produced more often, owing to the relative ease of ] and regulatory limits of ] availability.
===World War II===
One of the earliest uses of methamphetamine was during World War II, when it was used by Axis and Allied forces<!-- Axis use of meth per se emphasized in source -->.<ref>{{Cite book| last = Grinspoon | first = | authorlink = | coauthors = Hedblom | title = Speed Culture: Amphetamine Use and Abuse in America | publisher = Harvard University Press | date = 1975-01-01 | location = | pages = 18 | url = http://books.google.com/?id=LyStWcRD6QIC&lpg=PT1&pg=PA18 | doi = | id = | isbn = 978-0674831926 }}</ref> The German military dispensed it under the trademark name Pervitin. It was widely distributed across rank and division, from elite forces to tank crews and aircraft personnel, with many millions of tablets being distributed throughout the war.<ref name=Pervitin>{{Cite web|url=http://www.spiegel.de/international/0,1518,354606,00.html |title=The Nazi Death Machine: Hitler's Drugged Soldiers - SPIEGEL ONLINE - News - International |accessdate=2009-11-17 |last=Andreas Ulrich |first=Andreas |work=Spiegel Online }}</ref> From 1942 until his death in 1945, ] may have been given intravenous injections of methamphetamine by his personal physician ]. It is possible that it was used to treat Hitler's speculated ], or that his Parkinson-like symptoms that developed from 1940 onwards resulted from using methamphetamine.<ref>{{Cite journal| last= Doyle | first = D | year= 2005 | title= Hitler's Medical Care | url= http://www.rcpe.ac.uk/journal/issue/journal_35_1/Hitler%27s_medical_care.pdf | journal = Journal of the Royal College of Physicians of Edinburgh | volume=35 | pages=75–82 | format = PDF | accessdate=2006-12-28 | pmid= 15825245 | issue= 1}}</ref> In Japan, methamphetamine was sold under the registered trademark of {{Nihongo|Philopon|ヒロポン|hiropon}} by ] for civilian and military use. Similar to the rest of the world, the side effects of methamphetamine were not well studied, and regulation was not seen as necessary.


In low to moderate doses, methamphetamine can ], increase alertness, concentration and energy in fatigued individuals, reduce appetite, and promote weight loss. At very high doses, it can induce ], ], ], and ]. Chronic high-dose use can precipitate unpredictable and rapid ]s, ] (e.g., ], ]s, ], and ]s), and ]. Recreationally, methamphetamine's ability to ] has been reported to ] and ] 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 ] liability (i.e., a high likelihood that long-term or high dose use will lead to compulsive drug use) and high ] liability (i.e., a high likelihood that ] symptoms will occur when methamphetamine use ceases). Discontinuing methamphetamine after heavy use may lead to a ], which can persist for months beyond the typical ] period. At high doses, methamphetamine is ] to human ] ] ]s and, to a lesser extent, ] neurons.<ref name="pmid25861156">{{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 |issue = 103969 |pages = 1–11 |date = March 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 ] volume in several brain regions, as well as adverse changes in markers of metabolic integrity.<ref name="pmid19328213" />
===Post-war use===
After World War II, a large Japanese military stockpile of methamphetamine, known by its trademark Philopon, flooded the market.<ref name=Philopon>{{Cite web| url = http://web.archive.org/web/20071221115601/http://www.yama-arashi.com/medical/antidepressants.htm | title = 抗うつ薬いろいろ (Various Antidepressants) | accessdate = 2006-07-14 | author = Digital Creators Studio Yama-Arashi | date= 2006-04-16 | work = 医療情報提供サービス | language = Japanese}}</ref> The Japanese Ministry of Health banned it in 1951; since then, it has been increasingly produced by the ] criminal organization.<ref name=banning_in_1951>{{Cite web| url = http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1989-01-01_1_page007.html | title = Japan: stimulant epidemics past and present | accessdate = 14 July 2006 | author = M. Tamura | date= 1989-01-01 | work = Bulletin on Narcotics | publisher = United Nations Office on Drugs and Crime | pages = 83–93}}</ref> On the streets, it is also known as S, ], and Speed, in addition to its old trademarked name. In the 1950s, there was a rise in the legal prescription of methamphetamine to the American public. In the 1954 edition of ''Pharmacology and Therapeutics'', indications for methamphetamine included "], ] ], ], certain ] states, and in the treatment of ]."<ref>{{Cite book| last = Grollman | first = Arthur | authorlink = | coauthors = | title = Pharmacology and Therapeutics: a Textbook for Students and Practitioners of Medicine | publisher = Lea & Febiger | year = 1954 | location = | pages = 209 | isbn = 0812101057}}</ref> The 1960s saw the start of significant use of clandestinely manufactured methamphetamine as well as methamphetamine created in users' own homes for personal use. The recreational use of methamphetamine continues to this day.


Methamphetamine belongs to the ] and ] ]. It is related to the other ]s as a ] of these compounds, which share the common ] {{chem2|auto=1|C10H15N}}.<!--
===Legal restrictions===
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{{See also|#Legality|l1=Legality}}
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]
In 1983, laws were passed in the United States prohibiting possession of precursors and equipment for methamphetamine production. This was followed a month later by a bill passed in Canada enacting similar laws. In 1986, the U.S. government passed the Federal Controlled Substance Analogue Enforcement Act in an attempt to curb the growing use of ]s. Despite this, use of methamphetamine expanded throughout rural United States, especially through the Midwest and South.<ref></ref>


== Uses ==
Since 1989, five U.S. federal laws and dozens of state laws have been imposed in an attempt to curb the production of methamphetamine. Methamphetamine can be produced in home laboratories using pseudoephedrine or ephedrine, which, at the time, were the active ingredients in over-the-counter drugs such as ] and ]. Preventive legal strategies of the past 17 years have steadily increased restrictions to the distribution of pseudoephedrine/ephedrine-containing products.<ref name="Cunningham JK 2003">Cunningham JK, Liu LM. (2003) Impacts of Federal ephedrine and pseudoephedrine regulations on methamphetamine-related hospital admissions. Addiction, 98, 1229–1237.</ref>
=== Medical ===
]
In the United States, methamphetamine hydrochloride, sold under the brand name '''Desoxyn''', is ]-approved for the treatment of ] (ADHD);<ref name="Desoxyn FDA label" /><ref name="pmid22089317"/> however, the FDA notes that the limited therapeutic usefulness of methamphetamine should be weighed against the risks associated with its use.<ref name="Desoxyn FDA label" /> 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="d-meth review" /><ref name="pmid25724762" /><ref name="Desoxyn FDA label" /> Methamphetamine is sometimes prescribed ] for ], ], and ].<ref name="d-meth review"/><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, ] is available in some ] (OTC) ] products.<ref name="d-meth review" /><ref name="OTC levmetamfetamine" group="note" />


Although the pharmaceutical name "methamphetamine hydrochloride" may suggest a ], Desoxyn contains ] dextromethamphetamine, which is a more potent ] than both levomethamphetamine and racemic methamphetamine.<ref name="d-meth review" /><ref name="D-meth FDA label" group="note" /> This naming convention deviates from the standard practice observed with other stimulants, such as ] and ], where the dextrorotary ] is explicitly identified as an ] in both ] and brand-name pharmaceuticals.<ref name="methamfetamine INN">{{cite book | vauthors = Yoshida T | veditors = Klee H | title = Amphetamine Misuse: International Perspectives on Current Trends | date = 1997 | publisher = Harwood Academic Publishers | location = Amsterdam, Netherlands | isbn = 9789057020810 | page = | chapter-url = https://books.google.com/books?id=gVw_wzZU4x8C&pg=PA2| chapter = Chapter 1: Use and Misuse of Amphetamines: An International Overview | quote = Methamphetamine (INN: metamfetamine) is the N-methyl derivative of amphetamine. Unlike amfetamine (INN) which corresponds to the racemic mixture, metamfetamine (INN) refers to the dextro-isomer of l-phenyl-2-methylaminopropane. | url = https://archive.org/details/amphetaminemisus0000unse/page/2 }}</ref><ref name="Adderall IR">{{cite web | title=Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet | website=DailyMed | publisher = Teva Pharmaceuticals USA, Inc. | date=29 May 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f22635fe-821d-4cde-aa12-419f8b53db81 | access-date=3 December 2024}}</ref><ref name="Dextroamphetamine FDA label">{{cite web | title=Dextroamphetamine sulfate tablet | website=DailyMed | date=10 July 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e05cf690-d45a-4696-a1bf-40c9350cc084 | access-date=3 December 2024}}</ref>
As a result of the U.S. ], a subsection of the ], there are restrictions on the amount of pseudoephedrine and ephedrine one may purchase in a specified time period and further requirements that these products must be stored in order to prevent theft.<ref name="Cunningham JK 2003"/> Increasingly strict restrictions have resulted in the reformulation of many over-the-counter drugs, and some, such as ], have been discontinued entirely in the United States.


As methamphetamine is associated with a high potential for misuse, the drug is regulated under the ] and is ] in the United States.<ref name=":USAS2" /> Methamphetamine hydrochloride dispensed in the United States is required to include a ] regarding its potential for ] misuse and ] liability.<ref name="Desoxyn FDA label" />
==Pharmacology==
A member of the family of ]s, methamphetamine is ], with two ]s, ] and ].<ref name="Schep"/> The levorotary form, called ], is an ] used in ]s for nasal decongestion. Levomethamphetamine does not possess any significant ] activity or ] properties. This article deals only with the dextrorotatory form, called ], and the ] form.


'''Desoxyn''' and '''Desoxyn Gradumet''' are both pharmaceutical forms of the drug. The latter is no longer produced and is a ] 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>
Methamphetamine is a potent ] ] that affects neurochemical mechanisms responsible for regulating heart rate, body temperature, blood pressure, appetite, attention, mood and emotional responses associated with alertness or alarming conditions.<ref name="Schep"/> The acute physical effects of the drug closely resemble the physiological and psychological effects of an ]-provoked ], including increased heart rate and blood pressure, ] (constriction of the arterial walls), ], and ] (increased blood sugar). Users experience an increase in focus, increased mental alertness, and the elimination of fatigue, as well as a decrease in appetite.


=== Recreational ===
The ] is responsible for the potentiation of effects as compared to the related compound ], rendering the substance on the one hand more ], enhancing transport across the ], and on the other hand more stable against enzymatic degradation by ] (MAO).
{{Hatnote|See also: ] and the ]}}
Methamphetamine causes the ], ], and ] (5HT) transporters to reverse their direction of flow. This inversion leads to a release of these transmitters from the vesicles to the cytoplasm and from the cytoplasm to the synapse (releasing monoamines in rats with ratios of about ]:] = 1:2, NE:]= 1:60), causing increased stimulation of post-synaptic receptors. Methamphetamine also indirectly prevents the reuptake of these neurotransmitters, causing them to remain in the synaptic cleft for a prolonged period (inhibiting monoamine reuptake in rats with ratios of about: NE:DA = 1:2.35, NE:5HT = 1:44.5).<ref>Rothman, et al. "Amphetamine-Type Central Nervous System Potently than they Release Dopamine and Serotonin." (2001): Synapse ''39'', 32-41 (Table V. on page 37)</ref>


Methamphetamine is often used recreationally for its effects as a potent ] and stimulant as well as ] 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=dead }}</ref>
Methamphetamine is a potent neurotoxin, shown to cause dopaminergic degeneration.<ref>{{Cite journal|author=Itzhak Y, Martin JL, Ali SF |title=Methamphetamine-induced dopaminergic neurotoxicity in mice: long-lasting sensitization to the locomotor stimulation and desensitization to the rewarding effects of methamphetamine |journal=Progress in Neuro-psychopharmacology & Biological Psychiatry |volume=26 |issue=6 |pages=1177–83 |year=2002 |month=October |pmid=12452543 |doi=10.1016/S0278-5846(02)00257-9}}</ref><!-- This corresponds to a human equivalent dose of at least 100 mg! Even higher on a simple mg/kg basis, which is probably a better measure for acute toxicity. --><ref>{{Cite journal|author=Davidson C, Gow AJ, Lee TH, Ellinwood EH |title=Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment |journal=Brain Research. Brain Research Reviews |volume=36 |issue=1 |pages=1–22 |year=2001 |month=August |pmid=11516769 |doi=10.1016/S0165-0173(01)00054-6}}</ref> High doses of methamphetamine produce losses in several markers of brain dopamine and serotonin neurons. Dopamine and serotonin concentrations, dopamine and 5HT uptake sites, and tyrosine and tryptophan hydroxylase activities are reduced after the administration of methamphetamine. It has been proposed that dopamine plays a role in methamphetamine-induced neurotoxicity, because experiments that reduce dopamine production or block the release of dopamine decrease the toxic effects of methamphetamine administration. When dopamine breaks down, it produces ] such as hydrogen peroxide.


