Editing Amphetamine (section)

===Toxicity===
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic [[neurotoxicity]], or damage to dopamine neurons, which is characterized by dopamine [[axon terminal|terminal]] [[Neurodegeneration|degeneration]] and reduced transporter and receptor function.<ref name="Humans&Animals">{{cite journal| vauthors = Advokat C| title=Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD | journal=Journal of Attention Disorders| date = July 2007 | volume= 11 | issue= 1 | pages= 8–16 | pmid=17606768 | doi=10.1177/1087054706295605| s2cid=7582744 }}</ref><ref name="Amph-induced hyperthermia and neurotoxicity review" /> There is no evidence that amphetamine is directly neurotoxic in humans.<ref>{{cite web | title=Amphetamine | url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+300-62-9 | website=United States National Library of Medicine&nbsp;– Toxicology Data Network | publisher=Hazardous Substances Data Bank | access-date=2 October 2017 | archive-url=https://web.archive.org/web/20171002194327/https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/cgi-bin/sis/search2/f?.%2Ftemp%2F~mdjW95%3A1%3AFULL | archive-date=2 October 2017 | quote=Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation. }}</ref><ref name = "Malenka_2009_02">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, US | isbn = 9780071481274 | page = 370 | edition = 2nd | chapter = Chapter 15: Reinforcement and addictive disorders | quote = Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.}}</ref> However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of [[hyperpyrexia]], the excessive formation of [[reactive oxygen species]], and increased [[autoxidation]] of dopamine.{{#tag:ref|<ref name="pmid22392347"/><ref name="Amph-induced hyperthermia and neurotoxicity review" /><ref name="Autoxidation1">{{cite journal |vauthors=Sulzer D, Zecca L | title = Intraneuronal dopamine-quinone synthesis: a review | journal =Neurotoxicity Research| volume = 1 | issue = 3 | pages = 181–195 |date=February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289 | s2cid = 21892355 }}</ref><ref name="Autoxidation2">{{cite journal |vauthors=Miyazaki I, Asanuma M | title = Dopaminergic neuron-specific oxidative stress caused by dopamine itself | journal =Acta Medica Okayama| volume = 62 | issue = 3 | pages = 141–150 |date=June 2008 | pmid = 18596830| url = http://ousar.lib.okayama-u.ac.jp/files/public/3/30980/20160528022138672578/fulltext.pdf | doi=10.18926/AMO/30942}}</ref>|group="sources"}} [[Animal model]]s of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., [[core body temperature]]&nbsp;≥&nbsp;40&nbsp;°C) is necessary for the development of amphetamine-induced neurotoxicity.<ref name="Amph-induced hyperthermia and neurotoxicity review">{{cite journal | vauthors = Bowyer JF, Hanig JP | title = Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity | journal =Temperature| volume = 1 | issue = 3 | pages = 172–182 | date = November 2014 | pmid = 27626044 | pmc = 5008711 | doi = 10.4161/23328940.2014.982049 | quote = Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40&nbsp;°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production.&nbsp;... The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals.&nbsp;... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.}}</ref> Prolonged elevations of brain temperature above 40&nbsp;°C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing [[blood–brain barrier]] permeability.<ref name="Amph-induced hyperthermia and neurotoxicity review" />