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== Medical uses ==
== Medical uses ==
Stimulants have been used in medicine for many conditions including [[obesity]], [[sleep disorders]], [[mood disorders]], [[impulse control disorders]], [[asthma]], [[nasal congestion]] and, in case of cocaine, as [[local anesthetic]]s.<ref>{{cite journal|last1=Harper|first1=S. J.|last2=Jones|first2=N. S.|title=Cocaine: what role does it have in current ENT practice? A review of the current literature|journal=The Journal of Laryngology and Otology|date=1 October 2006|volume=120|issue=10|pages=808–811|doi=10.1017/S0022215106001459|pmid=16848922|s2cid=28169472|issn=1748-5460}}</ref> Drugs used to treat obesity are called [[anorectic]]s and generally include drugs that follow the general definition of a stimulant, but other drugs such as [[cannabinoid receptor antagonist]]s also belong to this group.<ref>{{cite journal|last1=Kaplan|first1=Lee M.|title=Pharmacological therapies for obesity|journal=Gastroenterology Clinics of North America|date=1 March 2005|volume=34|issue=1|pages=91–104|doi=10.1016/j.gtc.2004.12.002|pmid=15823441|issn=0889-8553}}</ref><ref>{{cite journal|last1=Palamara|first1=Kerri L.|last2=Mogul|first2=Harriette R.|last3=Peterson|first3=Stephen J.|last4=Frishman|first4=William H.|title=Obesity: new perspectives and pharmacotherapies|journal=Cardiology in Review|date=1 October 2016|volume=14|issue=5|pages=238–258|doi=10.1097/01.crd.0000233903.57946.fd|pmid=16924165|issn=1538-4683}}</ref> [[Eugeroic]]s are used in management of sleep disorders characterized by [[excessive daytime sleepiness]], such as [[narcolepsy]], and include stimulants such as [[modafinil]].<ref>{{cite web|title=The Voice of the Patient A series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative|url=https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|publisher=Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)|url-status=live|archive-url=https://web.archive.org/web/20170505031213/https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|archive-date=5 May 2017|df=dmy-all}}</ref><ref>{{cite journal|last1=Heal|first1=David J|last2=Smith|first2=Sharon L|last3=Gosden|first3=Jane|last4=Nutt|first4=David J|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=Journal of Psychopharmacology |date=7 January 2017|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|issn=0269-8811|pmid=23539642}}</ref> Stimulants are used in impulse control disorders such as [[ADHD]]<ref>{{cite web|last1=Research|first1=Center for Drug Evaluation and|title=Drug Safety and Availability - FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults|url=https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|website=www.fda.gov|language=en|url-status=live|archive-url=https://web.archive.org/web/20131030064843/https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|archive-date=30 October 2013|df=dmy-all|date=26 June 2019}}</ref> and [[off-label use|off-label]] in [[mood disorder]]s such as [[major depressive disorder]] to increase [[mental energy|energy]], focus and elevate mood.<ref>{{cite journal|last1=Stotz|first1=Gabriele|last2=Woggon|first2=Brigitte|last3=Angst|first3=Jules|title=Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients|journal=Dialogues in Clinical Neuroscience|date=1 December 1999|volume=1|issue=3|pages=165–174|doi=10.31887/DCNS.1999.1.3/gstotz |pmc=3181580|issn=1294-8322|pmid=22034135}}</ref> Stimulants such as [[epinephrine]],<ref name="pmid18733372">{{cite journal |author = Doig RL | title = Epinephrin; especially in asthma | journal = California State Journal of Medicine | volume = 3 | issue = 2 | pages = 54–5 |date=February 1905 | pmid = 18733372 | pmc = 1650334 }}</ref> [[theophylline]] and [[salbutamol]]<ref>{{cite journal|last1=Chu|first1=Eric K.|last2=Drazen|first2=Jeffrey M.|title=Asthma|journal=American Journal of Respiratory and Critical Care Medicine|date=1 June 2005|volume=171|issue=11|pages=1202–1208|doi=10.1164/rccm.200502-257OE|pmid=15778490|issn=1073-449X}}</ref> orally have been used to treat asthma, but inhaled adrenergic drugs are now preferred due to less systemic side effects. [[Pseudoephedrine]] is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection.<ref name="Bicopoulos">Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.</ref><ref>{{cite web|title=Pseudoephedrine (By mouth) – National Library of Medicine|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|website=PubMed Health|url-status=live|archive-url=https://web.archive.org/web/20140214034938/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|archive-date=14 February 2014|df=dmy-all}}</ref>
Stimulants have been used in medicine for many conditions including [[obesity]], [[sleep disorders]], [[mood disorders]], [[impulse control disorders]], [[asthma]], [[nasal congestion]] and, in case of cocaine, as [[local anesthetic]]s.<ref>{{cite journal|last1=Harper|first1=S. J.|last2=Jones|first2=N. S.|title=Cocaine: what role does it have in current ENT practice? A review of the current literature|journal=The Journal of Laryngology and Otology|date=1 October 2006|volume=120|issue=10|pages=808–811|doi=10.1017/S0022215106001459|pmid=16848922|s2cid=28169472|issn=1748-5460}}</ref> Drugs used to treat obesity are called [[anorectic]]s and generally include drugs that follow the general definition of a stimulant, but other drugs such as [[cannabinoid receptor antagonist]]s also belong to this group.<ref>{{cite journal|last1=Kaplan|first1=Lee M.|title=Pharmacological therapies for obesity|journal=Gastroenterology Clinics of North America|date=1 March 2005|volume=34|issue=1|pages=91–104|doi=10.1016/j.gtc.2004.12.002|pmid=15823441|issn=0889-8553}}</ref><ref>{{cite journal|last1=Palamara|first1=Kerri L.|last2=Mogul|first2=Harriette R.|last3=Peterson|first3=Stephen J.|last4=Frishman|first4=William H.|title=Obesity: new perspectives and pharmacotherapies|journal=Cardiology in Review|date=1 October 2016|volume=14|issue=5|pages=238–258|doi=10.1097/01.crd.0000233903.57946.fd|pmid=16924165|issn=1538-4683}}</ref> [[Eugeroic]]s are used in management of sleep disorders characterized by [[excessive daytime sleepiness]], such as [[narcolepsy]], and include stimulants such as [[modafinil]] and [[pitolisant]].<ref>{{cite web|title=The Voice of the Patient A series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative|url=https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|publisher=Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)|url-status=live|archive-url=https://web.archive.org/web/20170505031213/https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|archive-date=5 May 2017|df=dmy-all}}</ref><ref>{{cite journal|last1=Heal|first1=David J|last2=Smith|first2=Sharon L|last3=Gosden|first3=Jane|last4=Nutt|first4=David J|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=Journal of Psychopharmacology |date=7 January 2017|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|issn=0269-8811|pmid=23539642}}</ref> Stimulants are used in impulse control disorders such as [[ADHD]]<ref>{{cite web|last1=Research|first1=Center for Drug Evaluation and|title=Drug Safety and Availability - FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults|url=https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|website=www.fda.gov|language=en|url-status=live|archive-url=https://web.archive.org/web/20131030064843/https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|archive-date=30 October 2013|df=dmy-all|date=26 June 2019}}</ref> and [[off-label use|off-label]] in [[mood disorder]]s such as [[major depressive disorder]] to increase [[mental energy|energy]], focus and elevate mood.<ref>{{cite journal|last1=Stotz|first1=Gabriele|last2=Woggon|first2=Brigitte|last3=Angst|first3=Jules|title=Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients|journal=Dialogues in Clinical Neuroscience|date=1 December 1999|volume=1|issue=3|pages=165–174|doi=10.31887/DCNS.1999.1.3/gstotz |pmc=3181580|issn=1294-8322|pmid=22034135}}</ref> Stimulants such as [[epinephrine]],<ref name="pmid18733372">{{cite journal |author = Doig RL | title = Epinephrin; especially in asthma | journal = California State Journal of Medicine | volume = 3 | issue = 2 | pages = 54–5 |date=February 1905 | pmid = 18733372 | pmc = 1650334 }}</ref> [[theophylline]] and [[salbutamol]]<ref>{{cite journal|last1=Chu|first1=Eric K.|last2=Drazen|first2=Jeffrey M.|title=Asthma|journal=American Journal of Respiratory and Critical Care Medicine|date=1 June 2005|volume=171|issue=11|pages=1202–1208|doi=10.1164/rccm.200502-257OE|pmid=15778490|issn=1073-449X}}</ref> orally have been used to treat asthma, but inhaled adrenergic drugs are now preferred due to less systemic side effects. [[Pseudoephedrine]] is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection.<ref name="Bicopoulos">Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.</ref><ref>{{cite web|title=Pseudoephedrine (By mouth) – National Library of Medicine|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|website=PubMed Health|url-status=live|archive-url=https://web.archive.org/web/20140214034938/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|archive-date=14 February 2014|df=dmy-all}}</ref>


===Depression===
===Depression===
{{Main article|Modafinil}}
{{Main article|Modafinil}}
[[Modafinil]] is an [[eugeroic]] medication, which means that it promotes wakefulness and alertness. Modafinil is sold under the brand name Provigil among others. Modafinil is used to treat [[excessive daytime sleepiness]] due to [[narcolepsy]], [[shift work sleep disorder]], or [[obstructive sleep apnea]]. While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive.<ref>{{Cite journal|url=https://doi.org/10.1097/JCP.0000000000001085|title=The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis|first1=M Alexandra|last1=Kredlow|first2=Ani|last2=Keshishian|first3=Sarah|last3=Oppenheimer|first4=Michael W|last4=Otto|date=1 September 2019|journal=Journal of Clinical Psychopharmacology|volume=39|issue=5|pages=455–461|via=Europe PMC|doi=10.1097/jcp.0000000000001085|pmid=31433334|s2cid=201119084 }}</ref> Despite being a CNS stimulant, the addiction and [[drug dependence|dependence]] liabilities of modafinil are considered very low.<ref name="pmid23065655">{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–752 | date = October 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 }}</ref><ref name="FDA-2015-Provigil-Prescribing">{{cite web|date=January 2015|title=Provigil: Prescribing information |url= http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|access-date=August 16, 2015|website= FDA.gov| publisher= [[United States Food and Drug Administration]] |agency=Cephalon, Inc|archive-date=February 17, 2017|archive-url= https://web.archive.org/web/20170217165804/https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|url-status=live}}</ref><ref name="pmid33435717">{{cite journal |vauthors= Kakehi S, Tompkins DM |title=A Review of Pharmacologic Neurostimulant Use During Rehabilitation and Recovery After Brain Injury |journal=Ann Pharmacother |volume=55 |issue=10 |pages=1254–1266 |date=October 2021 |pmid=33435717 |doi=10.1177/1060028020983607 |s2cid=231593912 }}</ref> Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have [[Mood elevation|mood-elevating properties]].<ref name="FDA-2015-Provigil-Prescribing"/> The similarities in effects with [[caffeine]] are not clearly established.<ref name="pmid22375280">{{cite journal | vauthors = Kim D | title = Practical use and risk of modafinil, a novel waking drug | journal = Environmental Health and Toxicology | volume = 27 | pages = e2012007 | date = 2012 | pmid = 22375280 | pmc = 3286657 | doi = 10.5620/eht.2012.27.e2012007 }}</ref><ref name="Warot-1993">{{Cite journal|vauthors=Warot D, Corruble E, Payan C, Weil JS, Puech AJ|date=1993|title=Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo|journal=European Psychiatry |volume=8|issue=4|pages=201–208|doi=10.1017/S0924933800002923|s2cid=151797528 }}</ref> Unlike other stimulants, modafinil does not induce a subjective [[Pleasure|feeling of pleasure or reward]], which is commonly associated with [[euphoria]], an intense feeling of well-being. Euphoria is a potential indicator of [[Substance abuse|drug abuse]], which is the compulsive and excessive use of a substance despite adverse consequences. In clinical trials, modafinil has shown no evidence of abuse potential, that is why modafinil is considered to have a low risk of addiction and dependence, however, caution is advised.<ref name="pmid16741217">{{cite journal | vauthors = O'Brien CP, Dackis CA, Kampman K | title = Does modafinil produce euphoria? | journal = The American Journal of Psychiatry | volume = 163 | issue = 6 | pages = 1109 | date = June 2006 | pmid = 16741217 | doi = 10.1176/ajp.2006.163.6.1109 }}</ref><ref name="pmid30285371">{{cite book | vauthors = Greenblatt K, Adams N | chapter = Modafinil | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing | date = February 2022 | pmid = 30285371 | id={{NCBIBook|NBK531476}}}}</ref>