According to a ] TV documentary on methamphetamine, an entire subculture known as ] 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 ] sites and have sex.<ref name="SF Meth" /> Because of its strong stimulant and aphrodisiac effects and inhibitory effect on ], 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 ] (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>
It is likely that the approximate twelvefold increase in dopamine levels and subsequent ] that occurs after taking methamphetamine mediates its ].<ref>{{Cite journal|author=Yamamoto BK, Zhu W |title=The effects of methamphetamine on the production of free radicals and oxidative stress |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=287 |issue=1 |pages=107–14 |year=1998 |month=October |pmid=9765328 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9765328}}</ref>
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== Contraindications ==
Recent research published in the ''Journal of Pharmacology And Experimental Therapeutics'' (2007)<ref>{{Cite journal|author=Reese EA, Bunzow JR, Arttamangkul S, Sonders MS, Grandy DK |title=Trace amine-associated receptor 1 displays species-dependent stereoselectivity for isomers of methamphetamine, amphetamine, and para-hydroxyamphetamine |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=321 |issue=1 |pages=178–86 |year=2007 |month=April |pmid=17218486 |doi=10.1124/jpet.106.115402}}</ref> indicates that methamphetamine binds to and activates a ] called ]1.<ref name="pmid17888514">{{Cite journal|author=Grandy DK |title=Trace amine-associated receptor 1-Family archetype or iconoclast? |journal=Pharmacology & Therapeutics |volume=116 |issue=3 |pages=355–90 |year=2007 |month=December |pmid=17888514 |pmc=2767338 |doi=10.1016/j.pharmthera.2007.06.007}}</ref> ]s are a newly discovered receptor family<ref name="pmid11459929">{{Cite journal|author=Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C |title=Trace amines: identification of a family of mammalian G protein-coupled receptors |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue=16 |pages=8966–71 |year=2001 |pmid=11459929 |doi=10.1073/pnas.151105198 |pmc=55357}}</ref><ref name="pmid11723224">{{Cite journal|unused_data=pmid11723224 |author=Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK |title=Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor |journal=Mol. Pharmacol. |volume=60 |issue=6 |pages=1181–8 |year=2001 |pmid=11723224}}</ref> whose members are activated by a number of ]-like molecules<ref name="pmid11723224"/> called ], ]s,<ref name="pmid15146179">{{Cite journal|author=Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, Frascarelli S, Crossley DA, Bunzow JR, Ronca-Testoni S, Lin ET, Hatton D, Zucchi R, Grandy DK |title=3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone |journal=Nat. Med. |volume=10 |issue=6 |pages=638–42 |year=2004 |pmid=15146179 |doi=10.1038/nm1051}}</ref> and certain volatile odorants.<ref name="pmid16878137">{{Cite journal|author=Liberles SD, Buck LB |title=A second class of chemosensory receptors in the olfactory epithelium |journal=Nature |volume=442 |issue=7103 |pages=645–50 |year=2006 |pmid=16878137 |doi=10.1038/nature05066}}</ref>
Methamphetamine is ] in individuals with a history of ], ], or severe ] or anxiety, or in individuals currently experiencing ], ], ], or severe ].<ref name="Desoxyn FDA label" /> The FDA states that individuals who have experienced ] reactions to other stimulants in the past or are currently taking ]s should not take methamphetamine.<ref name="Desoxyn FDA label" /> The FDA also advises individuals with ], ], elevated ], liver or kidney problems, ], ], ], ], ] problems, ]s, or ] to monitor their symptoms while taking methamphetamine.<ref name="Desoxyn FDA label" /> 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 FDA label" />


== Adverse effects ==
It has been demonstrated that a high ambient temperature increases the neurotoxic effects of methamphetamine.<ref>{{Cite journal|author=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=1210–8 |year=2006 |month=March |pmid=16293712 |doi=10.1124/jpet.105.096503}}</ref>
]


==Effects== === Physical ===
===Physical effects=== ====Cardiovascular====
Methamphetamine is a ] drug that causes ] and ]. Methamphetamine also promotes ] and ] some of which may be life threatening.
Physical effects can include ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ],<ref>{{Cite book| last = Mohler | coauthors = Townsend | title = Advanced Therapy In Hypertension And Vascular Disease | pages = 469 | url = http://books.google.com/?id=sCgURxhCJ-8C&pg=PA469 | isbn = 978-1550093186 | publisher = PMPH-USA | date = 2006-04-01 }}</ref> ], dry and/or itchy skin, ], ], and with chronic and/or high doses, ],<ref name="CenTF2">{{Cite web| url=http://www.iir.com/centf/guide.htm#Are%20there%20any%20effective%20treatments%20for%20methamphetamine%20abusers |title=Are there any effective treatments for methamphetamine abusers?|year=2009|work=The Methamphetamine Problem: Question-and-Answer Guide|publisher=Institute for Intergovernmental Research|accessdate=2009-08-13 |location=Tallahassee}}</ref> ],<ref></ref> ],<ref name="Erowid"/> and ] can occur.<ref name="Erowid"></ref><ref name="DartToxicology">{{Cite book| last = Dart | first = Richard | title = Medical Toxicology | publisher = Lippincott Williams & Wilkins | pages = 1074 | url = http://books.google.com/?id=BfdighlyGiwC&pg=PA1074 | isbn = 978-0781728454 | year = 2004 }}</ref><ref name="CenTF1">{{Cite web| url=http://www.iir.com/centf/guide.htm#What%20are%20the%20signs%20that%20a%20person%20may%20be%20using%20methamphetamine |title=What are the signs that a person may be using methamphetamine?|year=2009|work=The Methamphetamine Problem: Question-and-Answer Guide|publisher=Institute for Intergovernmental Research|accessdate=2009-08-13 |location=Tallahassee}}</ref><ref name="kci"></ref><ref name="Drugs.com"></ref><ref name="cesar.umd.edu"></ref>
<ref>{{cite journal | vauthors = Kevil CG, Goeders NE, Woolard MD, Bhuiyan MS, Dominic P, Kolluru GK, Arnold CL, Traylor JG, Orr AW | title = Methamphetamine Use and Cardiovascular Disease | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 39 | issue = 9 | pages = 1739–1746 | date = September 2019 | pmid = 31433698 | pmc = 6709697 | doi = 10.1161/ATVBAHA.119.312461 }}</ref>


===Psychological effects=== ====Other physical effects====
The effects can also include ], hyperactivity, ], ], ], ], dry mouth and ] (potentially leading to condition informally known as '']''), headache, ], ], diarrhea, constipation, ], ], ], ], ]s, dry skin, ], and ].<ref name="Desoxyn FDA label" /><ref name="Westfall" /> Long-term meth users may have ] 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 = ], 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 ] 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> Additionally, "ostmortem examinations of human tissues have linked use of the drug to diseases associated with aging, such as coronary atherosclerosis and pulmonary fibrosis",<ref name="ScienceDaily">{{cite web |url=https://www.sciencedaily.com/releases/2015/02/150211153838.htm |title=Accelerated cellular aging caused by methamphetamine use limited in lab |author=<!-- Not stated --> |date=11 February 2015 |website=ScienceDaily |access-date=29 July 2024 |archive-date=22 September 2024 |archive-url=https://web.archive.org/web/20240922021108/https://www.sciencedaily.com/releases/2015/02/150211153838.htm |url-status=live }}</ref> which may be caused "by a considerable rise in the formation of ], pro-inflammatory molecules that can foster cell aging and death."<ref name="ScienceDaily"/>
Psychological effects can include ], ], increased ], ], ], ], ], ], ], ], ], ], ], ], excessive feelings of ] and ], repetitive and ] behaviors, ], and with chronic and/or high doses, ] can occur.<ref name="Erowid"/><ref></ref>


==== Dental and oral health ("meth mouth") ====
===Withdrawal effects===
{{Main|Meth mouth}}
Withdrawal symptoms of methamphetamine primarily consist of mental ], mental ] and an increased ]. Symptoms may last for days with occasional use and weeks or months with chronic use, with severity dependent on the length of time and the amount of methamphetamine used. Withdrawal symptoms may also include ], ], ], excessive ], ], deep ] and ].<ref>{{Cite journal|author=McGregor C, Srisurapanont M, Jittiwutikarn J, Laobhripatr S, Wongtan T, White JM |title=The nature, time course and severity of methamphetamine withdrawal |journal=Addiction |volume=100 |issue=9 |pages=1320–9 |year=2005 |month=September |pmid=16128721 |doi=10.1111/j.1360-0443.2005.01160.x}}</ref>
]]]


Methamphetamine users, particularly heavy users, may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as ].<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 ], meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in ] (dry mouth), extended periods of poor ], frequent consumption of high-calorie, carbonated beverages and ] (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 = 1 June 2008 }}</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>
===Long-term effects===
Methamphetamine use has a high association with depression and suicide as well as serious heart disease, ], anxiety and violent behaviours. Methamphetamine also has a very high addiction risk.<ref name="Darke-2008">{{Cite journal | last1 = Darke | first1 = S. | last2 = Kaye | first2 = S. | last3 = McKetin | first3 = R. | last4 = Duflou | first4 = J. | title = Major physical and psychological harms of methamphetamine use. | journal = Drug Alcohol Rev | volume = 27 | issue = 3 | pages = 253-62 | month = May | year = 2008 | doi = 10.1080/09595230801923702 | PMID = 18368606 }}</ref> Methamphetamine also is ] and is associated with an increased risk of ].<ref name="Thrash-">{{Cite journal | last1 = Thrash | first1 = B. | last2 = Thiruchelvan | first2 = K. | last3 = Ahuja | first3 = M. | last4 = Suppiramaniam | first4 = V. | last5 = Dhanasekaran | first5 = M. | title = Methamphetamine-induced neurotoxicity: the road to Parkinson's disease. | url = http://www.if-pan.krakow.pl/pjp/pdf/2009/6_966.pdf | format = PDF | journal = Pharmacol Rep | volume = 61 | issue = 6 | pages = 966-77 | month = | year = | doi = | PMID = 20081231 }}</ref><ref name="Cruickshank-2009"/> Methamphetamine abuse can cause neurotoxicity which is believed to be responsible for causing persisting cognitive deficits, such as memory, impaired attention and executive function. Over 20 percent of people addicted to methamphetamine develop a long-lasting ] resembling ] after stopping methamphetamine which persists for longer than 6 months and is often treatment resistant.<ref name="Barr-2006">{{Cite journal | last1 = Barr | first1 = AM. | last2 = Panenka | first2 = WJ. | last3 = MacEwan | first3 = GW. | last4 = Thornton | first4 = AE. | last5 = Lang | first5 = DJ. | last6 = Honer | first6 = WG. | last7 = Lecomte | first7 = T. | title = The need for speed: an update on methamphetamine addiction. | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1557685/?tool=pubmed | journal = J Psychiatry Neurosci | volume = 31 | issue = 5 | pages = 301-13 | month = Sep | year = 2006 | PMID = 16951733 }}</ref>