[[Modafinil]] is an [[eugeroic]] medication, which means that it promotes wakefulness and alertness. Modafinil is sold under the brand name Provigil among others. Modafinil is used to treat [[excessive daytime sleepiness]] due to [[narcolepsy]], [[shift work sleep disorder]], or [[obstructive sleep apnea]]. While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive.<ref>{{Cite journal|url=https://doi.org/10.1097/JCP.0000000000001085|title=The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis|first1=M Alexandra|last1=Kredlow|first2=Ani|last2=Keshishian|first3=Sarah|last3=Oppenheimer|first4=Michael W|last4=Otto|date=1 September 2019|journal=Journal of Clinical Psychopharmacology|volume=39|issue=5|pages=455–461|via=Europe PMC|doi=10.1097/jcp.0000000000001085|pmid=31433334|s2cid=201119084 }}</ref> Despite being a CNS stimulant, the addiction and [[drug dependence|dependence]] liabilities of modafinil are considered very low.<ref name="pmid23065655">{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–752 | date = October 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 }}</ref><ref name="FDA-2015-Provigil-Prescribing">{{cite web|date=January 2015|title=Provigil: Prescribing information |url= http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|access-date=August 16, 2015|website= FDA.gov| publisher= [[United States Food and Drug Administration]] |agency=Cephalon, Inc|archive-date=February 17, 2017|archive-url= https://web.archive.org/web/20170217165804/https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|url-status=live}}</ref><ref name="pmid33435717">{{cite journal |vauthors= Kakehi S, Tompkins DM |title=A Review of Pharmacologic Neurostimulant Use During Rehabilitation and Recovery After Brain Injury |journal=Ann Pharmacother |volume=55 |issue=10 |pages=1254–1266 |date=October 2021 |pmid=33435717 |doi=10.1177/1060028020983607 |s2cid=231593912 }}</ref> Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have [[Mood elevation|mood-elevating properties]].<ref name="FDA-2015-Provigil-Prescribing"/> The similarities in effects with [[caffeine]] are not clearly established.<ref name="pmid22375280">{{cite journal | vauthors = Kim D | title = Practical use and risk of modafinil, a novel waking drug | journal = Environmental Health and Toxicology | volume = 27 | pages = e2012007 | date = 2012 | pmid = 22375280 | pmc = 3286657 | doi = 10.5620/eht.2012.27.e2012007 }}</ref><ref name="Warot-1993">{{Cite journal|vauthors=Warot D, Corruble E, Payan C, Weil JS, Puech AJ|date=1993|title=Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo|journal=European Psychiatry |volume=8|issue=4|pages=201–208|doi=10.1017/S0924933800002923|s2cid=151797528 }}</ref> Unlike other stimulants, modafinil does not induce a subjective [[Pleasure|feeling of pleasure or reward]], which is commonly associated with [[euphoria]], an intense feeling of well-being. Euphoria is a potential indicator of [[Substance abuse|drug abuse]], which is the compulsive and excessive use of a substance despite adverse consequences. In clinical trials, modafinil has shown no evidence of abuse potential, that is why modafinil is considered to have a low risk of addiction and dependence, however, caution is advised.<ref name="pmid16741217">{{cite journal | vauthors = O'Brien CP, Dackis CA, Kampman K | title = Does modafinil produce euphoria? | journal = The American Journal of Psychiatry | volume = 163 | issue = 6 | pages = 1109 | date = June 2006 | pmid = 16741217 | doi = 10.1176/ajp.2006.163.6.1109 }}</ref><ref name="pmid30285371">{{cite book | vauthors = Greenblatt K, Adams N | chapter = Modafinil | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing | date = February 2022 | pmid = 30285371 | id={{NCBIBook|NBK531476}}}}</ref>

===Pitolisant===
{{Main article|Pitolisant}}
Pitolisant, an [[eugeroic]] medication, is an inverse agonist (antagonist) of the [[Histamine H3 receptor|histamine 3 (H<sub>3</sub>) autoreceptor]], that belongs to the class of [[CNS stimulant]]s.<ref>https://www.ncbi.nlm.nih.gov/books/NBK573784/</ref><ref>{{Cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK548702/|title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|date=22 January 2012|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|via=PubMed|pmid=31644012}}</ref><ref>{{Cite web|url=https://www.drugs.com/mtm/pitolisant.html|title=Pitolisant Uses, Side Effects & Warnings|website=Drugs.com}}</ref><ref>{{Cite web|url=https://www.drugs.com/drug-class/cns-stimulants.html|title=List of CNS stimulants + Uses & Side Effects|website=Drugs.com}}</ref> Pitolisant is also considered a medication of class "[[eugeroic]]", which means that it promotes wakefulness and alertness. Pitolisant is the first eugeroic drug that acts by blocking the [[Histamine H3 receptor|histamine 3 (H<sub>3</sub>) autoreceptor]], which increases the activity of histamine neurons in the brain. Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.<ref>{{Cite journal|url=https://doi.org/10.1001/jama.2021.1349|title=Pitolisant (Wakix) for Narcolepsy|date=21 September 2021|journal=JAMA|volume=326|issue=11|pages=1060–1061|via=Silverchair|doi=10.1001/jama.2021.1349|pmid=34546302 |s2cid=237583921 }}</ref><ref>{{Cite journal|url=https://doi.org/10.1016/j.sleep.2017.01.002|title=The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use|first1=Marta|last1=Kollb-Sielecka|first2=Pierre|last2=Demolis|first3=Joseph|last3=Emmerich|first4=Greg|last4=Markey|first5=Tomas|last5=Salmonson|first6=Manuel|last6=Haas|date=1 May 2017|journal=Sleep Medicine|volume=33|pages=125–129|via=Europe PMC|doi=10.1016/j.sleep.2017.01.002|pmid=28449891}}</ref><ref>{{Cite journal|url=https://doi.org/10.1007/s40263-020-00703-x|title=Pitolisant: A Review in Narcolepsy with or without Cataplexy|first=Yvette N|last=Lamb|date=1 February 2020|journal=CNS Drugs|volume=34|issue=2|pages=207–218|via=Europe PMC|doi=10.1007/s40263-020-00703-x|pmid=31997137|s2cid=210949049 }}</ref> The H<sub>3</sub> autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine synthesis and release upon binding to endogenous histamine.<ref>{{cite journal | vauthors = West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA | title = Identification of two H3-histamine receptor subtypes | journal = Molecular Pharmacology | volume = 38 | issue = 5 | pages = 610–613 | date = November 1990 | pmid = 2172771 | url = https://molpharm.aspetjournals.org/content/38/5/610 }}</ref> By preventing the binding of endogenous histamine at the H<sub>3</sub>, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.<ref>{{cite journal | vauthors = Sarfraz N, Okuampa D, Hansen H, Alvarez M, Cornett EM, Kakazu J, Kaye AM, Kaye AD | display-authors = 6 | title = pitolisant, a novel histamine-3 receptor competitive antagonist, and inverse agonist, in the treatment of excessive daytime sleepiness in adult patients with narcolepsy | journal = Health Psychology Research | volume = 10 | issue = 3 | pages = 34222 | date = 30 May 2022 | pmid = 35774905 | pmc = 9239364 | doi = 10.52965/001c.34222 }}</ref>

Pitolisant is the only non-controlled anti-narcoleptic drug in the US.<ref name="pmid31997137" /> Pitolisant has shown minimal abuse risk in studies.<ref name="pmid31997137">{{cite journal |vauthors=Lamb YN |title=Pitolisant: A Review in Narcolepsy with or without Cataplexy |journal=CNS Drugs |volume=34 |issue=2 |pages=207–218 |date=February 2020 |pmid=31997137 |doi=10.1007/s40263-020-00703-x |s2cid=210949049 }}</ref><ref name="pmid32941089">{{cite journal |vauthors=de Biase S, Pellitteri G, Gigli GL, Valente M |title=Evaluating pitolisant as a narcolepsy treatment option |journal=Expert Opinion on Pharmacotherapy |volume=22 |issue=2 |pages=155–162 |date=February 2021 |pmid=32941089 |doi=10.1080/14656566.2020.1817387 |s2cid=221788777}}</ref>


== Recreational use and issues of abuse ==
== Recreational use and issues of abuse ==

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'{{Short description|Overarching term covers many drugs that increase activity of the central nervous system}} {{cs1 config|name-list-style=vanc}} {{Use dmy dates|date=January 2021}} {{Use American English|date=January 2014}} [[File:Ritalin-SR-20mg-full.jpg|thumb|right|200px|[[Ritalin]]: 20 mg [[Modified-release dosage|sustained-release]] (SR) tablets]] '''Stimulants''' (also known as '''psychostimulants''' or colloquially as '''uppers''') is an overarching term that covers many [[drug]]s including those that increase the activity of the [[central nervous system]] and the body,<ref>{{cite web|title=stimulant – definition of stimulant in English {{!}} Oxford Dictionaries|url=https://en.oxforddictionaries.com/definition/stimulant|website=Oxford Dictionaries {{!}} English|url-status=dead|archive-url=https://web.archive.org/web/20170226074716/https://en.oxforddictionaries.com/definition/stimulant|archive-date=26 February 2017|df=dmy-all}}</ref> drugs that are pleasurable and invigorating, or drugs that have [[Sympathomimetic drug|sympathomimetic]] effects.<ref name=NBK64328>{{cite book|author1=Center for Substance Abuse Treatment |title=Chapter 2—How Stimulants Affect the Brain and Behavior|publisher=Substance Abuse and Mental Health Services Administration (US)|url=https://www.ncbi.nlm.nih.gov/books/NBK64328/|language=en|url-status=live|archive-url=https://web.archive.org/web/20170219042946/https://www.ncbi.nlm.nih.gov/books/NBK64328/|archive-date=19 February 2017|df=dmy-all|year=1999}}</ref> Stimulants are widely used throughout the world as [[prescription medicine]]s as well as without a prescription (either legally or [[Prohibition (drugs)|illicitly]]) as [[performance-enhancing substance|performance-enhancing]] or [[recreational drug use|recreational]] drugs. Among narcotics, stimulants produce a noticeable crash or ''[[Comedown (drugs)|comedown]]'' at the end of their effects. The most frequently prescribed stimulants as of 2013 were [[lisdexamfetamine]] (Vyvanse), [[methylphenidate]] (Ritalin), and [[amphetamine]] (Adderall).<ref>{{cite web|title=Top 100 Drugs for Q4 2013 by Sales – U.S. Pharmaceutical Statistics|url=https://www.drugs.com/stats/top100/sales|website=www.drugs.com|url-status=live|archive-url=https://web.archive.org/web/20130814232045/http://www.drugs.com/stats/top100/sales|archive-date=14 August 2013|df=dmy-all}}</ref> It was estimated in 2015 that the percentage of the world population that had used [[cocaine]] during a year was 0.4%. For the category "amphetamines and prescription stimulants" (with "amphetamines" including [[amphetamine]] and [[methamphetamine]]) the value was 0.7%, and for [[MDMA]] 0.4%.<ref>{{cite web|title=World Drug Report 2015|url=https://www.unodc.org/documents/wdr2015/World_Drug_Report_2015.pdf|url-status=live|archive-url=https://web.archive.org/web/20160215044543/https://www.unodc.org/documents/wdr2015/World_Drug_Report_2015.pdf|archive-date=15 February 2016|df=dmy-all|page=149}}</ref> == Effects == ===Acute=== Stimulants in therapeutic doses, such as those given to patients with [[Attention deficit hyperactivity disorder|ADHD]], increases ability to focus, vigor, sociability, libido and may elevate mood. However, in higher doses, stimulants may actually decrease the ability to focus, a principle of the [[Yerkes-Dodson Law]]. In higher doses, stimulants may also produce euphoria, vigor, and a decreased need for sleep. Many, but not all, stimulants have [[ergogenic]] effects. Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while cocaine has the opposite effect.<ref>{{cite journal|last1=Avois|first1=L|last2=Robinson|first2=N|last3=Saudan|first3=C|last4=Baume|first4=N|last5=Mangin|first5=P|last6=Saugy|first6=M|title=Central nervous system stimulants and sport practice|journal=British Journal of Sports Medicine|date=7 January 2017|volume=40|issue=Suppl 1|pages=i16–i20|doi=10.1136/bjsm.2006.027557|pmc=2657493|issn=0306-3674|pmid=16799095}}</ref> Neurocognitive enhancing effects of stimulants, specifically [[modafinil]], amphetamine and methylphenidate have been documented in healthy adolescents, and is a commonly cited reason among illicit drug users for use, particularly among college students in the context of studying.<ref>{{cite journal|last1=Bagot|first1=Kara Simone|last2=Kaminer|first2=Yifrah|title=Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review|journal=Addiction |date=1 April 2014|volume=109|issue=4|pages=547–557|pmid=24749160|issn=1360-0443|doi=10.1111/add.12460|pmc=4471173}}</ref> In some cases, psychiatric phenomena may emerge such as [[stimulant psychosis]], [[paranoia]], and [[suicidal ideation]]. Acute toxicity has been reportedly associated with homicide, paranoia, aggressive behavior, motor dysfunction, and [[punding]]. The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia.<ref>{{cite journal|last1=Morton|first1=W. Alexander|last2=Stockton|first2=Gwendolyn G.|title=Methylphenidate Abuse and Psychiatric Side Effects|journal=Primary Care Companion to the Journal of Clinical Psychiatry|date=8 January 2017|volume=2|issue=5|pages=159–164|pmc=181133|issn=1523-5998|pmid=15014637|doi=10.4088/PCC.v02n0502}}</ref> Most drugs classified as stimulants are sympathomimetics, that is they stimulate the sympathetic branch of the autonomic nervous system. This leads to effects such as [[mydriasis]], increased heart rate, blood pressure, respiratory rate and body temperature.<ref name=NBK64328/> When these changes become pathological, they are called [[Heart arrhythmia|arrhythmia]], [[hypertension]], and [[hyperthermia]], and may lead to [[rhabdomyolysis]], [[stroke]], [[cardiac arrest]], or [[seizures]]. However, given the complexity of the mechanisms that underlie these potentially fatal outcomes of acute stimulant toxicity, it is impossible to determine what dose may be lethal.<ref>{{cite book|title=Treatment for Stimulant Use Disorders.Chapter 5—Medical Aspects of Stimulant Use Disorders|chapter=Chapter 5—Medical Aspects of Stimulant Use Disorders |publisher=Center for Substance Abuse Treatment. Treatment for Stimulant Use Disorders. Rockville (MD): Substance Abuse and Mental Health Services Administration (US)|url=https://www.ncbi.nlm.nih.gov/books/NBK64323/|language=en|url-status=live|archive-url=https://web.archive.org/web/20170219043032/https://www.ncbi.nlm.nih.gov/books/NBK64323/|archive-date=19 February 2017|df=dmy-all|year=1999}}</ref> ===Chronic=== Assessment of the effects of stimulants is relevant given the large population currently taking stimulants. A systematic review of cardiovascular effects of prescription stimulants found no association in children, but found a correlation between prescription stimulant use and [[ischemic]] [[heart attack]]s.<ref>{{cite journal|last1=Westover|first1=Arthur N.|last2=Halm|first2=Ethan A.|title=Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review|journal=BMC Cardiovascular Disorders|date=9 June 2012|volume=12|issue=1 |pages=41|doi=10.1186/1471-2261-12-41|pmid=22682429|issn=1471-2261|pmc=3405448 |doi-access=free }}</ref> A review over a four-year period found that there were few negative effects of stimulant treatment, but stressed the need for longer-term studies.<ref>{{cite journal|last1=Fredriksen|first1=Mats|last2=Halmøy|first2=Anne|last3=Faraone|first3=Stephen V.|last4=Haavik|first4=Jan|title=Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies|journal=European Neuropsychopharmacology|date=1 June 2013|volume=23|issue=6|pages=508–527|doi=10.1016/j.euroneuro.2012.07.016|pmid=22917983|issn=1873-7862|hdl=10852/40257|s2cid=20400392|doi-access=free|hdl-access=free}}</ref> A review of a year long period of prescription stimulant use in those with [[Attention deficit hyperactivity disorder|ADHD]] found that cardiovascular side effects were limited to transient increases in blood pressure only.<ref>{{cite journal|last1=Hammerness|first1=Paul G.|last2=Karampahtsis|first2=Chris|last3=Babalola|first3=Ronke|last4=Alexander|first4=Mark E.|title=Attention-deficit/hyperactivity disorder treatment: what are the long-term cardiovascular risks?|journal=Expert Opinion on Drug Safety|date=1 April 2015|volume=14|issue=4|pages=543–551|doi=10.1517/14740338.2015.1011620|pmid=25648243|s2cid=39425997|issn=1744-764X}}</ref> Initiation of stimulant treatment in those with ADHD in early childhood appears to carry benefits into adulthood with regard to social and cognitive functioning, and appears to be relatively safe.<ref>{{cite journal|last1=Hechtman|first1=Lily|last2=Greenfield|first2=Brian|title=Long-term use of stimulants in children with attention deficit hyperactivity disorder: safety, efficacy, and long-term outcome|journal=Paediatric Drugs|date=1 January 2003|volume=5|issue=12|pages=787–794|pmid=14658920|issn=1174-5878|doi=10.2165/00148581-200305120-00002|s2cid=68191253}}</ref> Abuse of prescription stimulants (not following physician instruction) or of illicit stimulants carries many negative health risks. Abuse of cocaine, depending upon route of administration, increases risk of cardiorespiratory disease, [[stroke]], and [[sepsis]].<ref name=Sor2014>{{cite journal|last1=Sordo|first1=L|last2=Indave|first2=BI|last3=Barrio|first3=G|last4=Degenhardt|first4=L|last5=de la Fuente|first5=L|last6=Bravo|first6=MJ|title=Cocaine use and risk of stroke: a systematic review.|journal=Drug and Alcohol Dependence|date=1 September 2014|volume=142|pages=1–13|pmid=25066468|doi=10.1016/j.drugalcdep.2014.06.041|doi-access=free}}</ref> Some effects are dependent upon the route of administration, with intravenous use associated with the transmission of many disease such as [[Hepatitis C]], [[HIV/AIDS]] and potential medical emergencies such as [[infection]], [[thrombosis]] or [[pseudoaneurysm]],<ref>{{cite journal|last=COUGHLIN|first=P|author2=MAVOR, A|title=Arterial Consequences of Recreational Drug Use|journal=European Journal of Vascular and Endovascular Surgery|date=1 October 2006|volume=32|issue=4|pages=389–396|doi=10.1016/j.ejvs.2006.03.003|pmid=16682239|doi-access=free}}</ref> while inhalation may be associated with increased [[lower respiratory tract infection]], [[lung cancer]], and pathological restricting of lung tissue.<ref>{{cite journal|last1=Tashkin|first1=D. P.|title=Airway effects of marijuana, cocaine, and other inhaled illicit agents|journal=Current Opinion in Pulmonary Medicine|date=1 March 2001|volume=7|issue=2|pages=43–61|pmid=11224724|issn=1070-5287|doi=10.1097/00063198-200103000-00001|s2cid=23421796}}</ref> Cocaine may also increase risk for autoimmune disease<ref>{{cite journal|vauthors=Trozak D, Gould W |title = Cocaine abuse and connective tissue disease|journal = J Am Acad Dermatol|volume = 10|issue = 3|page = 525|year = 1984|pmid = 6725666|doi = 10.1016/S0190-9622(84)80112-7|doi-access = free}}</ref><ref>{{cite journal|title=Antiglomerular Basement Membrane Antibody-Mediated Glomerulonephritis after Intranasal Cocaine Use|author=Ramón Peces|journal=Nephron|year=1999|volume=81|issue=4|pages=434–438|pmid=10095180|doi=10.1159/000045328|last2=Navascués|first2=RA|last3=Baltar|first3=J|last4=Seco|first4=M|last5=Alvarez|first5=J|s2cid=26921706}}</ref><ref>{{cite journal |vauthors=Moore PM, Richardson B |title=Neurology of the vasculitides and connective tissue diseases |journal=J. Neurol. Neurosurg. Psychiatry |volume=65 |issue=1 |pages=10–22 |year=1998|pmid=9667555 |pmc=2170162|doi=10.1136/jnnp.65.1.10}}</ref> and damage nasal cartilage. Abuse of methamphetamine produces similar effects as well as marked degeneration of dopaminergic neurons, resulting in an increased risk for [[Parkinson's disease]].<ref name="pmid22392347">{{cite journal |vauthors=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L |title=Toxicity of amphetamines: an update |journal=Arch. Toxicol. |volume=86 |issue=8 |pages=1167–1231 |date=August 2012 |pmid=22392347 |doi=10.1007/s00204-012-0815-5 |s2cid=2873101 }}</ref><ref name="Thrash-">{{cite journal | vauthors = Thrash B, Thiruchelvan K, Ahuja M, Suppiramaniam V, Dhanasekaran M | title = Methamphetamine-induced neurotoxicity: the road to Parkinson's disease | journal = Pharmacol Rep | volume = 61 | issue = 6 | pages = 966–977 | year = 2009 | pmid = 20081231 | doi = 10.1016/s1734-1140(09)70158-6 | s2cid = 4729728 | url = http://www.if-pan.krakow.pl/pjp/pdf/2009/6_966.pdf | url-status = live | archive-url = https://web.archive.org/web/20110716111421/http://www.if-pan.krakow.pl/pjp/pdf/2009/6_966.pdf | archive-date = 16 July 2011 | df = dmy-all }}</ref><ref name="Autoxidation1">{{cite journal |vauthors=Sulzer D, Zecca L | title = Intraneuronal dopamine-quinone synthesis: a review | journal = Neurotox. Res. | volume = 1 | issue = 3 | pages = 181–195 |date=February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289 | 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 Med. Okayama | volume = 62 | issue = 3 | pages = 141–150 |date=June 2008 | pmid = 18596830 | doi = 10.18926/AMO/30942}}</ref> == Medical uses == Stimulants have been used in medicine for many conditions including [[obesity]], [[sleep disorders]], [[mood disorders]], [[impulse control disorders]], [[asthma]], [[nasal congestion]] and, in case of cocaine, as [[local anesthetic]]s.<ref>{{cite journal|last1=Harper|first1=S. J.|last2=Jones|first2=N. S.|title=Cocaine: what role does it have in current ENT practice? A review of the current literature|journal=The Journal of Laryngology and Otology|date=1 October 2006|volume=120|issue=10|pages=808–811|doi=10.1017/S0022215106001459|pmid=16848922|s2cid=28169472|issn=1748-5460}}</ref> Drugs used to treat obesity are called [[anorectic]]s and generally include drugs that follow the general definition of a stimulant, but other drugs such as [[cannabinoid receptor antagonist]]s also belong to this group.<ref>{{cite journal|last1=Kaplan|first1=Lee M.|title=Pharmacological therapies for obesity|journal=Gastroenterology Clinics of North America|date=1 March 2005|volume=34|issue=1|pages=91–104|doi=10.1016/j.gtc.2004.12.002|pmid=15823441|issn=0889-8553}}</ref><ref>{{cite journal|last1=Palamara|first1=Kerri L.|last2=Mogul|first2=Harriette R.|last3=Peterson|first3=Stephen J.|last4=Frishman|first4=William H.|title=Obesity: new perspectives and pharmacotherapies|journal=Cardiology in Review|date=1 October 2016|volume=14|issue=5|pages=238–258|doi=10.1097/01.crd.0000233903.57946.fd|pmid=16924165|issn=1538-4683}}</ref> [[Eugeroic]]s are used in management of sleep disorders characterized by [[excessive daytime sleepiness]], such as [[narcolepsy]], and include stimulants such as [[modafinil]].<ref>{{cite web|title=The Voice of the Patient A series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative|url=https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|publisher=Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)|url-status=live|archive-url=https://web.archive.org/web/20170505031213/https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|archive-date=5 May 2017|df=dmy-all}}</ref><ref>{{cite journal|last1=Heal|first1=David J|last2=Smith|first2=Sharon L|last3=Gosden|first3=Jane|last4=Nutt|first4=David J|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=Journal of Psychopharmacology |date=7 January 2017|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|issn=0269-8811|pmid=23539642}}</ref> Stimulants are used in impulse control disorders such as [[ADHD]]<ref>{{cite web|last1=Research|first1=Center for Drug Evaluation and|title=Drug Safety and Availability - FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults|url=https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|website=www.fda.gov|language=en|url-status=live|archive-url=https://web.archive.org/web/20131030064843/https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|archive-date=30 October 2013|df=dmy-all|date=26 June 2019}}</ref> and [[off-label use|off-label]] in [[mood disorder]]s such as [[major depressive disorder]] to increase [[mental energy|energy]], focus and elevate mood.<ref>{{cite journal|last1=Stotz|first1=Gabriele|last2=Woggon|first2=Brigitte|last3=Angst|first3=Jules|title=Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients|journal=Dialogues in Clinical Neuroscience|date=1 December 1999|volume=1|issue=3|pages=165–174|doi=10.31887/DCNS.1999.1.3/gstotz |pmc=3181580|issn=1294-8322|pmid=22034135}}</ref> Stimulants such as [[epinephrine]],<ref name="pmid18733372">{{cite journal |author = Doig RL | title = Epinephrin; especially in asthma | journal = California State Journal of Medicine | volume = 3 | issue = 2 | pages = 54–5 |date=February 1905 | pmid = 18733372 | pmc = 1650334 }}</ref> [[theophylline]] and [[salbutamol]]<ref>{{cite journal|last1=Chu|first1=Eric K.|last2=Drazen|first2=Jeffrey M.