==== Sexually transmitted infection ====
==Pharmacokinetics==
Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both ] 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 ] in men.<ref name="Desoxyn FDA label" /><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 ], increasing the risk of sexually transmitted infection.<ref name="Desoxyn FDA label" /><ref name="Patrick Moore" />
]


Besides the sexual transmission of HIV, it may also be transmitted between users who ].<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>
Following oral administration methamphetamine is readily absorbed with peak methamphetamine concentrations occurring in 3.13 to 6.3 hours post ingestion. The amphetamine metabolite peaks at 10 to 24 hours.<ref name="Schep"/> Methamphetamine is also well absorbed following inhalation and following intranasal administration.<ref name="Schep"/> It is ] to most parts of the body. Because methamphetamine has a high ] it is distributed across the ] and crosses the placenta.<ref name="Schep"/>


=== Psychological ===
Methamphetamine is metabolized in the liver with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine; other minor metabolites include ], ], and 4-hydroxynorephedrine.<ref name="Schep"/><ref name=pmid12507968>{{Cite journal|author=Schepers RJ, Oyler JM, Joseph RE, Cone EJ, Moolchan ET, Huestis MA |title=Methamphetamine and amphetamine pharmacokinetics in oral fluid and plasma after controlled oral methamphetamine administration to human volunteers |journal=Clinical Chemistry |volume=49 |issue=1 |pages=121–32 |year=2003 |month=January |pmid=12507968 |doi=10.1373/49.1.121}}</ref><ref name="meth_metabolites_quant">{{Cite journal|author=Hendrickson H, Laurenzana E, Owens SM |title=Quantitative determination of total methamphetamine and active metabolites in rat tissue by liquid chromatography with tandem mass spectrometric detection |journal=The AAPS Journal |volume=8 |issue=4 |pages=E709–17 |year=2006 |pmid=17233534 |pmc=2751367 |doi=10.1208/aapsj080480}}</ref> Other drugs metabolized to amphetamine and methamphetamine include ], ], and ].<ref>{{cite journal |author=Marsel J, Döring G, Remberg G, Spiteller G |title=Methamphetamine--a metabolite of the anorectics Benzphetamine and Furfenorex |journal=Zeitschrift für Rechtsmedizin. Journal of legal medicine |volume=70 |issue=4 |pages=245–50 |year=1972 |month= |pmid=5084766 |doi=}}</ref><ref>{{cite journal |author=Greenhill B, Valtier S, Cody JT |title=Metabolic profile of amphetamine and methamphetamine following administration of the drug famprofazone |journal=Journal of analytical toxicology |volume=27 |issue=7 |pages=479–84 |year=2003 |month= |pmid=14607003 |doi=}}</ref> Selegiline (marketed as Deprenyl, EMSAM, and others) is metabolized into the less active L-isomer of amphetamine and the inactive L-isomer of methamphetamine.<ref name="Schep"/> Although only the D-Isomer of selegiline will metabolize into active metabolites, both isomers may cause a positive result for methamphetamine and amphetamine on a drug test, in certain cases.<ref></ref>
The psychological effects of methamphetamine can include ], ], changes in ], ], apprehension and ], decreased sense of fatigue, ] or ], ], sociability, irritability, restlessness, ] and ] behaviors.<ref name="Desoxyn FDA label">{{cite web | title=Desoxyn- methamphetamine hydrochloride tablet | website=DailyMed | date=8 September 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=81bfc45f-c345-47d0-9fc9-77abe553b541 | access-date=20 June 2024 | archive-date=22 September 2024 | archive-url=https://web.archive.org/web/20240922021215/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=81bfc45f-c345-47d0-9fc9-77abe553b541 | 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 | chapter = Miscellaneous Sympathomimetic Agonists | chapter-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 "]", 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 ], ], ], ], 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>


=== Neurotoxicity ===
It is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH. Between 30-54% of an oral dose is excreted in urine as unchanged methamphetamine and 10-23% as unchanged amphetamine. Following an intravenous dose, 45% is excreted as unchanged parent drug and 7% amphetamine.<ref> {{Dead link|date=July 2010}}</ref> The ] of methamphetamine is variable with a mean value of between 9 and 12 hours.<ref name="Schep">{{cite journal |author=Schep LJ, Slaughter RJ, Beasley DM |title=The clinical toxicology of metamfetamine |journal=Clinical Toxicology (Philadelphia, Pa.) |volume=48 |issue=7 |pages=675–94 |year=2010 |month=August |pmid=20849327 |doi=10.3109/15563650.2010.516752|issn=1556-3650}}</ref>
] that mediate methamphetamine-induced neurodegeneration in the human brain.<ref name="Glial tox review – Ntox diagram" /> The ]-mediated neuroimmune response to methamphetamine use which results in the increased permeability of the ] arises through its binding at and activation of ]s, the increased production of ] (ROS), ] (RNS), and ] (DAMPs), the dysregulation of ]s (specifically, ] and ]) and ], and excessive ] influx in ]s and dopamine ]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 |publisher = Academic Press |isbn = 978-0-12-420118-7 }}</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 | volume = 118 | pages = 165–197 | year = 2014 | pmid = 25175865 | pmc = 4418472 | doi = 10.1016/B978-0-12-801284-0.00007-5 | isbn = 978-0-12-801284-0 | series = International Review of Neurobiology | publisher = Academic Press | 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) }}<br />{{cite journal | title = Figure 7.1: Neuroimmune mechanisms of methamphetamine-induced CNS toxicity | date = 2014 | pmc = 4418472 | journal = International Review of Neurobiology | volume = 118 | pages = 165–197 | doi = 10.1016/B978-0-12-801284-0.00007-5 | pmid = 25175865 | vauthors = Loftis JM, Janowsky A }}"</ref><ref name="Sigma" />]]


Methamphetamine is directly ] to dopaminergic neurons in both lab animals and humans.<ref name="pmid25861156" /><ref name="pmid19328213" /> ], ], metabolic compromise, UPS dysfunction, protein nitration, ], ] and other processes contributed to this neurotoxicity.<ref name="pmid25861156" /><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 |bibcode = 2012ArTox..86.1167C |s2cid = 2873101 }}</ref><ref name="pmid19426289" /> In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of ].<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 ] 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 }}</ref> Withdrawal of methamphetamine in dependent persons may lead to ] which persists months beyond the typical withdrawal period.<ref name="pmid19426289" />
===Detection in biological fluids===
Methamphetamine and amphetamine are often measured in urine, sweat or saliva as part of a drug-abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Chiral techniques may be employed to help distinguish the source of the drug, whether obtained legally (via prescription) or illicitly, or possibly as a result of formation from a prodrug such as famprofazone or selegiline. Chiral separation is needed to assess the possible contribution of l-methamphetamine (Vicks Inhaler) toward a positive test result.<ref>de la Torre R, Farré M, Navarro M, Pacifici R, Zuccaro P, Pichini S. Clinical pharmacokinetics of amfetamine and related substances: monitoring in conventional and non-conventional matrices. Clin. Pharmacokinet. 43: 157-185, 2004.</ref><ref>Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA. 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). J. Anal. Toxicol. 28: 449-455, 2004.</ref><ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 947-952.</ref>


] studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse ] changes in brain structure and function.<ref name="pmid19328213" /> In particular, methamphetamine appears to cause ] and ] of ], marked shrinkage of ], and reduced ] in the ], ], and ] in recreational methamphetamine users.<ref name="pmid19328213" /> Moreover, evidence suggests that adverse changes in the level of ]s of metabolic integrity and synthesis occur in recreational users, such as a reduction in ] and ] levels and elevated levels of ] and ].<ref name="pmid19328213" />
==Tolerance==
As with other amphetamines, tolerance to methamphetamine is not completely understood but known to be sufficiently complex that it cannot be explained by any single mechanism. The extent of tolerance and the rate at which it develops vary widely between individuals, and, even within one person, it is highly dependent on dosage, duration of use, and frequency of administration. Tolerance to the awakening effect of amphetamines does not readily develop, making them suitable for the treatment of ].<ref name="GhodseBehavior">{{Cite book| last = Ghodse | first = Hamid | title = Drugs and Addictive Behaviour: A Guide to Treatment | publisher = Cambridge University Press | pages = 114 | url = http://books.google.com/?id=3WF79shLxB4C&lpg=PA114&pg=PA114#v=onepage | isbn = 978-0521000017 | date = 2002-08-15 }}</ref>


Methamphetamine has been shown to activate ] in human ] and generate ] 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 ] (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>
Short-term tolerance can be caused by depleted levels of ] within the ]s available for release into the ] following subsequent reuse (]). Short-term tolerance typically lasts until neurotransmitter levels are fully replenished; because of the toxic effects on dopaminergic neurons, this can be greater than 2–3 days. Prolonged overstimulation of ] caused by methamphetamine may eventually cause the receptors to ] in order to compensate for increased levels of ] within the synaptic cleft.<ref>{{Cite journal|author=Bennett BA, Hollingsworth CK, Martin RS, Harp JJ |title=Methamphetamine-induced alterations in dopamine transporter function |journal=Brain Research |volume=782 |issue=1-2 |pages=219–27 |year=1998 |month=January |pmid=9519266 |doi=10.1016/S0006-8993(97)01281-X}}</ref> To compensate, larger quantities of the drug are needed in order to achieve the same level of effects.


Methamphetamine binds to and activates both ] subtypes, ] and ], with micromolar affinity.<ref name="Sigma" /><ref name="SigmaB" /> Sigma receptor activation may promote methamphetamine-induced neurotoxicity by facilitating ], increasing dopamine synthesis and release, influencing microglial activation, and modulating ] signaling cascades and the formation of reactive oxygen species.<ref name="Sigma" /><ref name="SigmaB" />
] or sensitization can also occur.<ref name="GhodseBehavior"/> The effect is well established, but the mechanism is not well understood.


==Addiction== === Addiction ===
{{Addiction glossary|collapse=yes|width=610px}}
Methamphetamine is ].<ref>. Centre for Addiction and Mental Health.</ref> While the withdrawal itself may not be dangerous, ] symptoms are common with heavy use and ] is common.
{{Psychostimulant addiction|align=right}}


Current models of addiction from chronic drug use involve alterations in ] in certain parts of the brain, particularly the ].<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 ]s{{#tag:ref|Transcription factors are proteins that increase or decrease the ] 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 ], ] response element binding protein (]), and nuclear factor kappa B (]).<ref name="Nestler" /> ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in ] ]s in the nucleus accumbens is ]{{#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 ], ]s, ], ], ], ]s, ], ], and ], 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>
Methamphetamine-induced hyperstimulation of pleasure pathways leads to ]. It is possible that daily administration of the amino acids L-] and ]/] can aid in the recovery process by making it easier for the body to reverse the depletion of ], ], and ]. Although studies involving the use of these amino acids have shown some success, this method of recovery has not been shown to be consistently effective.