|title=Asthma|journal=American Journal of Respiratory and Critical Care Medicine|date=1 June 2005|volume=171|issue=11|pages=1202–1208|doi=10.1164/rccm.200502-257OE|pmid=15778490|issn=1073-449X}}</ref> orally have been used to treat asthma, but inhaled adrenergic drugs are now preferred due to less systemic side effects. [[Pseudoephedrine]] is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection.<ref name="Bicopoulos">Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.</ref><ref>{{cite web|title=Pseudoephedrine (By mouth) – National Library of Medicine|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|website=PubMed Health|url-status=live|archive-url=https://web.archive.org/web/20140214034938/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|archive-date=14 February 2014|df=dmy-all}}</ref> ===Depression=== Stimulants were one of the first classes of drugs to be used in the treatment of depression, beginning after the introduction of the amphetamines in the 1930s.<ref name="pmid18321627">{{cite journal | vauthors = Moncrieff J | title = The creation of the concept of an antidepressant: an historical analysis | journal = Soc Sci Med | volume = 66 | issue = 11 | pages = 2346–55 | date = June 2008 | pmid = 18321627 | doi = 10.1016/j.socscimed.2008.01.047 | url = }}</ref><ref name="Moncrieff2016">{{cite book | author = J. Moncrieff | date = 13 April 2016 | title = The Myth of the Chemical Cure: A Critique of Psychiatric Drug Treatment | publisher = Springer | pages = 121– | isbn = 978-0-230-58944-5 | oclc = 1047624331 | url = https://books.google.com/books?id=2tD7CwAAQBAJ&pg=PA121 | quote = A well-known textbook of physical treatments described stimulants as having 'limited value in depression' because the euphoria they induce quickly wears off and 'the patient slips back' (Sargant & Slater 1944).}}</ref><ref name="pmid34000249">{{cite journal | vauthors = Morelli M, Tognotti E | title = Brief history of the medical and non-medical use of amphetamine-like psychostimulants | journal = Exp Neurol | volume = 342 | issue = | pages = 113754 | date = August 2021 | pmid = 34000249 | doi = 10.1016/j.expneurol.2021.113754 | s2cid = 234768496 | url = }}</ref> However, they were largely abandoned for treatment of depression following the introduction of conventional [[antidepressant]]s in the 1950s.<ref name="pmid18321627"/><ref name="Moncrieff2016"/> Subsequent to this, there has been a resurgence in interest in stimulants for depression in recent years.<ref name="pmid26906078">{{cite journal | vauthors = Malhi GS, Byrow Y, Bassett D, Boyce P, Hopwood M, Lyndon W, Mulder R, Porter R, Singh A, Murray G | title = Stimulants for depression: On the up and up? | journal = Aust N Z J Psychiatry | volume = 50 | issue = 3 | pages = 203–7 | date = March 2016 | pmid = 26906078 | doi = 10.1177/0004867416634208 | s2cid = 45341424 | url = }}</ref><ref name="pmid17338594">{{cite journal | vauthors = Orr K, Taylor D | title = Psychostimulants in the treatment of depression : a review of the evidence | journal = CNS Drugs | volume = 21 | issue = 3 | pages = 239–57 | date = 2007 | pmid = 17338594 | doi = 10.2165/00023210-200721030-00004 | s2cid = 35761979 | url = }}</ref> Stimulants produce a fast-acting and pronounced but transient and short-lived mood lift.<ref name="pmid36009115">{{cite journal | vauthors = Pallikaras V, Shizgal P | title = Dopamine and Beyond: Implications of Psychophysical Studies of Intracranial Self-Stimulation for the Treatment of Depression | journal = Brain Sci | volume = 12 | issue = 8 | date = August 2022 | page = 1052 | pmid = 36009115 | doi = 10.3390/brainsci12081052 | pmc = 9406029 | url = | doi-access = free }}</ref><ref name="pmid35431828">{{cite journal | vauthors = Pallikaras V, Shizgal P | title = The Convergence Model of Brain Reward Circuitry: Implications for Relief of Treatment-Resistant Depression by Deep-Brain Stimulation of the Medial Forebrain Bundle | journal = Front Behav Neurosci | volume = 16 | issue = | pages = 851067 | date = 2022 | pmid = 35431828 | pmc = 9011331 | doi = 10.3389/fnbeh.2022.851067 | url = | doi-access = free }}</ref><ref name="pmid26906078" /><ref name="Moncrieff2016" /> In relation to this, they are minimally effective in the treatment of depression when administered continuously.<ref name="pmid36009115" /><ref name="pmid35431828" /> In addition, tolerance to the mood-lifting effects of amphetamine has led to dose escalation and [[drug dependence|dependence]].<ref name="pmid17338594"/> Although the efficacy for depression with continuous administration is modest, it may still reach [[statistical significance]] over [[placebo]] and provide benefits similar in magnitude to those of conventional antidepressants.<ref name="pmid29028590">{{cite journal | vauthors = Giacobbe P, Rakita U, Lam R, Milev R, Kennedy SH, McIntyre RS | title = Efficacy and tolerability of lisdexamfetamine as an antidepressant augmentation strategy: A meta-analysis of randomized controlled trials | journal = J Affect Disord | volume = 226 | issue = | pages = 294–300 | date = January 2018 | pmid = 29028590 | doi = 10.1016/j.jad.2017.09.041 | url = }}</ref><ref name="pmid28590365">{{cite journal | vauthors = McIntyre RS, Lee Y, Zhou AJ, Rosenblat JD, Peters EM, Lam RW, Kennedy SH, Rong C, Jerrell JM | title = The Efficacy of Psychostimulants in Major Depressive Episodes: A Systematic Review and Meta-Analysis | journal = J Clin Psychopharmacol | volume = 37 | issue = 4 | pages = 412–418 | date = August 2017 | pmid = 28590365 | doi = 10.1097/JCP.0000000000000723 | s2cid = 27622964 | url = }}</ref><ref name="pmid34144366">{{cite journal | vauthors = Bahji A, Mesbah-Oskui L | title = Comparative efficacy and safety of stimulant-type medications for depression: A systematic review and network meta-analysis | journal = J Affect Disord | volume = 292 | issue = | pages = 416–423 | date = September 2021 | pmid = 34144366 | doi = 10.1016/j.jad.2021.05.119 | url = }}</ref><ref name="pmid34986373">{{cite journal | vauthors = Nuñez NA, Joseph B, Pahwa M, Kumar R, Resendez MG, Prokop LJ, Veldic M, Seshadri A, Biernacka JM, Frye MA, Wang Z, Singh B | title = Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis | journal = J Affect Disord | volume = 302 | issue = | pages = 385–400 | date = April 2022 | pmid = 34986373 | pmc = 9328668 | doi = 10.1016/j.jad.2021.12.134 | url = }}</ref> The reasons for the short-term mood-improving effects of stimulants are unclear, but may relate to rapid [[drug tolerance|tolerance]].<ref name="pmid36009115" /><ref name="pmid35431828" /><ref name="Moncrieff2016" /><ref name="pmid15893821" /> Tolerance to the effects of stimulants has been studied and characterized both in animals<ref name="pmid15893821" /><ref name="pmid30768951">{{cite journal | vauthors = Folgering JH, Choi M, Schlumbohm C, van Gaalen MM, Stratford RE | title = Development of a non-human primate model to support CNS translational research: Demonstration with D-amphetamine exposure and dopamine response | journal = J Neurosci Methods | volume = 317 | issue = | pages = 71–81 | date = April 2019 | pmid = 30768951 | doi = 10.1016/j.jneumeth.2019.02.005 | s2cid = 72333922 | url = | doi-access = free }}</ref><ref name="pmid30733244">{{cite journal | vauthors = van Gaalen MM, Schlumbohm C, Folgering JH, Adhikari S, Bhattacharya C, Steinbach D, Stratford RE | title = Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine | journal = J Pharmacol Exp Ther | volume = 369 | issue = 1 | pages = 107–120 | date = April 2019 | pmid = 30733244 | doi = 10.1124/jpet.118.254508 | s2cid = 73441294 | url = | doi-access = free }}</ref><ref name="vanGaalenSchlumbohm2019">{{cite journal | last1=van Gaalen | first1=Marcel M. | last2=Schlumbohm | first2=Christina | last3=Folgering | first3=Joost H. | last4=Adhikari | first4=Saugat | last5=Bhattacharya | first5=Chandrali | last6=Steinbach | first6=Douglas | last7=Stratford | first7=Robert E. | title=Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine | journal=Journal of Pharmacology and Experimental Therapeutics | publisher=American Society for Pharmacology & Experimental Therapeutics (ASPET) | volume=369 | issue=1 | date=7 February 2019 | issn=0022-3565 | doi=10.1124/jpet.118.254508 | pages=107–120| pmid=30733244 | s2cid=73441294 | doi-access=free }}</ref> and humans.<ref name="pmid27021968">{{cite journal | vauthors = Ermer JC, Pennick M, Frick G | title = Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy | journal = Clin Drug Investig | volume = 36 | issue = 5 | pages = 341–56 | date = May 2016 | pmid = 27021968 | pmc = 4823324 | doi = 10.1007/s40261-015-0354-y | url = }}</ref><ref name="pmid28936175">{{cite journal | vauthors = Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME | title = Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects | journal = Front Pharmacol | volume = 8 | issue = | pages = 617 | date = 2017 | pmid = 28936175 | pmc = 5594082 | doi = 10.3389/fphar.2017.00617 | url = | doi-access = free }}</ref><ref name="pmid8834422">{{cite journal | vauthors = Brauer LH, Ambre J, De Wit H | title = Acute tolerance to subjective but not cardiovascular effects of d-amphetamine in normal, healthy men | journal = J Clin Psychopharmacol | volume = 16 | issue = 1 | pages = 72–6 | date = February 1996 | pmid = 8834422 | doi = 10.1097/00004714-199602000-00012 | url = }}</ref><ref name="pmid11441429">{{cite journal | vauthors = Comer SD, Hart CL, Ward AS, Haney M, Foltin RW, Fischman MW | title = Effects of repeated oral methamphetamine administration in humans | journal = Psychopharmacology (Berl) | volume = 155 | issue = 4 | pages = 397–404 | date = June 2001 | pmid = 11441429 | doi = 10.1007/s002130100727 | s2cid = 19103494 | url = }}</ref> Stimulant [[drug withdrawal|withdrawal]] is remarkably similar in its symptoms to those of major depressive disorder.<ref name="pmid12368072">{{cite journal | vauthors = Barr AM, Markou A, Phillips AG | title = A 'crash' course on psychostimulant withdrawal as a model of depression | journal = Trends Pharmacol Sci | volume = 23 | issue = 10 | pages = 475–82 | date = October 2002 | pmid = 12368072 | doi = 10.1016/s0165-6147(02)02086-2 | url = }}</ref><ref name="pmid15893821">{{cite journal | vauthors = Barr AM, Markou A | title = Psychostimulant withdrawal as an inducing condition in animal models of depression | journal = Neurosci Biobehav Rev | volume = 29 | issue = 4–5 | pages = 675–706 | date = 2005 | pmid = 15893821 | doi = 10.1016/j.neubiorev.2005.03.012 | s2cid = 23653608 | url = }}</ref><ref name="pmid21161752">{{cite journal | vauthors = D'Souza MS, Markou A | title = Neural substrates of psychostimulant withdrawal-induced anhedonia | journal = Curr Top Behav Neurosci | series = Current Topics in Behavioral Neurosciences | volume = 3 | issue = | pages = 119–78 | date = 2010 | location = Berlin, Heidelberg | pmid = 21161752 | doi = 10.1007/7854_2009_20 | isbn = 978-3-642-03000-0 | url = }}</ref><ref name="pmid16140055">{{cite journal | vauthors = Baicy K, Bearden CE, Monterosso J, Brody AL, Isaacson AJ, London ED | title = Common substrates of dysphoria in stimulant drug abuse and primary depression: therapeutic targets | journal = Int Rev Neurobiol | series = International Review of Neurobiology | volume = 65 | issue = | pages = 117–45 | date = 2005 | pmid = 16140055 | doi = 10.1016/S0074-7742(04)65005-7 | isbn = 9780123668660 | url = }}</ref> == Chemistry == {{For|details on stimulant classes|Substituted phenethylamine|Substituted amphetamine|Substituted phenylmorpholine|Substituted cathinone}} [[File:Methamphetamines.PNG|thumb|A chart comparing the chemical structures of different [[Template:Amphetamines|amphetamine derivatives]]]] Classifying stimulants is difficult, because of the large number of classes the drugs occupy, and the fact that they may belong to multiple classes; for example, [[MDMA|ecstasy]] can be classified as a [[substituted methylenedioxyphenethylamine]], a [[substituted amphetamine]] and consequently, a [[substituted phenethylamine]].{{Citation needed|reason=who says they are hard to classify?|date=January 2017}} When referring to stimulants, the parent drug (e.g., ''amphetamine'') will always be expressed in the singular{{According to whom|date=January 2017}}; with the word "substituted" placed before the parent drug ([[substituted amphetamine|''substituted amphetamines'']]).<!--Referring to the class as "amphetamines" is an abuse of language. Racemic, levo-, and dextro-amphetamine are "amphetamines"; methamphetamine and the like are substituted amphetamines or "amphetamine-type" compounds.--> Major stimulant classes include [[substituted phenethylamine|phenethylamines]] and their daughter class [[substituted amphetamines]].