], a transcription factor, and ], a ] 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="pmid23643695">{{cite journal |vauthors = Nestler EJ |title = Epigenetic mechanisms of drug addiction |journal = Neuropharmacology |volume = 76 | issue = Pt B |pages = 259–268 |date = January 2014 |pmid = 23643695 |pmc = 3766384 |doi = 10.1016/j.neuropharm.2013.04.004 |quote = <!-- Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors.&nbsp;... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).<br />G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB, in turn, suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a).&nbsp;... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with 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 ]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 ]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 ] 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<sup>14,22–24</sup>. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high-fat food, sex, wheel running, where it promotes that consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. }}</ref><ref name="Natural and drug addictions" /> ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced ]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 ] which occurs in some patients taking ], 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>
It is shown that taking ] prior to using methamphetamine may help reduce acute toxicity to the brain, as rats given the human equivalent of 5–10&nbsp;grams of ascorbic acid 30 minutes prior to methamphetamine dosage had toxicity mediated,<ref>{{Cite journal|author=Wagner GC, Carelli RM, Jarvis MF |title=Pretreatment with ascorbic acid attenuates the neurotoxic effects of methamphetamine in rats |journal=Research Communications in Chemical Pathology and Pharmacology |volume=47 |issue=2 |pages=221–8 |year=1985 |month=February |pmid=3992009}}</ref><ref>{{Cite journal|author=Wagner GC, Carelli RM, Jarvis MF |title=Ascorbic acid reduces the dopamine depletion induced by methamphetamine and the 1-methyl-4-phenyl pyridinium ion |journal=Neuropharmacology |volume=25 |issue=5 |pages=559–61 |year=1986 |month=May |pmid=3488515 |doi=10.1016/0028-3908(86)90184-X}}</ref> yet this will likely be of little avail in solving the other serious behavioral problems associated with methamphetamine use and addiction that many users experience. Large doses of ascorbic acid also lower urinary ], reducing methamphetamine's elimination ] and thus decreasing the duration of its actions.<ref>{{Cite journal|author=Oyler JM, Cone EJ, Joseph RE, Moolchan ET, Huestis MA |title=Duration of detectable methamphetamine and amphetamine excretion in urine after controlled oral administration of methamphetamine to humans |journal=Clinical Chemistry |volume=48 |issue=10 |pages=1703–14 |year=2002 |month=October |pmid=12324487 |url=http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=12324487}}</ref>


====Epigenetic factors====
To combat addiction, doctors are beginning to use other forms of ] such as ], the dextrorotatory (right-handed) isomer of the ] molecule, to break the addiction cycle in a method similar to the use of ] in the treatment of ] addicts. There are no publicly available drugs comparable to ], which blocks opiate receptors and is therefore used in treating ] dependence, for use with methamphetamine problems.<ref>The Ice Age (See Below)</ref> However, experiments with some monoamine reuptake inhibitors such as ] have been successful in blocking the action of methamphetamine.<ref>{{Cite journal|author=Rothman RB, Partilla JS, Baumann MH, Dersch CM, Carroll FI, Rice KC |title=Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: a pharmacological strategy for treating stimulant abuse |journal=Synapse |volume=35 |issue=3 |pages=222–7 |year=2000 |month=March |pmid=10657029 |doi=10.1002/(SICI)1098-2396(20000301)35:3<222::AID-SYN7>3.0.CO;2-K}}</ref> There are studies indicating that ], bupropion and imipramine may reduce craving and improve adherence to treatment.<ref name="pmid17990840">{{Cite journal|author=Winslow BT, Voorhees KI, Pehl KA |title=Methamphetamine abuse |journal=American family physician |volume=76 |issue=8 |pages=1169–74 |year=2007 |pmid=17990840 |doi=}}</ref> Research has also suggested that ] can help addicts quit methamphetamine use.<ref>{{Cite journal|author=Grabowski J, Shearer J, Merrill J, Negus SS |title=Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence |journal=Addictive Behaviors |volume=29 |issue=7 |pages=1439–64 |year=2004 |month=September |pmid=15345275 |doi=10.1016/j.addbeh.2004.06.018}}</ref><ref>{{Cite web| title = Sleep medicine 'can help ice addicts quit' | url = http://www.abc.net.au/news/stories/2007/12/01/2107027.htm | accessdate = 2007-12-02}}</ref>
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 ] may occur in particular regions of the brain, and may contribute importantly to the addiction phenotype. In 2014, a crucial role was found for ] mechanisms in driving lasting changes in gene expression in the brain.<ref name="pmid23643695" />
Methamphetamine addiction is one of the most difficult forms of addictions to treat. ], ], and ] have been employed to treat post-withdrawal cravings, although the success rate is low. ] is somewhat more successful, but this is a Class IV scheduled drug. ] has been used with success in Europe, where it is a Class I drug and available only for scientific research. ] has been reported useful in some small-population studies.<ref>AJ Giannini. ''Drugs of Abuse—Second Edition''. Los Angeles, Practice Management Information Company, 1997.</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 ], including areas like ], ], and dorsal ], the ], and the ]. Chronic methamphetamine use caused gene-specific ] and ]. Gene-specific DNA methylations in particular regions of the brain were also observed. The various epigenetic alterations caused ] of specific genes important in addiction. For instance, chronic methamphetamine use caused ] in position 4 of histone 3 located at the ] of the '']'' and the ''] (ccr2)'' genes, activating those genes in the nucleus accumbens (NAc).<ref name=Godino /> c-fos is well known to be important in ].<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 />
As the ] ] is a constitutional isomer of methamphetamine, it has been suggested that it may be effective in treating methamphetamine addiction. Phentermine is a ] stimulant that acts on ] and ]. When comparing (+)-Amphetamine, (+/-)-ephedrine, and phentermine, one key difference among the three drugs is their selectivity for norepinephrine (NE) release vs. dopamine (DA) release. The NE/DA selectivity ratios for these drugs as determined in vitro are (+/-)-ephedrine (18.6) > phentermine (6.7) > (+)-amphetamine (3.5).<ref></ref>


In methamphetamine addicted rats, epigenetic regulation through reduced ] of histones, in brain striatal neurons, caused reduced transcription of ].<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 addictive 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>
Abrupt interruption of chronic methamphetamine use results in the withdrawal syndrome in almost 90% of the cases.


Administration of methamphetamine to rodents causes ] in their brain, particularly in the ] 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 ] or the acetylation or ] 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 ] in the ] that contribute to the persistent epigenetic changes found in methamphetamine addiction.
The mental depression associated with methamphetamine withdrawal lasts longer and is more severe than that of ] withdrawal.<ref name="pmid17990840" />


==== Treatment and management ====
==Medical use==
{{Further|Addiction#Research}}
])]]
A 2018 systematic review and ] of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that ] with both ] and ] 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 ] with contingency management or community reinforcement approach, ], ]s, non-contingent reward-based therapies, ], and other combination therapies involving these.<ref name="Psychosocial interventions network meta-analysis" />
Methamphetamine has been approved by the FDA for use in children and adults under the trademark name '''Desoxyn'''. It is prescribed as a treatment for ] and ], as well as ] for the treatment of ] and ].<ref name="Mitler MM, Hajdukovic R, Erman MK 1993 306–17"/> Methamphetamine is known to produce ] similar to other ], but at smaller doses, with fewer ].<ref></ref> Methamphetamine's ] also allows it to enter the brain faster than other stimulants, where it is more stable against degradation by ] (MAO).


{{As of|December 2019}}, there is no effective ] 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 ]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, ], ]), antipsychotics (]), anticonvulsants (], ], ]), ], ], ], ], ], ], ], dextroamphetamine, and ].<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" />{{verify source|date=June 2023|reason=Although the abstract says "Studies of anticonvulsants, ... provided either low-strength or insufficient evidence of no effect on the outcomes of interest", this sounds like a misprint for "of any effect...".<!-- I can't read the main text to check -->}}
===Other uses===
A 2006 study by a group of ] scientists showed that methamphetamine appears to lessen damage to the brains of rats and gerbils that have suffered ]s. Their preliminary research has found that small amounts of methamphetamine created a protective effect, while higher doses increased damage. The findings have shown that methamphetamine could be used medically to lessen stroke damage.<ref>{{Cite news|url=http://www.boston.com/news/education/higher/articles/2006/10/12/um_study_meth_may_lessen_stroke_damage/ |title=UM study: Meth may lessen stroke damage |publisher=AP |date=2006-10-12 |archiveurl=http://www.webcitation.org/5drWLLkEb |archivedate=2009-01-15 |accessdate=2008-06-29 }}
</ref>


==== Dependence and withdrawal ====
==Health issues==
] 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 = 2013 |issue = 9 |pages = CD009695 |year = 2013 |pmid = 23996457 |doi = 10.1002/14651858.CD009695.pub2 | veditors = Pérez-Mañá C |doi-access = free |pmc = 11521360 }}</ref> In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.<ref name="Cochrane Withdrawal" /> ] from methamphetamine withdrawal lasts longer and is more severe than that of ] 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>
===Meth mouth===
{{Main|Meth mouth}}
Methamphetamine users and addicts may lose their teeth abnormally quickly, a condition informally known as ]. According to the ], meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in ] (dry mouth), extended periods of poor ], frequent consumption of high-calorie, carbonated beverages and ] (teeth grinding and clenching). Some reports have also speculated that the acidic nature of the drug is a contributing factor."<ref name="ADA">{{Cite web|url=http://web.archive.org/web/20080601035323/http://www.ada.org/prof/resources/topics/methmouth.asp |title=Methamphetamine Use (Meth Mouth) |accessdate=2006-12-16 |publisher=American Dental Association }}</ref> Similar, though far less severe, symptoms have been reported in clinical use of regular amphetamine, where effects are not exacerbated by extended periods of poor oral hygiene.<ref>{{Cite journal|author=Hasan AA, Ciancio S |title=Relationship between amphetamine ingestion and gingival enlargement |journal=Pediatric Dentistry |volume=26 |issue=5 |pages=396–400 |year=2004 |pmid=15460293 |url=http://openurl.ingenta.com/content/nlm?genre=article&issn=0164-1263&volume=26&issue=5&spage=396&aulast=Hasan}}</ref><ref>{{Cite journal|author=Shaner JW |title=Caries associated with methamphetamine abuse |journal=The Journal of the Michigan Dental Association |volume=84 |issue=9 |pages=42–7 |year=2002 |month=September |pmid=12271905}}</ref>


According to the current Cochrane review on ] and ] in recreational users of methamphetamine, "when chronic heavy users abruptly discontinue 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, ], ], ], ], ] or ], ], ] or ], and ].<ref name="Cochrane Withdrawal" />
===Hygiene===
Serious health and appearance problems can be caused by unsterilized needles, lack or ignoring of hygiene needs (more typical on chronic use), and obsessive skin-picking, which may lead to ]es.<ref name="pmid17990840"/>