{{According to whom|date=January 2017}} === Amphetamines (class) === {{Main|Substituted amphetamines}} [[Substituted amphetamines]] are a [[chemical class|class of compounds]] based upon the [[amphetamine]] structure;<ref name="Amphetamine - a substituted amphetamine" /> it includes all [[derivative (chemistry)|derivative]] compounds which are formed by replacing, or [[substitution reaction|substituting]], one or more [[hydrogen atom]]s in the amphetamine core structure with [[substituent]]s.<ref name="Amphetamine - a substituted amphetamine">{{cite journal | vauthors = Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ | title = Biosynthesis of amphetamine analogs in plants | journal = Trends Plant Sci. | volume = 17 | issue = 7 | pages = 404–412 | date = 2012 | pmid = 22502775 | doi = 10.1016/j.tplants.2012.03.004 | quote = Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). Countless variation in functional group substitutions has yielded a collection of synthetic drugs with diverse pharmacological properties as stimulants, empathogens and hallucinogens [3].&nbsp;... Beyond (1''R'',2''S'')-ephedrine and (1''S'',2''S'')-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. The stereochemistry at the α-carbon is often a key determinant of pharmacological activity, with (''S'')-enantiomers being more potent. For example, (''S'')-amphetamine, commonly known as d-amphetamine or dextroamphetamine, displays five times greater psychostimulant activity compared with its (''R'')-isomer [78]. Most such molecules are produced exclusively through chemical syntheses and many are prescribed widely in modern medicine. For example, (''S'')-amphetamine (Figure 4b), a key ingredient in Adderall and Dexedrine, is used to treat attention deficit hyperactivity disorder (ADHD) [79].&nbsp;... <br />[Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.}}</ref><ref name="Substituted amphetamines">{{cite book | author = Glennon RA |veditors=Lemke TL, Williams DA, Roche VF, Zito W | title=Foye's principles of medicinal chemistry | date=2013 | publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins | location=Philadelphia, USA | isbn=9781609133450 | pages=646–648 | edition=7th | section-url=https://books.google.com/books?id=Sd6ot9ul-bUC&q=substituted%20derivatives%20substituents%20amphetamine%20substitution&pg=PA646 | section=Phenylisopropylamine stimulants: amphetamine-related agents | quote = The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39).}}</ref><ref name="pmid1855720">{{cite journal | vauthors = Lillsunde P, Korte T | title = Determination of ring- and N-substituted amphetamines as heptafluorobutyryl derivatives | journal = Forensic Sci. Int. | volume = 49 | issue = 2 | pages = 205–213 | date = March 1991 | pmid = 1855720 | doi=10.1016/0379-0738(91)90081-s}}</ref> Examples of substituted amphetamines are amphetamine (itself),<ref name="Amphetamine - a substituted amphetamine" /><ref name="Substituted amphetamines" /> [[methamphetamine]],<ref name="Amphetamine - a substituted amphetamine" /> [[ephedrine]],<ref name="Amphetamine - a substituted amphetamine" /> [[cathinone]],<ref name="Amphetamine - a substituted amphetamine" /> [[phentermine]],<ref name="Amphetamine - a substituted amphetamine" /> [[mephentermine]],<ref name="Amphetamine - a substituted amphetamine" /> [[bupropion]],<ref name="Amphetamine - a substituted amphetamine" /> [[methoxyphenamine]],<ref name="Amphetamine - a substituted amphetamine" /> [[selegiline]],<ref name="Amphetamine - a substituted amphetamine" /> [[amfepramone]],<ref name="Amphetamine - a substituted amphetamine" /> [[pyrovalerone]],<ref name="Amphetamine - a substituted amphetamine" /> [[MDMA]] (ecstasy), and [[2,5-dimethoxy-4-methylamphetamine|DOM]] (STP). Many drugs in this class work primarily by activating [[trace amine-associated receptor 1]] (TAAR1);<ref name="Miller" /> in turn, this causes [[reuptake inhibition]] and effluxion, or release, of [[dopamine]], [[norepinephrine]], and [[serotonin]].<ref name="Miller" /> An additional mechanism of some substituted amphetamines is the release of [[synaptic vesicle|vesicular stores]] of [[monoamine neurotransmitter]]s through [[VMAT2]], thereby increasing the concentration of these neurotransmitters in the [[cytosol]], or intracellular fluid, of the [[presynaptic neuron]].<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> Amphetamines-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treat [[major depression]], where subjects do not respond well to traditional [[selective serotonin reuptake inhibitor|SSRI]] medications,{{Citation needed|date=May 2015}} but evidence supporting this use is poor/mixed.<ref>{{cite journal |vauthors=Orr K, Taylor D | title = Psychostimulants in the Treatment of Depression | journal = CNS Drugs | volume = 21 | issue = 3 | pages = 239–57 | year = 2007 | pmid = 17338594 | doi = 10.2165/00023210-200721030-00004 | s2cid = 35761979 }}</ref> Notably, two recent large [[Phase III clinical trials|phase III]] studies of [[lisdexamfetamine]] (a [[prodrug]] to amphetamine) as an adjunct to an SSRI or SNRI in the treatment of [[major depressive disorder]] showed no further benefit relative to [[placebo]] in effectiveness.<ref name="DaleBang-Andersen2015">{{cite journal|last1=Dale|first1=Elena|last2=Bang-Andersen|first2=Benny|last3=Sánchez|first3=Connie|title=Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs|journal=Biochemical Pharmacology|volume=95|issue=2|year=2015|pages=81–97|issn=0006-2952|doi=10.1016/j.bcp.2015.03.011|pmid=25813654|doi-access=free}}</ref> Numerous studies have demonstrated the effectiveness of drugs such as [[Adderall]] (a mixture of [[salt (chemistry)|salts]] of [[amphetamine]] and [[dextroamphetamine]]) in controlling symptoms associated with [[ADHD]]. Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse.<ref>[http://www.drugabuse.gov/Testimony/7-26-06Testimony.html Efforts of the National Institute on Drug Abuse to Prevent and Treat Prescription Drug Abuse] {{webarchive|url=https://web.archive.org/web/20070929083259/http://www.drugabuse.gov/Testimony/7-26-06Testimony.html |date=29 September 2007 }}, Testimony Before the Subcommittee on Criminal Justice, Drug Policy, and Human Resources Committee on Government Reform, United States House of Representatives, 26 July 2006</ref> ===Cocaine analogues=== {{Main|List of cocaine analogues}} Hundreds of cocaine analogues have been created, all of them usually maintaining a benzyloxy connected to the 3 carbon of a tropane. Various modifications include substitutions on the benzene ring, as well as additions or substitutions in place of the normal carboxylate on the tropane 2 carbon. Various compound with similar structure activity relationships to cocaine that aren't technically analogues have been developed as well. ==Mechanisms of action== Most stimulants exert their activating effects by enhancing [[catecholamine]] neurotransmission. Catecholamine neurotransmitters are employed in regulatory pathways implicated in attention, arousal, motivation, task salience and reward anticipation. Classical stimulants either [[Monoamine reuptake inhibitor|block the reuptake]] or [[Monoamine releasing agent|stimulate the efflux]] of these catecholamines, resulting in increased activity of their circuits. Some stimulants, specifically those with [[empathogen]]ic and [[hallucinogen]]ic effects, also affect [[Serotonin|serotonergic]] transmission. Some stimulants, such as some amphetamine derivatives and, notably, [[yohimbine]], can decrease [[negative feedback]] by antagonizing regulatory autoreceptors.<ref>{{cite journal|last1=Docherty|first1=J R|title=Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)|journal=British Journal of Pharmacology|date=7 January 2017|volume=154|issue=3|pages=606–622|doi=10.1038/bjp.2008.124|pmc=2439527|issn=0007-1188|pmid=18500382}}</ref> [[Adrenergic agonist]]s, such as, in part, [[ephedrine]], act by directly binding to and activating [[adrenergic receptor]]s, producing sympathomimetic effects. There are also more indirect mechanisms a drug can elicit activating effects. Caffeine is an [[adenosine receptor antagonist]], and only indirectly increases catecholamine transmission in the brain.<ref>{{cite book|title=Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations.|publisher=National Academies Press (US)|location=Washington (DC)|url=https://www.ncbi.nlm.nih.gov/books/NBK223808/|language=en|url-status=live|archive-url=https://web.archive.org/web/20171009140913/https://www.ncbi.nlm.nih.gov/books/NBK223808/|archive-date=9 October 2017|df=dmy-all|year=2001}}</ref> [[Pitolisant]] is an [[H3 receptor antagonist|H3-receptor inverse agonist]]. As H3 receptors mainly act as autoreceptors, pitolisant decreases negative feedback to [[histamine]]rgic neurons, enhancing histaminergic transmission. == Notable stimulants == === Amphetamine === {{Main|Amphetamine}} Amphetamine is a potent [[central nervous system]] (CNS) stimulant of the [[substituted phenethylamine|phenethylamine class]] that is approved for the treatment of [[attention deficit hyperactivity disorder]] (ADHD) and [[narcolepsy]].<ref name="FDA Abuse & OD">{{cite web |title=Adderall XR Prescribing Information |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s024lbl.pdf |page=11 |work=United States Food and Drug Administration |date=June 2013 |access-date=7 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20141006101218/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s024lbl.pdf |archive-date=6 October 2014 |df=dmy-all }}</ref> Amphetamine is also used off-label as a [[performance enhancer|performance]] and [[Nootropic|cognitive enhancer]], and recreationally as an [[aphrodisiac]] and [[euphoriant]].<ref name="Ergogenics" /><ref name="Malenka_2009">{{cite book|vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |year=2009 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-148127-4 |page=318 |edition=2nd |chapter=Chapter 13: Higher Cognitive Function and Behavioral Control |quote=Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in individuals with ADHD and in normal subjects...it is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control, as will be discussed below. It is important to recognize, however, that stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks...through indirect stimulation of dopamine and norepinephrine receptors.}}</ref><ref name="Libido">{{cite journal|author=Montgomery KA |title=Sexual desire disorders |journal=Psychiatry |volume=5 |issue=6 |pages=50–55 |date=June 2008 |pmid=19727285 |pmc=2695750 }}</ref><ref name="Nonmedical">{{cite journal|vauthors=Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S |title=Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature |journal=J. Am. Acad. Child Adolesc. Psychiatry |volume=47 |issue=1 |pages=21–31 |date=January 2008 |pmid=18174822 |doi=10.1097/chi.0b013e31815a56f1 |quote=Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile)...<br /><br />Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.}}</ref> Although it is a prescription medication in many countries, unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use.<ref name="UN Convention">{{cite web |title=Convention on psychotropic substances |url=http://treaties.un.org/Pages/ViewDetails.aspx?src=TREATY&mtdsg_no=VI-16&chapter=6&lang=en |work=United Nations Treaty Collection |publisher=United Nations |access-date=7 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20160331074842/https://treaties.un.org/pages/ViewDetails.aspx?src=TREATY&mtdsg_no=VI-16&chapter=6&lang=en |archive-date=31 March 2016 |df=dmy-all }}</ref><ref name="drugpolicy">{{cite web |title=Methamphetamine facts |url=http://www.drugpolicy.org/drug-facts/methamphetamine-facts |work=DrugPolicy.org |access-date=7 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20180417185214/https://www.drugpolicy.org/drug-facts/methamphetamine-facts |archive-date=17 April 2018 |df=dmy-all }}</ref> As a consequence, amphetamine is illegally manufactured in [[clandestine chemistry|clandestine labs]] to be trafficked and sold to users.<ref name="World Drug Report" /> Based upon drug and [[drug precursor]] seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of [[methamphetamine]].<ref name="World Drug Report">{{cite web |vauthors=Chawla S, Le Pichon T |title=World Drug Report 2006 |year=2006 |pages=128–135 |work=United Nations Office on Drugs and Crime |url=http://www.unodc.org/pdf/WDR_2006/wdr2006_volume1.pdf |access-date=7 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20130530231143/http://www.unodc.org/pdf/WDR_2006/wdr2006_volume1.pdf |archive-date=30 May 2013 |df=dmy-all }}</ref> The first pharmaceutical amphetamine was [[Benzedrine]], a brand of inhalers used to treat a variety of conditions.<ref name="Amph Uses">{{cite journal|vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ|date=June 2013|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=J. Psychopharmacol.|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|pmid=23539642}}</ref><ref name="Benzedrine">{{cite journal|author=Rasmussen N |title=Making the first anti-depressant: amphetamine in American medicine, 1929–1950 |journal=J. Hist. Med. Allied Sci. |volume=61 |issue=3 |pages=288–323 |date=July 2006 |pmid=16492800 |doi=10.1093/jhmas/jrj039|s2cid=24974454 }}</ref> Because the dextrorotary isomer has greater stimulant properties, Benzedrine was gradually discontinued in favor of formulations containing all or mostly dextroamphetamine. Presently, it is typically prescribed as [[Adderall|mixed amphetamine salts]], [[dextroamphetamine]], and [[lisdexamfetamine]].<ref name="Amph Uses" /><ref name="Adderall IR">{{cite web |title=Adderall IR Prescribing Information |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf |work=United States Food and Drug Administration |date=March 2007 |access-date=2 November 2013 |page=5 |url-status=live |archive-url=https://web.archive.org/web/20130926063018/http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf |archive-date=26 September 2013 |df=dmy-all }}</ref> Amphetamine is a [[Norepinephrine–dopamine releasing agent|norepinephrine-dopamine releasing agent]] (NDRA). It enters neurons through [[Dopamine transporter|dopamine]] and [[norepinephrine transporter]]s and facilitates neurotransmitter efflux by activating [[TAAR1]] and inhibiting [[Vesicular monoamine transporter 2|VMAT2]].<ref name="Miller">{{cite journal|author=Miller GM |title=The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity |journal=J. Neurochem. |volume=116 |issue=2 |pages=164–176 |date=January 2011 |pmid=21073468 |pmc=3005101 |doi=10.1111/j.1471-4159.2010.07109.x}}</ref> At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved [[cognitive control]].<ref name="Malenka_2009" /><ref name="Libido" /><ref name="FDA Effects">{{cite web |title=Adderall XR Prescribing Information |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s024lbl.pdf |pages=4–8 |work=United States Food and Drug Administration |date=June 2013 |access-date=7 October 2013 |url-status=live |archive-url=https://web.archive.org/web/20141006101218/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s024lbl.pdf |archive-date=6 October 2014 |df=dmy-all }}</ref> Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.<ref name="Ergogenics">{{cite journal|vauthors=Liddle DG, Connor DJ |title=Nutritional supplements and ergogenic AIDS |journal=Prim. Care |volume=40 |issue=2 |pages=487–505 |date=June 2013 |pmid=23668655 |doi=10.1016/j.pop.2013.02.009 |quote=Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training...<br />Physiologic and performance effects<br />{{bull}}Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation<br />{{bull}}Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40<br />{{bull}}Improved reaction time<br />{{bull}}Increased muscle strength and delayed muscle fatigue<br />{{bull}}Increased acceleration<br />{{bull}}Increased alertness and attention to task}}</ref> In contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapid [[rhabdomyolysis|muscle breakdown]].<ref name="FDA Abuse & OD" /><ref name="Malenka_2009" /><ref name="Westfall">{{cite book|veditors=Brunton LL, Chabner BA, Knollmann BC |title=Goodman & Gilman's Pharmacological Basis of Therapeutics |year=2010 |publisher=McGraw-Hill |location=New York |isbn=978-0-07-162442-8 |vauthors=Westfall DP, Westfall TC |section=Miscellaneous Sympathomimetic Agonists |section-url=http://www.accessmedicine.com/content.aspx?aID=16661601 |edition=12th}}</ref> Very high doses can result in [[Stimulant psychosis#Amphetamines|psychosis]] (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use.<ref name="Cochrane">{{cite journal|vauthors=Shoptaw SJ, Kao U, Ling W |title=Treatment for amphetamine psychosis (Review) |journal=Cochrane Database of Systematic Reviews |year=2009 |volume=2009 |issue=1|doi=10.1002/14651858.CD003026.pub3 |pmid=19160215 |pmc=7004251 |pages=CD003026}}</ref><ref name="Stimulant Misuse">{{cite web |author=Greydanus D |title=Stimulant Misuse: Strategies to Manage a Growing Problem |type=Review Article |url=http://www.acha.org/prof_dev/ADHD_docs/ADHD_PDprogram_Article2.pdf |work=American College Health Association |publisher=ACHA Professional Development Program |access-date=2 November 2013 |page=20 |url-status=dead |archive-url=https://web.archive.org/web/20131103155156/http://www.acha.org/prof_dev/ADHD_docs/ADHD_PDprogram_Article2.pdf |archive-date=3 November 2013 |df=dmy-all }}</ref> As recreational doses are generally much larger than prescribed therapeutic doses, recreational use carries a far greater risk of serious side effects, such as dependence, which only rarely arises with therapeutic amphetamine use.<ref name="FDA Abuse & OD" /><ref name="Westfall" /><ref name="Cochrane" /> === Caffeine === {{Main|Caffeine}} [[File:Roasted coffee beans.jpg|180px|right|thumb|Roasted coffee beans, a common source of caffeine.]] Caffeine is a stimulant compound belonging to the [[xanthine]] class of chemicals naturally found in [[coffee]], [[tea]], and (to a lesser degree) [[Cocoa solids|cocoa]] or [[chocolate]]. It is included in many [[soft drink]]s, as well as a larger amount in [[energy drink]]s. Caffeine is the world's most widely used psychoactive drug and by far the most common stimulant. In North America, 90% of adults consume caffeine daily.<ref name="demon drink">{{cite journal |author=Lovett R |title=Coffee: The demon drink? |journal=New Scientist |issue=2518 |date=24 September 2005 |url=https://www.newscientist.com/article.ns?id=mg18725181.700 |access-date=3 August 2009 |url-status=live |archive-url=https://web.archive.org/web/20071024030810/http://www.newscientist.com/article.ns?id=mg18725181.700 |archive-date=24 October 2007 |df=dmy-all }} {{subscription required}}</ref> A few jurisdictions restrict its sale and use.{{Citation needed|date=November 2020|reason=This claim needs a reliable source; There may be a few jurisdictions that restrict its sale and use, but this needs to be verifiable.}} Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient, or reducing one of its side-effects (especially drowsiness). Tablets containing standardized doses of caffeine are also widely available. Caffeine's mechanism of action differs from many stimulants, as it produces stimulant effects by inhibiting adenosine receptors.<ref>{{cite journal|last1=Nehlig|first1=A.|last2=Daval|first2=J. L.|last3=Debry|first3=G.|title=Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects|journal=Brain Research. Brain Research Reviews|date=1 August 2016|volume=17|issue=2|pages=139–170|pmid=1356551|doi=10.1016/0165-0173(92)90012-b|s2cid=14277779}}</ref> Adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness.<ref>{{cite journal|last1=Bjorness|first1=Theresa E|last2=Greene|first2=Robert W|title=Adenosine and Sleep|journal=Current Neuropharmacology|date=8 January 2017|volume=7|issue=3|pages=238–245|doi=10.2174/157015909789152182|pmc=2769007|issn=1570-159X|pmid=20190965}}</ref> Caffeine has been found to increase striatal dopamine in animal models,<ref>{{cite journal|last1=Solinas|first1=Marcello|last2=Ferré|first2=Sergi|last3=You|first3=Zhi-Bing|last4=Karcz-Kubicha|first4=Marzena|last5=Popoli|first5=Patrizia|last6=Goldberg|first6=Steven R.|title=Caffeine Induces Dopamine and Glutamate Release in the Shell of the Nucleus Accumbens|journal=Journal of Neuroscience|date=1 August 2002|volume=22|issue=15|pages=6321–6324|language=en|issn=0270-6474|df=dmy-all|doi=10.1523/JNEUROSCI.22-15-06321.2002|pmid=12151508|pmc=6758129}}</ref> as well as inhibit the inhibitory effect of adenosine receptors on dopamine receptors,<ref name="pmid12804599">{{cite journal | vauthors = Kamiya T, Saitoh O, Yoshioka K, Nakata H | title = Oligomerization of adenosine A2A and dopamine D2 receptors in living cells | journal = Biochemical and Biophysical Research Communications | volume = 306 | issue = 2 | pages = 544–9 | date = Jun 2003 | pmid = 12804599 | doi = 10.1016/S0006-291X(03)00991-4 }}</ref> however the implications for humans are unknown. Unlike most stimulants, caffeine has no addictive potential. Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, per a study on drug abuse liability published in an NIDA research monograph that described a group preferring placebo over caffeine.<ref>{{cite book|last1=Fishchman|first1=N|last2=Mello|first2=N|title=Testing for Abuse Liability of Drugs in Humans|publisher=U.S. Department of Health and Human Services Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse |location=Rockville, MD |page=179|url=http://ww1.drugabuse.gov/pdf/monographs/92.pdf|url-status=dead|archive-url=https://web.archive.org/web/20161222041641/http://ww1.drugabuse.gov/pdf/monographs/92.pdf|archive-date=22 December 2016|df=dmy-all}}</ref> In large telephone surveys only 11% reported dependence symptoms. However, when people were tested in labs, only half of those who claim dependence actually experienced it, casting doubt on caffeine's ability to produce dependence and putting societal pressures in the spotlight.<ref name="pmid19428492">{{cite journal | vauthors = Temple JL | title = Caffeine use in children: what we know, what we have left to learn, and why we should worry | journal = Neuroscience and Biobehavioral Reviews | volume = 33 | issue = 6 | pages = 793–806 | year = 2009 | pmid = 19428492 | pmc = 2699625 | doi = 10.1016/j.neubiorev.2009.01.001 }}</ref> Coffee consumption is associated with a lower overall risk of [[cancer]].<ref name="pmid18834663">{{cite journal | author = Nkondjock A | title = Coffee consumption and the risk of cancer: an overview | journal = Cancer Lett. | volume = 277 | issue = 2 | pages = 121–5 | date = May 2009 | pmid = 18834663 | doi = 10.1016/j.canlet.2008.08.022 }}</ref> This is primarily due to a decrease in the risks of [[hepatocellular carcinoma|hepatocellular]] and [[endometrial cancer]], but it may also have a modest effect on colorectal cancer.<ref name=Cancer10/> There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of [[bladder cancer]].<ref name=Cancer10>{{cite journal | author = Arab L | title = Epidemiologic evidence on coffee and cancer | journal = Nutrition and Cancer | volume = 62 | issue = 3 | pages = 271–83 | year = 2010 | pmid = 20358464 | doi = 10.1080/01635580903407122 | s2cid = 44949233 }}</ref> A protective effect of caffeine against [[Alzheimer's disease]] is possible, but the evidence is inconclusive.<ref name="pmid20182026">{{cite journal |vauthors=Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N | title = Caffeine intake and dementia: systematic review and meta-analysis | journal = J. Alzheimers Dis. | volume = 20 |issue=Suppl 1 | pages = S187–204 | year = 2010 | pmid = 20182026 | doi = 10.3233/JAD-2010-091387 | doi-access = free }}</ref><ref name="pmid21427489">{{cite journal |vauthors=Marques S, Batalha VL, Lopes LV, Outeiro TF | title = Modulating Alzheimer's disease through caffeine: a putative link to epigenetics | journal = J. Alzheimers Dis. | volume = 24 | issue = 2 | pages = 161–71 | year = 2011 | pmid = 21427489 | doi = 10.3233/JAD-2011-110032 }}</ref><ref name="pmid20182037">{{cite journal |vauthors=Arendash GW, Cao C | title = Caffeine and coffee as therapeutics against Alzheimer's disease | journal = J. Alzheimers Dis. | volume = 20 |issue=Suppl 1 | pages = S117–26 | year = 2010 | pmid = 20182037 | doi = 10.3233/JAD-2010-091249 | doi-access = free }}</ref> Moderate coffee consumption may decrease the risk of [[cardiovascular disease]],<ref name=Ding2014>{{cite journal |vauthors=Ding M, Bhupathiraju SN, Satija A, van Dam RM, Hu FB | title = Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies. | journal = Circulation | volume = 129 | issue = 6 | pages = 643–59 | date = 11 February 2014 | pmid = 24201300 | pmc = 3945962 | doi = 10.1161/circulationaha.113.005925 }}</ref> and it may somewhat reduce the risk of [[Diabetes mellitus type 2|type 2 diabetes]].<ref name=Dam08>{{cite journal | author = van Dam RM | title = Coffee consumption and risk of type 2 diabetes, cardiovascular diseases, and cancer | journal = Applied Physiology, Nutrition, and Metabolism | volume = 33 | issue = 6 | pages = 1269–1283 | year = 2008 | pmid = 19088789 | doi = 10.1139/H08-120 }}</ref> Drinking 1-3 cups of coffee per day does not affect the risk of [[hypertension]] compared to drinking little or no coffee. However those who drink 2–4 cups per day may be at a slightly increased risk.