Methamphetamine that is present in a mother's ] can pass through the ] to a ] and be secreted into ].<ref name="pmid17990840" /> Infants born to methamphetamine-abusing mothers may experience a ] syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and ].<ref name="pmid17990840" /> This withdrawal syndrome is relatively mild and only requires medical intervention in approximately&nbsp;4% of cases.<ref name="pmid17990840" />
===Increased risk of sexually transmitted disease===
{{clear right}}
{{See also|Sex and drugs|Party and play}}
{{Addiction-related plasticity|Table title=Summary of addiction-related plasticity}}
Men who use methamphetamine, ], ], and ] are twice as likely to have unprotected sex, according to British research.<ref></ref> American ] ] performed an analysis using data collected from community-based participants among gay and bisexual men to examine the associations between methamphetamine use and sexual risk taking behaviors. Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both HIV-positive and unknown casual partners. The association between methamphetamine use and unprotected acts were also more pronounced in HIV-positive participants. These findings suggested that methamphetamine use and engagement in unprotected anal intercourse are co-occurring risk behaviors that potentially heighten the risk of HIV transmission among gay and bisexual men.<ref>{{Cite journal
|author= 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=15590381
|doi=10.1007/s10461-008-9432-y
}}</ref>
Methamphetamine allows users to engage in prolonged sexual activity, which may cause genital sores and abrasions. Methamphetamine can also cause sores and abrasions in the mouth via ] (teeth clenching and grinding), which can turn typically low-risk sex acts, such as oral sex, into high-risk sexual activity.<ref></ref> As with the injection of any drug, if a group of users ] without sterilization procedures, blood-borne diseases, such as ] or ], can be transmitted. The level of needle sharing among methamphetamine users is similar to that among other drug injection users.<ref></ref>


===Neonatal===
===Use in pregnancy and breastfeeding===
Unlike other drugs, babies with ] 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">{{cite web | url = https://www.abc.net.au/news/2020-01-03/the-hidden-problem-of-babies-born-to-meth-affected-mothers/11829668 | title = Babies born to meth-affected mothers seem well behaved, but their passive nature masks a serious problem | archive-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 | archive-date = 24 October 2021 | vauthors = Kennedy E | work = ] | date = 3 January 2020 }}</ref>
Methamphetamine passes through the ] and is secreted into breast milk. Infants born to methamphetamine-abusing mothers were found to have a significantly smaller ] age-adjusted head circumference and birth weight measurements. Methamphetamine exposure was also associated with ] symptoms of agitation, vomiting and ].<ref></ref> This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.<ref name="pmid17990840"/>


A ] 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 ] and ] (ADHD).<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 | 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>
===Public health issues===
Short-term exposure to high concentrations of chemical vapors that may exist in methamphetamine laboratories can cause severe health problems or even result in death. Exposure to these substances can occur from volatile air emissions, spills, fires, and explosions.<ref></ref> Methamphetamine labs are often discovered when fire fighters respond to a blaze. Methamphetamine cooks, their families, and first responders are at highest risk of acute health effects from chemical exposure, including lung damage and chemical burns to the body. Following a seizure of a methamphetamine lab, there is often a low exposure risk to chemical residues, however this contamination should be sanitized. Chemical residues and lab wastes that are left behind at a former methamphetamine lab can result in health problems for people who use the property, therefore local health departments should thoroughly assess the property for hazards prior to allowing it to be reinhabited, especially by children.<ref></ref>


== Overdose ==
==Routes of administration==
Methamphetamine overdose is a diverse term. It frequently refers to the exaggeration of the unusual effects with features such as irritability, agitation, hallucinations and paranoia.<ref name="Schep" /><ref name="Desoxyn FDA label" /> The cardiovascular effects are typically not noticed in young healthy people. Hypertension and tachycardia are not apparent unless measured. A moderate overdose of methamphetamine may induce symptoms such as: ], confusion, ], high or low blood pressure, ], ], ], severe ], ], ], ], and ].<ref name="Schep" /><ref name="Westfall" /> An extremely large overdose may produce symptoms such as ], ], ], ], ], ], ] (i.e., dangerously high body temperature), ], ], ], ], and a form of ] ("tweaking").{{#tag:ref|<ref name="Schep" /><ref name="Desoxyn FDA label" /><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 ] owing to ] and ] neurotoxicity.<ref name="Malenka">{{cite book |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |vauthors=Malenka RC, Nestler EJ, Hyman SE, Holtzman DM |publisher=McGraw-Hill Medical |year=2015 |isbn=9780071827706 |edition=3rd |location=New York |chapter=Chapter 16: Reinforcement and Addictive Disorders |quote=Unlike cocaine and amphetamine, methamphetamine is directly toxic at higher doses to midbrain dopamine neurons}}</ref><ref name="pmid19328213" /> Death from methamphetamine poisoning is typically preceded by convulsions and ].<ref name="Desoxyn FDA label" />
Studies have shown that the subjective pleasure of drug use (the reinforcing component of addiction) is proportional to the rate at which the blood level of the drug increases.<ref></ref> Intravenous injection is the fastest route of drug administration, causing blood concentrations to rise the most quickly, followed by smoking, ] (anal or vaginal insertion), ] (snorting), and ] (swallowing). Ingestion does not produce a ], an ] ] state of ], as forerunner to the high experienced with the use of methamphetamine, which is most pronounced with intravenous use. While the onset of the rush induced by injection can occur in as little as a few seconds, the oral route of administration requires approximately half an hour before the high sets in. Thus, with both higher the dosage of methamphetamine used and faster the route of administration applied, the higher potential risk for psychological addiction.


===Injection=== === Psychosis ===
{{hatnote|Main section: {{section link|Stimulant psychosis|Substituted amphetamines}}}}
], also known as "slamming", "banging", "shooting up" or "mainlining", is a popular method used by addicts which carries relatively greater risks than other methods of administration. The hydrochloride salt of methamphetamine is soluble in water. Intravenous users may use any dose range, from less than 100 ]s to over one ], using a ], although it should be noted that typically street methamphetamine is "cut" with a water-soluble cutting material, which constitutes a significant portion of a given street methamphetamine dose. Intravenous users risk developing ] (PE), a blockage of the main artery of the lung or one of its branches, and commonly develop skin rashes (also known as "speed bumps") or infections at the site of injection. As with the injection of any drug, if a group of users ] without sterilization procedures, blood-borne diseases, such as ] or ], can be transmitted.


Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g., ], ]s, ], and ]s).<ref name="Schep" /><ref name="Cochrane" /> A ] 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 = |edition = 2nd |url = https://archive.org/details/handbookondrugal0002hofm/page/329 }}</ref> The same review asserts that, based upon at least one trial, ] medications effectively resolve the symptoms of acute amphetamine psychosis.<ref name="Cochrane" /> ] 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>
===Smoking===
Smoking amphetamines refers to vaporizing it to inhale the resulting fumes, not burning it to inhale the resulting smoke. It is commonly smoked in glass pipes made from ] ] and light bulbs. It can also be smoked off aluminium foil, which is heated underneath by a flame. This method is also known as "chasing the ''white'' dragon" (whereas smoking ] is known as "]"). There is little evidence that methamphetamine inhalation results in greater toxicity than any other route of administration.<ref></ref> Lung damage has been reported with long-term use, but manifests in forms independent of route (] (PH)), or limited to injection users (] (PE)).


===Insufflation=== === Death from overdose ===
The CDC reported that the number of deaths in the United States involving psychostimulants with abuse potential to be 23,837 in 2020 and 32,537 in 2021.<ref>{{cite journal | vauthors = Spencer MR, Miniño AM, Warner M | title = Drug Overdose Deaths in the United States, 2001–2021 | journal = NCHS Data Brief | issue = 457 | pages = 1–8 | date = December 2022 | pmid = 36598401 | doi = 10.15620/cdc:122556 | publisher = National Center for Health Statistics (U.S.) | s2cid = 254388862 | doi-access = free }}</ref> This category code (ICD–10 of T43.6) includes primarily methamphetamine but also other stimulants such as amphetamine, and methylphenidate. The mechanism of death in these cases is not reported in these statistics and is difficult to know.<ref>{{cite journal | vauthors = Parish DC, Goyal H, Dane FC | title = Mechanism of death: there's more to it than sudden cardiac arrest | journal = Journal of Thoracic Disease | volume = 10 | issue = 5 | pages = 3081–3087 | date = May 2018 | pmid = 29997977 | pmc = 6006107 | doi = 10.21037/jtd.2018.04.113 | doi-access = free }}</ref> Unlike fentanyl which causes respiratory depression, methamphetamine is not a respiratory depressant. Some deaths are as a result of intracranial hemorrhage<ref>{{cite journal | vauthors = Noblett D, Hacein-Bey L, Waldau B, Ziegler J, Dahlin B, Chang J | title = Increased rupture risk in small intracranial aneurysms associated with methamphetamine use | journal = Interventional Neuroradiology | volume = 27 | issue = 1 | pages = 75–80 | date = February 2021 | pmid = 32967503 | pmc = 7903554 | doi = 10.1177/1591019920959534 }}</ref> and some deaths are cardiovascular in nature including flash pulmonary edema<ref>{{cite journal | vauthors = Paone S, Clarkson L, Sin B, Punnapuzha S | title = Recognition of Sympathetic Crashing Acute Pulmonary Edema (SCAPE) and use of high-dose nitroglycerin infusion | journal = The American Journal of Emergency Medicine | volume = 36 | issue = 8 | pages = 1526.e5–1526.e7 | date = August 2018 | pmid = 29776826 | doi = 10.1016/j.ajem.2018.05.013 | s2cid = 21698404 }}</ref> and ventricular fibrillation.<ref>{{Cite journal |vauthors=Gholami F, Hosseini SH, Ahmadi A, Nabati M |date=15 October 2019 |title=A Case report of hemodynamic instability, cardiac arrest, and acute severe dyspnea subsequent to inhalation of crystal methamphetamine |url=https://publish.kne-publishing.com/index.php/PBR/article/view/1585 |journal=Pharmaceutical and Biomedical Research |doi=10.18502/pbr.v5i2.1585 |issn=2423-4494 |doi-access=free |access-date=26 December 2023 |archive-date=26 December 2023 |archive-url=https://web.archive.org/web/20231226003031/https://publish.kne-publishing.com/index.php/PBR/article/view/1585 |url-status=live }}</ref><ref>{{cite journal | vauthors = De Letter EA, Piette MH, Lambert WE, Cordonnier JA | title = Amphetamines as potential inducers of fatalities: a review in the district of Ghent from 1976-2004 | journal = Medicine, Science, and the Law | volume = 46 | issue = 1 | pages = 37–65 | date = January 2006 | pmid = 16454462 | doi = 10.1258/rsmmsl.46.1.37 }}</ref>
Another popular route to intake methamphetamine is insufflation (snorting), where a user crushes the methamphetamine into a fine powder and then sharply inhales it (sometimes with a straw or a rolled up ], as with ]) into the nose where methamphetamine is absorbed through the soft tissue in the ] of the ] and straight into the bloodstream. This method of administration redirects ], with a quicker onset and higher ] than oral administration, though the duration of action is shortened. This method is sometimes preferred by users who do not want to prepare and administer methamphetamine for injection or smoking, but still experience a fast onset with a rush.


===Suppository=== === Emergency treatment ===
Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of ] and ].<ref name="Schep" /> There is not enough evidence on ] or ] in cases of methamphetamine intoxication to determine their usefulness.<ref name="Desoxyn FDA label" /> ] (e.g., with ]) 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 ] (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous ] or ].<ref name="Schep" /> Blood pressure often drops gradually following sufficient sedation with a ] and providing a calming environment.<ref name="Schep" />
Little research has been focused on the ] (anal or vaginal insertion) method of administration. This method of administration is commonly administered using an ]. Methamphetamine can be dissolved in water and withdrawn into an oral syringe which may then be lubricated and inserted into the anus or vagina before the plunger is pushed. Anecdotal evidence of its effects are infrequently discussed, possibly due to social taboos in many cultures. The rectum and the vaginal canal is where the majority of the drug would likely be taken up, through the membranes lining its walls. This method is often known within methamphetamine communities as a "butt rocket", a "booty bump", "potato thumping", "turkey basting", "plugging", "keistering", "shafting", "bumming" and "shelving" (vaginal). It is anecdotally reported to increase sexual pleasure, while the effects of the drug last longer.<ref>{{Dead link|date=July 2009}}</ref> As methamphetamine is ] in the brain, these effects are likely experienced through the higher bioavailability of the drug in the bloodstream (second to injection) and the faster onset of action (than insufflation).