<ref name="pmid21450934">{{cite journal |vauthors=Zhang Z, Hu G, Caballero B, Appel L, Chen L | title = Habitual coffee consumption and risk of hypertension: a systematic review and meta-analysis of prospective observational studies | journal = Am. J. Clin. Nutr. | volume = 93 | issue = 6 | pages = 1212–9 | date = June 2011 | pmid = 21450934 | doi = 10.3945/ajcn.110.004044 | doi-access = free }}</ref> Caffeine increases [[intraocular pressure]] in those with [[glaucoma]] but does not appear to affect normal individuals.<ref name="pmid20706731">{{cite journal |vauthors=Li M, Wang M, Guo W, Wang J, Sun X | title = The effect of caffeine on intraocular pressure: a systematic review and meta-analysis | journal = Graefes Arch. Clin. Exp. Ophthalmol. | volume = 249 | issue = 3 | pages = 435–42 | date = March 2011 | pmid = 20706731 | doi = 10.1007/s00417-010-1455-1 | s2cid = 668498 }}</ref> It may protect people from [[liver cirrhosis]].<ref name="pmid19825397">{{cite journal |vauthors=Muriel P, Arauz J | title = Coffee and liver diseases | journal = Fitoterapia | volume = 81 | issue = 5 | pages = 297–305 | year = 2010 | pmid = 19825397 | doi = 10.1016/j.fitote.2009.10.003 }}</ref> There is no evidence that coffee stunts a child's growth.<ref>{{cite book|author=O'Connor A |title=Never shower in a thunderstorm : surprising facts and misleading myths about our health and the world we live in |year=2007 |publisher=Times Books |location=New York |isbn=978-0-8050-8312-5 |page=144 |edition=1st |url=https://books.google.com/books?id=neuEbVUZik0C&pg=PA144 |access-date=15 January 2014}}</ref> Caffeine may increase the effectiveness of some medications including ones used to treat [[headaches]].<ref name="pmid21302868">{{cite journal |vauthors=Gilmore B, Michael M | title = Treatment of acute migraine headache | journal = Am Fam Physician | volume = 83 | issue = 3 | pages = 271–80 | date = February 2011 | pmid = 21302868 }}</ref> Caffeine may lessen the severity of [[acute mountain sickness]] if taken a few hours prior to attaining a high altitude.<ref name="pmid20367483">{{cite journal | author = Hackett PH | title = Caffeine at high altitude: java at base Camp | journal = High Alt. Med. Biol. | volume = 11 | issue = 1 | pages = 13–7 | year = 2010 | pmid = 20367483 | doi = 10.1089/ham.2009.1077 | s2cid = 8820874 }}</ref> === Ephedrine === {{Main|Ephedrine}} Ephedrine is a [[sympathomimetic]] [[amine]] similar in molecular structure to the well-known drugs [[phenylpropanolamine]] and [[methamphetamine]], as well as to the important [[neurotransmitter]] [[epinephrine]] (adrenaline). Ephedrine is commonly used as a stimulant, [[appetite suppressant]], concentration aid, and [[decongestant]], and to treat [[hypotension]] associated with anaesthesia. In chemical terms, it is an [[alkaloid]] with a [[phenethylamine]] skeleton found in various plants in the genus ''[[Ephedra (genus)|Ephedra]]'' (family [[Ephedraceae]]). It works mainly by increasing the activity of [[norepinephrine]] (noradrenaline) on [[adrenergic receptors]].<ref name=merck>[http://www.merckmanuals.com/professional/lexicomp/ephedrine.html Merck Manuals EPHEDrine] {{webarchive|url=https://web.archive.org/web/20110324031411/http://www.merckmanuals.com/professional/lexicomp/ephedrine.html |date=24 March 2011 }} Last full review/revision January 2010</ref> It is most usually marketed as the ''hydrochloride'' or ''sulfate'' salt. The herb ''má huáng'' (''[[Ephedra sinica]]''), used in [[traditional Chinese medicine]] (TCM), contains ephedrine and [[pseudoephedrine]] as its principal active constituents. The same may be true of other herbal products containing extracts from other ''Ephedra'' species. === MDMA === [[File:Ecstasy monogram.jpg|thumb|240px|Tablets containing MDMA]] {{Main|MDMA}} {{See also|Substituted methylenedioxyphenethylamines|l1=Its parent class|3,4-methylenedioxyamphetamine|l2=MDA}} 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, or molly) is a euphoriant, [[empathogen]], and stimulant of the amphetamine class.<ref>{{cite journal|last1=Meyer|first1=Jerrold S|title=3,4-methylenedioxymethamphetamine (MDMA): current perspectives|journal=Substance Abuse and Rehabilitation|date=21 November 2013|volume=4|pages=83–99|doi=10.2147/SAR.S37258|pmc=3931692|issn=1179-8467|pmid=24648791 |doi-access=free }}</ref> Briefly used by some psychotherapists as an adjunct to therapy, the drug became popular recreationally and the [[Drug Enforcement Administration|DEA]] listed MDMA as a [[Controlled substances act#Schedule I controlled substances|Schedule I controlled substance]], prohibiting most medical studies and applications. MDMA is known for its [[entactogen]]ic properties. The stimulant effects of MDMA include [[hypertension]], [[anorexia (symptom)|anorexia]] (appetite loss), [[euphoria]], social disinhibition, [[insomnia]] (enhanced wakefulness/inability to sleep), improved [[mental energy|energy]], increased arousal, and increased [[perspiration]], among others. Relative to catecholaminergic transmission, MDMA enhances serotonergic transmission significantly more, when compared to classical stimulants like amphetamine. MDMA does not appear to be significantly addictive or dependence forming.<ref>{{cite journal|last1=Nutt|first1=David|last2=King|first2=Leslie A.|last3=Saulsbury|first3=William|last4=Blakemore|first4=Colin|title=Development of a rational scale to assess the harm of drugs of potential misuse|journal=Lancet |date=24 March 2007|volume=369|issue=9566|pages=1047–1053|doi=10.1016/S0140-6736(07)60464-4|pmid=17382831|s2cid=5903121|issn=1474-547X}}</ref> Due to the relative safety of MDMA, some researchers such as [[David Nutt]] have criticized the scheduling level, writing a satirical article finding MDMA to be 28 times less dangerous than horseriding, a condition he termed "equasy" or "Equine Addiction Syndrome".<ref>{{Cite news|title = Ecstasy 'no more dangerous than horse riding'|url = https://www.telegraph.co.uk/news/uknews/law-and-order/4537874/Ecstasy-no-more-dangerous-than-horse-riding.html|website = Telegraph.co.uk |access-date = 4 December 2015|url-status = live|archive-url = https://web.archive.org/web/20151210201615/http://www.telegraph.co.uk/news/uknews/law-and-order/4537874/Ecstasy-no-more-dangerous-than-horse-riding.html|archive-date = 10 December 2015|df = dmy-all|date = 2009-02-07|editor-last1 = Hope |editor-first1 = Christopher }}</ref> === MDPV === {{Main|Methylenedioxypyrovalerone|l1=MDPV}} Methylenedioxypyrovalerone (MDPV) is a [[psychoactive drug]] with stimulant properties that acts as a [[norepinephrine-dopamine reuptake inhibitor]] (NDRI).<ref name="SimmlerBuser2012">{{cite journal|last1=Simmler |first1=L. D. |last2=Buser |first2=T. A. |last3=Donzelli |first3=M. |last4=Schramm |first4=Y |last5=Dieu |first5=L-H. |last6=Huwyler |first6=J. |last7=Chaboz |first7=S. |last8=Hoener |first8=M. C. |last9=Liechti |first9=M. E. |title=Pharmacological characterization of designer cathinones in vitro |journal=[[British Journal of Pharmacology]] |year=2012 |pages=458–470 |issn=0007-1188 |doi=10.1111/j.1476-5381.2012.02145.x |volume=168 |issue=2 |pmid=22897747 |pmc=3572571}}</ref> It was first developed in the 1960s by a team at Boehringer Ingelheim.<ref>US Patent 3478050 – 1-(3,4-methylenedioxy-phenyl)-2-pyrrolidino-alkanones</ref> MDPV remained an obscure stimulant until around 2004, when it was reported to be sold as a [[designer drug]]. Products labeled as [[Bath salts (drug)|bath salts]] containing MDPV were previously sold as recreational drugs in gas stations and convenience stores in the United States, similar to the marketing for [[Spice (drug)|Spice]] and [[K2 (drug)|K2]] as incense.<ref>{{cite news |url=http://www.kmbc.com/news/26256067/detail.html |title=Abuse Of Fake 'Bath Salts' Sends Dozens To ER |date=23 December 2010 |work=KMBC.com |url-status=dead |archive-url=https://web.archive.org/web/20110713161635/http://www.kmbc.com/news/26256067/detail.html |archive-date=13 July 2011 |df=dmy-all }}</ref><ref>{{cite web |url=http://healthybodydaily.com/dr-oz-in-case-you-missed-it/dr-oz-bath-salts-mdpv-bath-salts-drug-over-the-counter |title=MDPV Bath Salts Drug Over The Counter |url-status=dead |archive-url=https://web.archive.org/web/20110310193146/http://healthybodydaily.com/dr-oz-in-case-you-missed-it/dr-oz-bath-salts-mdpv-bath-salts-drug-over-the-counter |archive-date=10 March 2011 |df=dmy-all }}</ref> Incidents of psychological and physical harm have been attributed to MDPV use.<ref>{{cite news |access-date=16 May 2011 |url=http://www.nbc33tv.com/consumer-alert/parents-cautioned-against-over-the-counter-synthetic-speed |title=Parents cautioned against over the counter synthetic speed |date=9 November 2010 |publisher=NBC 33 News |author=Samantha Morgan |url-status=live |archive-url=https://web.archive.org/web/20110928084237/http://www.nbc33tv.com/consumer-alert/parents-cautioned-against-over-the-counter-synthetic-speed |archive-date=28 September 2011 |df=dmy-all }}</ref><ref>{{cite news |access-date=16 May 2011 |url=http://www.nbc33tv.com/news/bath-salts-used-to-get-high |title=Bath Salts Used to Get High |date=6 January 2011 |publisher=NBC 33 News |author=Kelsey Scram |url-status=live |archive-url=https://web.archive.org/web/20110928084244/http://www.nbc33tv.com/news/bath-salts-used-to-get-high |archive-date=28 September 2011 |df=dmy-all }}</ref> === Mephedrone === {{Main|Mephedrone}} Mephedrone is a [[Organic compound#Synthetic compounds|synthetic]] stimulant drug of the [[substituted amphetamine|amphetamine]] and [[substituted cathinone|cathinone]] classes. Slang names include drone<ref name=Cumming>{{cite news|last=Cumming |first=E. |url=https://www.telegraph.co.uk/health/7614099/Mephedrone-Chemistry-lessons.html |title=Mephedrone: Chemistry lessons |newspaper=The Daily Telegraph |date=22 April 2010 |access-date=14 September 2010 |location=London |archive-url=https://web.archive.org/web/20140107033621/http://news.bbc.co.uk/2/hi/uk_news/scotland/north_east/8555872.stm |archive-date=7 January 2014 |url-status=dead}}</ref> and MCAT.<ref name=bbc0803>{{cite news|url=http://news.bbc.co.uk/1/hi/scotland/north_east/8555872.stm |title=Drugs crackdown hailed a success |work=BBC News |date=8 March 2010 |access-date=31 March 2010 |archive-url=https://web.archive.org/web/20120826231758/http://www.telegraph.co.uk/health/7614099/Mephedrone-Chemistry-lessons.html |archive-date=26 August 2012 |url-status=live}}</ref> It is reported to be manufactured in China and is chemically similar to the cathinone compounds found in the [[khat]] plant of [[eastern Africa]]. It comes in the form of tablets or a powder, which users can swallow, snort, or inject, producing similar effects to [[MDMA]], [[amphetamine]]s, and [[cocaine]]. Mephedrone was first synthesized in 1929, but did not become widely known until it was rediscovered in 2003. By 2007, mephedrone was reported to be available for sale on the Internet; by 2008 law enforcement agencies had become aware of the compound; and, by 2010, it had been reported in most of Europe, becoming particularly prevalent in the United Kingdom. Mephedrone was first made illegal in Israel in 2008, followed by Sweden later that year. In 2010, it was made illegal in many European countries, and, in December 2010, the EU ruled it illegal. In Australia, New Zealand, and the US, it is considered an [[structural analog|analog]] of other illegal drugs and can be controlled by laws similar to the [[Federal Analog Act]]. In September 2011, the USA temporarily classified mephedrone as illegal, in effect from October 2011. === Methamphetamine === {{Main|Methamphetamine}} Methamphetamine (contracted from {{nowrap|[[Methyl group|''N''-'''meth'''yl]]-[[amphetamine|'''a'''lpha-'''m'''ethyl'''ph'''en'''et'''hyl'''amine''']]}}) is a potent psychostimulant of the [[phenethylamine]] and [[substituted amphetamine|amphetamine]] [[chemical classification|classes]] that is used to treat [[attention deficit hyperactivity disorder]] (ADHD) and [[obesity]].<ref name = "Malenka">{{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 |isbn=9780071481274 |page=370 |edition=2nd |chapter=15 |quote=Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.