Antipsychotics such as ] are useful in treating agitation and psychosis from methamphetamine overdose.<ref name="Richards_2015" /><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> ]s with lipophilic properties and CNS penetration such as ] and ] may be useful for treating CNS and cardiovascular toxicity.<ref name="Medscape meth toxicity">{{cite web | title = Methamphetamine Toxicity: Treatment & Management | url = http://emedicine.medscape.com/article/820918-treatment#showall |vauthors = Richards JR, Derlet RW, Albertson TE | work = 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 ] and ] labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.<ref name="Richards_2015">{{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" />
==Illicit production==
] methamphetamine]]
===Synthesis===
Synthesis is relatively simple, but entails risk with flammable and corrosive chemicals, particularly the solvents used in extraction and purification; therefore, illicit production is often discovered by fires and explosions caused by the improper handling of volatile or flammable solvents. Most of the necessary chemicals are readily available in household products or ] cold or allergy medicines. When illicitly produced, methamphetamine is commonly made by the ] of ] or ]. The maximum conversion rate for ephedrine and pseudoephedrine is 92%, although typically, illicit methamphetamine laboratories convert at a rate of 50% to 75%.<ref></ref>


== Interactions ==
Most methods of illicit production involve ] of the ] group on the ] or ] molecule. Methamphetamine is most structurally similar to ] and ]. The most common method for small-scale methamphetamine labs in the United States is primarily called the "Red, White, and Blue Process", which involves red ], ] or ] (white), and blue ] (which is technically a purple color in elemental form), from which ] is formed. In Australia, criminal groups have been known to substitute "red" phosphorus with either hypophosphorous acid or phosphorous acid.<ref>{{Dead link|date=August 2009}}</ref> This is a hazardous process for amateur chemists, because ] gas, a side-product from ] hydroiodic acid production, is extremely toxic to inhale.
Methamphetamine is metabolized by the liver enzyme ], so ] will prolong the ] of methamphetamine.<ref name="Desoxyn FDA label" /><ref name="DrugBank Enzymes">{{cite web |title = Methamphetamine: Enzymes | url = http://www.drugbank.ca/drugs/DB01577#enzymes |work = DrugBank |publisher = University of Alberta |date = 8 February 2013 |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 ] (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.<ref name="Desoxyn FDA label" /> Methamphetamine may decrease the effects of ]s and ]s and increase the effects of ]s and other ]s as well.<ref name="Desoxyn FDA label" /> Methamphetamine may counteract the effects of ] and ]s owing to its effects on the cardiovascular system and cognition respectively.<ref name="Desoxyn FDA label" /> The ] of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.<ref name="Desoxyn FDA label" /> Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.<ref name="Desoxyn FDA label" /> Owing to the effect pH has on absorption, ]s, which reduce ], are known to interact with methamphetamine.<ref name="Desoxyn FDA label" />


== Pharmacology ==
Another common method uses the ] (also called the "Nagai method"),<ref></ref> in which metallic ], commonly extracted from non-rechargeable ], is substituted for difficult-to-find metallic ]. However, the Birch reduction is dangerous because the alkali metal and liquid ] are both extremely reactive, and the temperature of liquid ammonia makes it susceptible to explosive boiling when reactants are added.


=== Pharmacodynamics ===
], ]. Anhydrous ammonia is a common farm fertilizer which is also a critical ingredient in making methamphetamine. In 2005, Iowa state used grant money to give out thousands of locks to prevent criminals from getting into the tanks.<ref>{{Cite news|url=http://thegazette.com/2009/10/06/anhydrous-ammonia-tank-locks-have-flaws |title=Anhydrous ammonia tank locks have flaws|author=The Gazette Staff|publisher=Cedar Rapids Gazette|date=6 Oct 2009}}</ref>]]
{| class="wikitable floatright" style="font-size:small;"
A completely different procedure of synthesis uses the ] of ] with ],<ref></ref> both of which are currently ] ] chemicals (as are pseudoephedrine and ephedrine). The reaction requires a catalyst that acts as a reducing agent, such as ] or platinum dioxide, also known as ]. This was once the preferred method of production by ] in ],<ref>{{Cite book|url=http://books.google.com/?id=8lWBixJv0QAC |title=No Speed Limit: The Highs and Lows of Meth |first=Frank |last=Owen |publisher=Macmillan |year=2007 |isbn=9780312356163 |chapter=Chapter 1: The Rise of Nazi Dope |pages=17–18}}</ref> until DEA restrictions on the chemicals made the process difficult. Other less common methods use other means of hydrogenation, such as ] ] in the presence of a ].{{Citation needed|date=June 2009}}
|+ {{Nowrap|] of ] and related agents ({{Abbrlink|EC<sub>50</sub>|Half maximal effective concentration}}, nM)}}
|-
! Compound !! data-sort-type="number" | {{abbrlink|NE|Norepinephrine}} !! data-sort-type="number" | {{abbrlink|DA|Dopamine}} !! data-sort-type="number" | {{abbrlink|5-HT|Serotonin}} !! Ref
|-
| ] || 10.9 || 39.5 || >10,000 || <ref name="ReithBLoughHong2015">{{cite journal | vauthors = Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL | title = Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter | journal = Drug and Alcohol Dependence | volume = 147 | issue = | pages = 1–19 | date = February 2015 | pmid = 25548026 | pmc = 4297708 | doi = 10.1016/j.drugalcdep.2014.12.005 }}</ref><ref name="Forsyth2012" /><ref name="Blough2008" />
|-
| ] || 6.6–7.2 || 5.8–24.8 || 698–1,765 || <ref name="RothmanBaumannDersch2001">{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | url = }}</ref><ref name="BaumannPartillaLehner2013">{{cite journal | vauthors = Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW | title = Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products | journal = Neuropsychopharmacology | volume = 38 | issue = 4 | pages = 552–562 | year = 2013 | pmid = 23072836 | pmc = 3572453 | doi = 10.1038/npp.2012.204 }}</ref>
|-
| ] || 9.5 || 27.7 || {{abbr|ND|No data}} || <ref name="Forsyth2012">{{cite journal | vauthors = Forsyth AN | title=Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | website=ScholarWorks@UNO | date=22 May 2012 | url=https://scholarworks.uno.edu/td/1436/ | access-date=4 November 2024}}</ref><ref name="Blough2008">{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}</ref>
|-
| ] || 12.3–13.8 || 8.5–24.5 || 736–1,292 || <ref name="RothmanBaumannDersch2001" /><ref name="BaumannAyestasPartilla2012">{{cite journal | vauthors = Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV | title = The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue | journal = Neuropsychopharmacology | volume = 37 | issue = 5 | pages = 1192–1203 | year = 2012 | pmid = 22169943 | pmc = 3306880 | doi = 10.1038/npp.2011.304 }}</ref>
|-
| ] || 28.5 || 416 || 4,640 || <ref name="RothmanBaumannDersch2001" />
|-
| colspan="7" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' The smaller the value, the more strongly the drug releases the neurotransmitter. See also ] for a larger table with more compounds. '''Refs:''' <ref name="RothmanBaumann2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = Eur J Pharmacol | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 | url = }}</ref><ref name="RothmanBaumann2006">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 | url = https://zenodo.org/record/1235860 }}</ref>
|}


] 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 ] (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]]
Methamphetamine labs can give off noxious fumes, such as ] gas, ] gas, solvent vapors, ] or ], ] vapors, white ], anhydrous ], ]/], ], ]/] metal, ], or methamphetamine vapors. If performed by amateurs, manufacturing methamphetamine can be extremely dangerous. If the red ] overheats, because of a lack of ventilation, phosphine gas can be produced. This gas is highly toxic and, if present in large quantities, is likely to explode upon autoignition from ], which is formed by overheating ].{{Citation needed|date=June 2009}}


Methamphetamine has been identified as a potent ] of ] (TAAR1), a ] (GPCR) that regulates brain ] 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 web |title = Methamphetamine: Targets | url = http://www.drugbank.ca/drugs/DB01577#targets |work = DrugBank |publisher = University of Alberta |date = 8 February 2013 |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 ] (cAMP) production and either completely inhibits or reverses the transport direction of the ] (DAT), ] (NET), and ] (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 ] via ] (PKA) and ] (PKC) signaling, ultimately resulting in the ] or reverse function of ]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 ] (CAMK)-dependent signaling pathway, in turn producing dopamine efflux.<ref name="TAAR1 IUPHAR">{{cite web |title = TA<sub>1</sub> 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 . In addition, coupling to a promiscuous Gαq has been observed, resulting in increased intracellular calcium concentration . --> |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 , although the mechanisms do not appear to be identical for each drug . These processes are PKCβ– and CaMK–dependent , and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion . }}</ref> TAAR1 has been shown to reduce the ] of neurons through direct activation of ]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 ] appears to negatively modulate the membrane expression and function of ], a type of ].<ref name="Cisneros_2014 and review" />
In recent years, reports of a simplified "Shake 'n Bake" synthesis have surfaced. The method is suitable for such small batches that pseudoephedrine restrictions are less effective, it uses chemicals that are easier to obtain (though no less dangerous than traditional methods), and it is so easy to carry out that some addicts have made the drug while driving.<ref>{{Cite news|url=http://www.nydailynews.com/lifestyle/health/2009/08/25/2009-08-25_new_method_for_making_crystal_meth_gets_around_drug_laws.html |title=New 'shake-and-bake' method for making crystal meth gets around drug laws but is no less dangerous |author=Associated Press |publisher=New York Daily News |date=August 25, 2009}}</ref> Producing methamphetamine in this fashion can be extremely dangerous and has been linked to several fatalities.<ref>{{Cite web|url=http://alcoholism.about.com/od/meth/a/shake_and_bake.htm |title=Shake and Bake Meth | New 'Shake and Bake' Meth Method Explodes |accessdate=2009-12-01 }}</ref>


In addition to its effect on the plasma membrane monoamine transporters, methamphetamine inhibits synaptic vesicle function by inhibiting ], which prevents monoamine uptake into the vesicles and promotes their release.<ref name="Meth Transporters" /> This results in the outflow of monoamines from ]s into the ] (intracellular fluid) of the ], 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 ] that methamphetamine is known to inhibit are ] and ].<ref name="Meth Transporters">{{cite web |title = Methamphetamine: Transporters | url = http://www.drugbank.ca/drugs/DB01577#transporters |work = DrugBank |publisher = University of Alberta |date = 8 February 2013 |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 ] transporter.<ref name="Meth Targets" /><ref name="pmid13677912">{{cite journal |vauthors = Inazu M, Takeda H, Matsumiya T |title = |language = ja |journal = Nihon Shinkei Seishin Yakurigaku Zasshi |volume = 23 |issue = 4 |pages = 171–178 |date = August 2003 |pmid = 13677912 }}</ref>
===Production and distribution===
].]]
Until the early 1990s, methamphetamine for the U.S. market was made mostly in labs run by drug traffickers in ] and ]. Since then, authorities{{Which?|date=July 2009}} have discovered increasing numbers of small-scale methamphetamine labs all over the United States, mostly in rural, suburban, or low-income areas.{{Citation needed|date=July 2009}} ] ] found 1,260 labs in 2003, compared to just 6 in 1995, although this may be partly a result of increased police activity.<ref>{{cite web| url=http://www.in.gov/cji/methfreeindiana/enforce.html | archiveurl=http://web.archive.org/web/20070926225227/http://www.in.gov/cji/methfreeindiana/enforce.html |archivedate=2007-09-22 |title=Law Enforcement Facts |date=2007 |publisher=Indiana State Goverment |location=U.S.}}</ref> As of 2007, drug and lab seizure data suggests that approximately 80 percent of the methamphetamine used in the United States originates from larger laboratories operated by Mexican-based syndicates on both sides of the border and that approximately 20 percent comes from small toxic labs (STLs) in the United States.<ref>{{Cite book
|url=http://www.usdoj.gov/dea/pubs/cngrtest/ct032207attach.html
|title=DEA Congressional Testimony, "Drug Threats And Enforcement Challenges"
|publisher=U.S. Drug Enforcement Administration
|date=March 22, 2007
|accessdate=2008-05-03}}</ref>


Methamphetamine is also an ] of the ]s and ]s with a greater ] for ] than ], and inhibits ] (MAO-A) and ] (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) . 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 . σ-2 Receptors modulate DAT and the release of dopamine via protein kinase C (PKC) and Ca2+-calmodulin systems .<br />σ-1 Receptor antisense and antagonists have been shown to block the acute locomotor stimulant effects of METH . 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 . Additionally, σ receptor antagonists&nbsp;... prevent the development of behavioral sensitization to METH .&nbsp;...<br /> σ Receptor agonists have been shown to facilitate dopamine release, through both σ-1 and σ-2 receptors . }}</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" /> ] is a stronger ], but ] has stronger ] effects, a longer half-life, and longer perceived effects among heavy substance users.<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 ] and ],<ref name="Kuczenski" /> but levomethamphetamine has shorter psychodynamic effects.<ref name="Mendelson" />
Mobile and motel-based methamphetamine labs have caught the attention of both the U.S. news media and the police. Such labs can cause explosions and fires and expose the public to hazardous chemicals. Those who manufacture methamphetamine are often harmed by toxic gases. Many police departments have specialized task forces with training to respond to cases of methamphetamine production. The National Drug Threat Assessment 2006, produced by the ], found "decreased domestic methamphetamine production in both small and large-scale laboratories", but also that "decreases in domestic methamphetamine production have been offset by increased production in Mexico." They concluded that "methamphetamine availability is not likely to decline in the near term."<ref>{{Cite web|url=http://www.usdoj.gov/ndic/pubs11/18862/meth.htm |title=Methamphetamine | National Drug Threat Assessment 2006 |accessdate=2009-08-25 |date = January 2006|publisher=National Drug Intelligence Center }}</ref>


=== Pharmacokinetics ===
In July 2007, Mexican officials at the port of ] seized a ship carrying 19 tons of ], a raw material needed for methamphetamine.<ref> AP, The Telegram (The Canadian Press), July 26, 2007. Olga R. Rodriguez</ref> The shipment originated in ] and passed through the United States at the port of ] prior to its arrival in Mexico.
The ] of methamphetamine is 67% ], 79% ], 67 to 90% via ] (]), and 100% ].<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 ] of methamphetamine due to its methyl group, it can readily move through the ] faster than other stimulants, where it is more resistant to degradation by ].<ref name="Schep" /><ref name="DrugBank methamphetamine metabolism" /><ref name="pmid30731099">{{cite journal |vauthors=Xu J, Zhang Z, Liu R, Sun Y, Liu H, Nie Z, Zhao X, Pu X |title=Function of complement factor H and imaging of small molecules by MALDI-MSI in a methamphetamine behavioral sensitization model |journal=Behavioural Brain Research |volume=364 |issue= |pages=233–244 |date=May 2019 |pmid=30731099 |doi=10.1016/j.bbr.2019.02.002 |s2cid=72333584 |quote=Methamphetamine (METH) is a potent amphetamine-type stimulant that has high abuse potential and can be smoked, snorted, injected, or taken orally. The drug is high in lipid solubility and can cross the blood-brain barrier more readily than amphetamine due to the addition of an extra methyl group.}}</ref> 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 FDA label" /><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 ] 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 ], but is subject to substantial ].<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 = 1085–1099 | date = July 2009 | pmid = 19426289 | doi = 10.1111/j.1360-0443.2009.02564.x | s2cid = 37079117 | doi-access = free }}</ref>


], ], ], ], and ] 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 />{{cite journal | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ | title = Table 5: N-containing drugs and xenobiotics oxygenated by FMO | date = 2005 | pmc = 1828602 | archive-url = https://web.archive.org/web/20180916144516/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ | archive-date=16 September 2018 | journal = Pharmacology & Therapeutics | volume = 106 | issue = 3 | pages = 357–387 | doi = 10.1016/j.pharmthera.2005.01.001 | pmid = 15922018 | vauthors = Krueger SK, Williams DE }}</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 | chapter-url = https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646 | chapter = 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 web |title = butyrate-CoA ligase: Substrate/Product | 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. |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 web |title = glycine N-acyltransferase: Substrate/Product | 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. |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 ];<ref name="DrugBank methamphetamine metabolism">{{cite web |title = Methamphetamine: Pharmacology | 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|]}}, {{nowrap|]}}, {{nowrap|]}}, ], ], ], and ], the metabolites of amphetamine.<ref name="FDA Pharmacokinetics" /><ref name="DrugBank methamphetamine metabolism" /><ref name="Metabolites" /> Among these metabolites, the active ] are amphetamine, {{nowrap|4‑hydroxyamphetamine}},<ref>{{cite web |title = p-Hydroxyamphetamine: Compound Summary | url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3651 |work = PubChem Compound |publisher = National Center for Biotechnology Information |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 web |title = p-Hydroxynorephedrine: Compound Summary | url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11099 |work = PubChem Compound |publisher = National Center for Biotechnology Information|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 web |title = Phenylpropanolamine: Compound Summary | url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=26934 |work = PubChem Compound |publisher = National Center for Biotechnology Information |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" />
Methamphetamine is distributed by prison gangs, ], street gangs, traditional ] operations, and impromptu small networks.{{Citation needed|date=May 2009}} In the United States, illicit methamphetamine comes in a variety of forms with prices varying widely over time.<ref>{{cite web |url=http://www.whitehousedrugpolicy.gov/publications/price_purity/ |title=The Price and Purity of Illicit Drugs: 1981 Through the Second Quarter of 2003 |publisher=WhiteHouseDrugPolicy.gov |month=November |year=2004 |archiveurl=http://web.archive.org/web/20051027062908/http://www.whitehousedrugpolicy.gov/publications/price_purity/ |archivedate=2005-10-27}}</ref> Most commonly, it is found as a colorless ] solid. Impurities may result in a brownish or tan color. Colorful flavored pills containing methamphetamine and ] are known as ] (Thai for "crazy medicine").


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 web |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:
An impure form of methamphetamine is sold as a crumbly brown or off-white rock, commonly referred to as "peanut butter crank".<ref>{{cite web |title=The Ice Epidemic |url=http://www.wctu.com.au/pages/education_papers/Education+Paper+2007-09.pdf |archiveurl=http://web.archive.org/web/20080719104248/http://www.wctu.com.au/pages/education_papers/Education+Paper+2007-09.pdf |archivedate=2008-07-19 |publisher=Woman's Christian Temperance Union |location=Australia |work=WCTU.com.au |first=Glenda |last=Amos |date=September 2007 |accessdate=2010-11-17}}</ref> Methamphetamine found on the street is rarely pure, but adulterated with chemicals that were used to synthesize it.{{Citation needed|date=November 2009}} It may be diluted or ] with non-psychoactive substances like ], ] or ]. Another popular method is to combine methamphetamine with other ], such as ] or ], into a pill known as a "Kamikaze", which can be particularly dangerous due to the ] of multiple stimulants. It may also be flavored with high-sugar candies, drinks, or drink mixes to mask the bitter taste of the drug. Coloring may be added to the meth, as is the case with "Strawberry Quick".<ref> CBS News, May 2, 2007. Lloyd De Vries. Accessed 2009-12-29.</ref><ref>{{Cite web |url=http://www.snopes.com/horrors/drugs/candymeth.asp |title=Strawberry Meth |publisher=Snopes.com |accessdate=2009-08-25 |last=Mikkelson |first=Barbara }}</ref>
{{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" /> ], particularly '']'', '']'', and '']'' 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 />{{cite journal | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526672/table/T2/ | title = Table 2: Xenobiotics metabolized by the human gut microbiota | journal = Pharmacological Research | date = March 2013 | volume = 69 | issue = 1 | doi = 10.1016/j.phrs.2012.07.009 | pmid = 22902524 | pmc = 3526672 | archive-url = https://web.archive.org/web/20211031105429/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526672/table/T2/ | archive-date = 31 October 2021 | vauthors = Haiser HJ, Turnbaugh PJ | pages = 21–31 }}</ref><ref name="Meth demethylation primary">{{cite journal | vauthors = Caldwell J, Hawksworth GM | title = The demethylation of methamphetamine by intestinal microflora | journal = The Journal of Pharmacy and Pharmacology | volume = 25 | issue = 5 | pages = 422–424 | date = May 1973 | pmid = 4146404 | doi = 10.1111/j.2042-7158.1973.tb10043.x | s2cid = 34050001 }}</ref>}}
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==== Detection in biological fluids ====
==Natural occurrence==
Methamphetamine and amphetamine are often measured in urine or blood as part of a ] 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 ], 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>
Methamphetamine has been reported to occur naturally in '']'', and possibly '']'', trees that grow in ].<ref>BA Clement, CM Goff, TDA Forbes, Phytochemistry Vol.49, No 5, pp 1377–1380 (1998) "Toxic amines and alkaloids from Acacia rigidula"</ref> Methamphetamine and regular amphetamine were long thought to be strictly human-synthesized,<ref></ref> but ''Acacia'' trees contain these and numerous other psychoactive compounds (e.g., ], ], ]), and the related compound ] is known to occur from numerous ''Acacia'' species.<ref>{{Cite journal|author= Siegler, D.S.|title=Phytochemistry of ''Acacia—sensu lato'' |journal= Biochemical Systematics and Ecology |volume=31 |issue=8 |pages=845–873 |year=2003 |month=August |doi=10.1016/S0305-1978(03)00082-6 |url=}}</ref> The findings, however, have never been confirmed or repeated, leading some researchers to believe the results were the result of cross-contamination.{{Citation needed|date=November 2010}}


==Terminology== == Chemistry ==
{{multiple image|perrow = 1|total_width=300
] for methamphetamine are numerous and vary from region to region.
| image1 = Crystal Meth.jpg
| image2 = Crystal methamphetamine Canadian quarter.jpg
| footer = Shards of pure methamphetamine hydrochloride, also known as crystal meth
}}
Methamphetamine is a ] compound with two enantiomers, ] and ]. At room temperature, the ] of methamphetamine is a clear and colorless liquid with an odor characteristic of ] leaves.<ref name="Pubchem2" /> It is ] in ] and ] as well as ] with ].<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 ] 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 ] with P2<sub>1</sub> ]; at {{convert|90|K|C F}}, it has ]s ''a'' = 7.10&nbsp;], ''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 | bibcode = 2008AcCrE..64O.940H }}</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 ], 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}}

] methamphetamine may be prepared starting from ] by either the ]<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 ] 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|]}} to produce the formyl ] of methamphetamine plus carbon dioxide and ] as side products.<ref name="pmid19637924" /> In this reaction, an ] cation is formed as an intermediate which is ] by the second equivalent of {{nowrap|''N''-methylformamide}}.<ref name="pmid19637924" /> The intermediate formyl amide is then ] 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" />
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|image1=Methamphetamine reductive amination.png
|caption1=Method of methamphetamine synthesis of methamphetamine via ]
|alt1=Diagram of methamphetamine synthesis by reductive amination
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|image2=Methamphetamine leuckart synthesis.png
|caption2=Methods of methamphetamine synthesis via the ]
|alt2=Diagram of methamphetamine synthesis by Leuckart reaction
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== History, society, and culture ==
{{Main|History and culture of substituted amphetamines}}
], was dispensed in these tablet containers.]]
] related fatalities in 2017 were 70,200, including 10,333 of those related to psychostimulants (including methamphetamine).<ref name=NIDA-deaths>{{cite web | url = https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates | title = Overdose Death Rates | archive-url = https://web.archive.org/web/20171213234138/https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates | archive-date=13 December 2017 | work = ] (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 ] 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 ] in 1893 by Japanese ] ].<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 ] via ] of ephedrine using red ] and ].<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 ] 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 ] of the ], for its stimulant effects and to induce extended ].<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 "]-Tablets" (''Stuka-Tabletten'') and "]-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 = 978-0-19-026347-8 |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: ].


], patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of ], 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 ] under the ].<ref name=":USAS22" /> Currently, methamphetamine is sold under the trade name ''Desoxyn'', ]ed by the Danish pharmaceutical company ].<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>
Some common names include:


== Trafficking ==
*"''ice''"
The ], specifically ], Myanmar, is the world's leading producer of methamphetamine as production has shifted to ] 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>
*"''meth''"
*"''gak''"
*"''crystal''"
*"''crystal meth''"
*"''crank''"
*"''glass''"
*"''chalk''"
*"''fire''"
*"''go-fast''"
*"''tweak''"
*"''jib''"
*"''Wag''"
*"''Pint''"
*"''Nazi dope''"
* "''P''" (])<ref></ref>
* "''tik''" (])<ref name="UCT">{{Cite news|work=UCT|accessdate=2009-08-13 |last=Plüddemann|first=Andreas| date=2005-06|title=Tik, memory loss and stroke|journal=Science in Africa|publisher=Science magazine for Africa CC|location=South Africa|url=http://www.scienceinafrica.co.za/2005/june/tik.htm}}</ref>
*"'']''" (Thai for "madness drug") (])
*"''shabu''" (], ], ], ])
*"''bato''" (])<ref name=nicknames></ref>
*"''batu or batunas''" (])<ref name=nicknames/>
*"''batu kilat''" (Malaysian for "shining rocks") (])<ref name=nicknames/>
*"''poor man's cocaine''" (])<ref></ref>
*"''Sissonville Slimfast''" (])<ref></ref>
*"''vint''" (Russian for "a screw") (])<ref></ref>
*"''Piko''" (Czech from the P in pervitin)


Concerning the accelerating synthetic drug production in the region, the Cantonese Chinese syndicate ], 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=] |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 ] and ]. 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 ], 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=]|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 ], a gangster born in ], ] who also holds a Canadian passport.
The nickname most commonly used in the ] is "''Tina''".<ref></ref>


] 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" />
Methamphetamine may also be referred to as "''speed''", a term that is commonly used for ] (in ] or ] form), which differs from methamphetamine by the absence of a ] in its ].<ref></ref>


==Legality== == Legal status ==
{{Main|Legal status of methamphetamine}} {{Main|Legal status of methamphetamine}}
The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many ]s. Methamphetamine has been placed in Schedule II of the ] ] treaty.<ref>{{Cite web|url=http://www.incb.org/pdf/e/list/green.pdf |title=List of psychotropic substances under international control |accessdate=2010-05-10 |format=PDF |publisher=International Narcotics Control Board }}</ref> <!-- Please add only information that contributes to the general, global overview of legality. Details like country-specific laws may be appropriate, but the main article is probably the best place for that. --> The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many ]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> In some jurisdictions, it is legally available as a prescription medication. Methamphetamine has been placed in schedule II of the ] ] treaty, indicating that it has limited medical use.<ref name=incb />


==See also== == Research ==
Animal models have shown that low-dose methamphetamine improves cognitive and behavioural functioning following TBI (]).<ref name="pmid25724762" /> This is in contrast to high, repeated doses which cause neurotoxicity. These models demonstrate that low-dose methamphetamine increases neurogenesis and reduces apoptosis in the dentate gyrus of the hippocampus following TBI.<ref>{{cite journal | vauthors = Rau TF, Kothiwal AS, Rova AR, Brooks DM, Poulsen DJ | title = Treatment with low-dose methamphetamine improves behavioral and cognitive function after severe traumatic brain injury | language = en-US | journal = The Journal of Trauma and Acute Care Surgery | volume = 73 | issue = 2 Suppl 1 | pages = S165–S172 | date = August 2012 | pmid = 22847088 | doi = 10.1097/TA.0b013e318260896a }}</ref> It has also been found that TBI patients testing positive for methamphetamine at the time of emergency department admission have lower rates of mortality.<ref>{{cite journal | vauthors = O'Phelan K, McArthur DL, Chang CW, Green D, Hovda DA | title = The impact of substance abuse on mortality in patients with severe traumatic brain injury | language = en-US | journal = The Journal of Trauma | volume = 65 | issue = 3 | pages = 674–677 | date = September 2008 | pmid = 18784583 | doi = 10.1097/TA.0b013e31817db0a5 }}</ref>
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]


It has been suggested, based on animal research, that calcitriol, the active metabolite of ], 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 = 261–271 | date = August 2006 | pmid = 17105922 | doi = 10.1196/annals.1369.023 | bibcode = 2006NYASA1074..261C | s2cid = 8537458 }}</ref> Protection against methamphetamine-induced neurotoxicity has also been observed following administration of ascorbic acid (vitamin C),<ref>{{cite journal | vauthors = Huang YN, Yang LY, Wang JY, Lai CC, Chiu CT, Wang JY | title = L-Ascorbate Protects Against Methamphetamine-Induced Neurotoxicity of Cortical Cells via Inhibiting Oxidative Stress, Autophagy, and Apoptosis | journal = Molecular Neurobiology | volume = 54 | issue = 1 | pages = 125–136 | date = January 2017 | pmid = 26732595 | doi = 10.1007/s12035-015-9561-z }}</ref> cobalamin (vitamin B<sub>12</sub>),<ref>{{cite journal | vauthors = Moshiri M, Hosseiniyan SM, Moallem SA, Hadizadeh F, Jafarian AH, Ghadiri A, Hoseini T, Seifi M, Etemad L | title = The effects of vitamin B<sub>12</sub> on the brain damages caused by methamphetamine in mice | journal = Iranian Journal of Basic Medical Sciences | volume = 21 | issue = 4 | pages = 434–438 | date = April 2018 | pmid = 29796230 | pmc = 5960763 | doi = 10.22038/IJBMS.2018.23362.5897 }}</ref> and vitamin E.<ref>{{Cite journal | vauthors = Anazodo G |date=May 2024 |title=Protective effects of vitamin C and E on amygdala of methamphetamine-induced brain disorder on adult male Wistar rats |url=https://wjpr.s3.ap-south-1.amazonaws.com/article_issue/eefe2451ff2a6848f0249c533e1fc88d.pdf |journal=World Journal of Pharmaceutical Research |volume=13 |issue=9 |pages=2121–2170 |access-date=19 September 2024 |archive-date=22 September 2024 |archive-url=https://web.archive.org/web/20240922021107/https://wjpr.s3.ap-south-1.amazonaws.com/article_issue/eefe2451ff2a6848f0249c533e1fc88d.pdf |url-status=live }}</ref>
==References==
{{Reflist|colwidth=30em}}


==Further reading== == See also ==
* ]
* {{Cite book|last=Yudko|first=Errol|coauthors=McPherson, Sandra; Hall, Harold|title=Methamphetamine Use: Clinical and Forensic Aspects|publisher=CRC Press|location=Boca Raton, FL|date=2008-10-29|edition=2|series=408|isbn=978-0849372735|url=http://search.barnesandnoble.com/booksearch/isbninquiry.asp?ean=9780849372735&box=978-0849372735&pos=-1}}
* '']'', a TV drama series centered on illicit methamphetamine synthesis
* ]
* ], a drug prevention project
* ]
* ]
* ]
* ]
* ]
* ]
* ], a Montana-based organization aiming to reduce meth use among teenagers
* ]
* ], a transportable laboratory that is used to illegally produce methamphetamine
* ], Southeast Asian tablets containing a mixture of methamphetamine and caffeine


==External links== == Footnotes ==
{{reflist|group=Color legend}}
* - Entry for d-methamphetamine
{{reflist|group=note}}
* : Prescription form of the drug.
*
*
*
* - A comprehensive thematic index of methamphetamine research published in academic and scientific journals with links from citations to the PubMed abstracts.
** - More detailed synthesis and synthesis from other sources.
*
* (PIM 334: Methamphetamine)
* - a thorough review on the effects of chronic use (American College of Neuropsychopharmacology)
* - Self-help guide for family members and loved ones of methamphetamine addicts
*
*
* - Video of rats suffering from methamphetamine addiction.


== Reference notes ==
===Documentaries===
<references group="sources" />
* - ABC Australia - 4 Corners&nbsp;— Australian methamphetamine use.
{{clear}}
* - PBS United States&nbsp;— Frontline.
* - National Geographic.
*


== References ==
===Academic Sources===
{{Reflist}}
*
*
*


== Further reading ==
{{refbegin}}
* {{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 journal | vauthors = Rusyniak DE | title = Neurologic manifestations of chronic methamphetamine abuse | journal = Neurologic Clinics | volume = 29 | issue = 3 | pages = 641–655 | date = August 2011 | pmid = 21803215 | pmc = 3148451 | doi = 10.1016/j.ncl.2011.05.004 }}
* {{cite magazine |vauthors=Szalavitz M |date=21 November 2011 |title=Why the Myth of the Meth-Damaged Brain May Hinder Recovery |magazine=Time |url=https://healthland.time.com/2011/11/21/why-the-myth-of-the-meth-damaged-brain-may-hinder-recovery/ |access-date=22 September 2024 |archive-date=22 September 2024 |archive-url=https://web.archive.org/web/20240922021109/https://healthland.time.com/2011/11/21/why-the-myth-of-the-meth-damaged-brain-may-hinder-recovery/ |url-status=live }}
{{refend}}

== External links ==
{{Commons category}}
*
* , ]

{{Amphetamine}}
{{Methamphetamine}} {{Methamphetamine}}
{{Drug use}} {{Drug use}}
{{Stimulants}} {{Stimulants}}
{{ADHD pharmacotherapies}}
{{Antihyperkinetics}}
{{Navboxes
{{Anorectics}}
| title = ]
{{Adrenergics}}
| titlestyle = background:#ccccff
{{Dopaminergics}}
| list1 =
{{Monoamine releasing agents}}
{{TAAR ligands}}
{{Sigma receptor modulators}}
{{Monoamine neurotoxins}}
}}
{{Phenethylamines}} {{Phenethylamines}}
{{Authority control}}


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