}}</ref><ref name="Desoxyn">{{cite web |title=Desoxyn Prescribing Information |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/005378s028lbl.pdf |date=December 2013 |work=United States Food and Drug Administration |access-date=6 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20140102192621/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/005378s028lbl.pdf |archive-date=2 January 2014 |df=dmy-all }}</ref><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> Methamphetamine exists as two [[enantiomer]]s, [[dextrorotary]] and [[levorotary]].<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 |doi=10.1523/JNEUROSCI.15-02-01308.1995|pmc=6577819 }}</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> Dextromethamphetamine is a stronger CNS stimulant than [[levomethamphetamine]];<ref name="Westfall" /><ref name="Kuczenski" /><ref name="Mendelson" /> however, both are addictive and produce the same toxicity symptoms at high doses.<ref name="Mendelson" /> Although rarely prescribed due to the potential risks, methamphetamine hydrochloride is approved by the [[United States Food and Drug Administration]] (USFDA) under the trade name ''Desoxyn''.<ref name="Desoxyn" /> Recreationally, methamphetamine is used to [[aphrodisiac|increase sexual desire]], [[euphoriant|lift the mood]], and increase [[mental energy|energy]], allowing some users to engage in sexual activity continuously for several days straight.<ref name="Desoxyn" />{{not in citation|date=December 2021}}<ref name="SF Meth" />{{unreliable source|date=December 2021}} Methamphetamine may be sold illicitly, either as pure dextromethamphetamine or in an [[racemate|equal parts]] mixture of the right- and left-handed molecules (i.e., 50%&nbsp;levomethamphetamine and 50%&nbsp;dextromethamphetamine).<ref name="SF Meth">{{cite episode |date=11 August 2013 |title=San Francisco Meth Zombies |url=http://channel.nationalgeographic.com/drugs-inc/episodes/san-francisco-meth-zombies/ |series=Drugs, Inc. |series-link=Drugs, Inc. |season=4 |number=1 |network=National Geographic Channel |minutes=43 |asin=B00EHAOBAO |url-status=dead |archive-url=https://web.archive.org/web/20160708142916/http://channel.nationalgeographic.com/drugs-inc/episodes/san-francisco-meth-zombies/ |archive-date=8 July 2016 |df=dmy-all }}</ref> Both dextromethamphetamine and racemic methamphetamine are [[Schedule II Controlled Substance|schedule II]] controlled substances in the United States.<ref name="Desoxyn" /> Also, the production, distribution, sale, and possession of methamphetamine is restricted or illegal in many other countries due to its placement in schedule II of the [[Convention on Psychotropic Substances|United Nations Convention on Psychotropic Substances]] treaty.<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=9789211482232 |url=http://www.unodc.org/pdf/youthnet/ATS.pdf |access-date=11 November 2013 |url-status=live |archive-url=https://web.archive.org/web/20131016082310/http://www.unodc.org/pdf/youthnet/ATS.pdf |archive-date=16 October 2013 |df=dmy-all }}</ref><ref name="incb">{{cite web|title=List of psychotropic substances under international control |work=International Narcotics Control Board |publisher=United Nations |url=http://www.incb.org/pdf/e/list/green.pdf |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 contrast, [[levomethamphetamine]] is an [[over-the-counter drug]] in the United States.{{#tag:ref|The active ingredient in some OTC inhalers in the United States is listed as ''levmetamfetamine'', the [[International Nonproprietary Name|INN]] and [[United States Adopted Name|USAN]] of levomethamphetamine.<ref name="FDA levmetamfetamine">{{cite web|title=CFR TITLE 21: 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|access-date=7 March 2016|date=April 2015|quote=Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in each 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.|url-status=live|archive-url=https://web.archive.org/web/20150918190451/http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=341.80|archive-date=18 September 2015|df=dmy-all}}</ref><ref>{{cite encyclopedia | title=Levomethamphetamine| section=Identification | section-url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604#section=Identification | work=Pubchem Compound| publisher=National Center for Biotechnology Information }}</ref>|name="OTC levmetamfetamine"|group = "note"}} In low doses, methamphetamine can cause an [[euphoria|elevated mood]] and increase alertness, concentration, and energy in fatigued individuals.<ref name="Westfall" /><ref name="Desoxyn" /> At higher doses, it can induce [[methamphetamine psychosis|psychosis]], [[rhabdomyolysis]], and [[cerebral hemorrhage]].<ref name="Westfall" /><ref name="Desoxyn" /> Methamphetamine is known to have a high potential for [[substance abuse|abuse]] and [[substance dependence|addiction]].<ref name="Westfall" /><ref name="Desoxyn" /> Recreational use of methamphetamine may result in psychosis or lead to [[post-withdrawal syndrome]], a withdrawal syndrome that can persist for months beyond the typical withdrawal period.<ref name="Cruickshank-2009">{{cite journal|vauthors=Cruickshank CC, Dyer KR |title=A review of the clinical pharmacology of methamphetamine |journal=Addiction |volume=104 |issue=7 |pages=1085–1099 |date=July 2009 |pmid=19426289 |doi=10.1111/j.1360-0443.2009.02564.x|s2cid=37079117 |doi-access=free }}</ref> Unlike [[amphetamine]] and [[cocaine]], methamphetamine is [[neurotoxic]] to humans, damaging both [[dopamine]] and [[serotonin]] neurons in the [[central nervous system]] (CNS).<ref name = "Malenka" /><ref name="pmid19328213" /> Unlike the long-term use of amphetamine in prescription doses, which may improve certain brain regions in individuals with ADHD, there is evidence that methamphetamine causes brain damage from long-term use in humans;<ref name = "Malenka" /><ref name="pmid19328213" /> this damage includes adverse changes in brain structure and function, such as reductions in [[gray matter]] volume in several brain regions and adverse changes in markers of metabolic integrity.<ref name="Neuroplasticity 1">{{cite journal|vauthors=Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K |title=Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects |journal=JAMA Psychiatry |volume=70 |issue=2 |pages=185–198 |date=February 2013 |pmid=23247506 |doi=10.1001/jamapsychiatry.2013.277 }}</ref><ref name="Neuroplasticity 2">{{cite journal|vauthors=Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J |title=Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies |journal=J. Clin. Psychiatry |volume=74 |issue=9 |pages=902–917 |date=September 2013 |pmid=24107764 |doi=10.4088/JCP.12r08287 |pmc=3801446}}</ref><ref name="pmid19328213" /> However, recreational amphetamine doses may also be neurotoxic. <ref>{{Cite journal|url=https://www.cambridge.org/core/journals/psychological-medicine/article/continuous-amphetamine-intoxication-an-animal-model-of-the-acute-psychotic-episode/7DEB3BCC38395608F1C4FE87529D4C8F|doi=10.1017/S003329170005145X|title=Continuous amphetamine intoxication: An animal model of the acute psychotic episode|year=1983|last1=Ellison|first1=Gaylord D.|last2=Eison|first2=Michael S.|journal=Psychological Medicine|volume=13|issue=4|pages=751–761|pmid=6320247|s2cid=2337423 }}</ref> === Methylphenidate === {{Main|Methylphenidate}} Methylphenidate is a stimulant drug that is often used in the treatment of ADHD and narcolepsy and occasionally to treat obesity in combination with diet restraints and exercise. Its effects at therapeutic doses include increased focus, increased alertness, decreased appetite, decreased need for sleep and decreased impulsivity. Methylphenidate is not usually used recreationally, but when it is used, its effects are very similar to those of amphetamines. Methylphenidate acts as a norepinephrine-dopamine reuptake inhibitor, by blocking the [[norepinephrine transporter]] (NET) and the [[dopamine transporter]] (DAT). Methylphenidate has a higher affinity for the dopamine transporter than for the norepinephrine transporter, and so its effects are mainly due to elevated dopamine levels caused by the inhibited reuptake of dopamine, however increased norepinephrine levels also contribute to various of the effects caused by the drug. Methylphenidate is sold under a number of brand names including Ritalin. Other versions include the long lasting tablet Concerta and the long lasting transdermal patch Daytrana. === Cocaine === [[File:Cocaine lines 2.jpg|thumb|180px|right|Lines of illicit [[cocaine]], used as a [[recreational drug|recreational]] stimulant]] {{Main|Cocaine}} Cocaine is an [[SNDRI]]. Cocaine is made from the leaves of the [[coca]] shrub, which grows in the mountain regions of South American countries such as [[Bolivia]], [[Colombia]], and [[Peru]], regions in which it was cultivated and used for centuries mainly by the [[Aymara people]]. In Europe, North America, and some parts of Asia, the most common form of cocaine is a white crystalline powder. Cocaine is a stimulant but is not normally prescribed therapeutically for its stimulant properties, although it sees clinical use as a local anesthetic, in particular in [[ophthalmology]].<ref>{{Cite web|date=2020|title=Efectos psicológicos del consumo de la cocaína|url=https://www.avancepsicologos.com/efectos-psicologicos-del-consumo-de-la-cocaina/|website=Avance Psicólogos|language=es}}</ref> Most cocaine use is recreational and its abuse potential is high (higher than amphetamine), and so its sale and possession are strictly controlled in most jurisdictions. Other [[tropane]] derivative drugs related to cocaine are also known such as [[troparil]] and [[lometopane]] but have not been widely sold or used recreationally.<ref>{{cite journal|author1=AJ Giannini |author2=WC Price |title=Contemporary drugs of abuse |journal=American Family Physician |volume=33 |pages=207–213 |year=1986}}</ref> === Nicotine === {{Main|Nicotine}} [[Nicotine]] is the active chemical constituent in [[tobacco]], which is available in many forms, including [[cigarette]]s, [[cigar]]s, [[chewing tobacco]], and [[smoking cessation]] aids such as [[nicotine patch]]es, [[nicotine gum]], and [[electronic cigarette]]s. Nicotine is used widely throughout the world for its stimulating and relaxing effects. Nicotine exerts its effects through the agonism of [[nicotinic acetylcholine receptors]], resulting in multiple downstream effects such as increase in activity of dopaminergic neurons in the midbrain [[reward system]], and acetaldehyde one of the tobacco constituent decreased the expression of [[monoamine oxidase]] in the brain.<ref>{{cite journal|last1=Talhouth|first1=Reinskje|last2=Opperhuizen|first2=Antoon|last3=van Amsterdam G. C.|first3=Jan|title=Role of acetaldehyde in tobacco smoke addiction|journal=European Neuropsychopharmacology|date=October 2007|volume=17|issue=10|pages=627–636|doi=10.1016/j.euroneuro.2007.02.013|pmid=17382522|s2cid=25866206}}</ref> Nicotine is addictive and dependence forming. Tobacco, the most common source of nicotine, has an overall harm to user and self score 3 percent below cocaine, and 13 percent above amphetamines, ranking 6th most harmful of the 20 drugs assessed, as determined by a multi-criteria decision analysis.<ref>{{cite journal|last1=Nutt|first1=David J.|last2=King|first2=Leslie A.|last3=Phillips|first3=Lawrence D.|title=Drug harms in the UK: a multicriteria decision analysis|journal=Lancet |date=6 November 2010|volume=376|issue=9752|pages=1558–1565|doi=10.1016/S0140-6736(10)61462-6|pmid=21036393|issn=1474-547X|citeseerx=10.1.1.690.1283|s2cid=5667719}}</ref> === Phenylpropanolamine === {{Main|Phenylpropanolamine}} Phenylpropanolamine (PPA; Accutrim; β-hydroxyamphetamine), also known as the [[stereoisomerism|stereoisomers]] norephedrine and norpseudoephedrine, is a [[psychoactive drug]] of the [[phenethylamine]] and [[amphetamine]] [[chemical class]]es that is used as a stimulant, [[decongestant]], and [[anorectic]] agent.<ref name="pmid15608085">{{cite journal|author=Flavahan NA |title=Phenylpropanolamine constricts mouse and human blood vessels by preferentially activating alpha2-adrenoceptors |journal=Journal of Pharmacology and Experimental Therapeutics |volume=313 |issue=1 |pages=432–9 |date=April 2005 |pmid=15608085 |doi=10.1124/jpet.104.076653 |s2cid=41470513 }}</ref> It is commonly used in [[prescription drug|prescription]] and [[over-the-counter drug|over-the-counter]] [[cough and cold preparation]]s. In [[veterinary medicine]], it is used to control [[urinary incontinence]] in dogs under [[trade name]]s Propalin and Proin. In the United States, PPA is no longer sold without a prescription due to a proposed increased risk of [[stroke]] in younger women. In a few countries in Europe, however, it is still available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001.<ref>{{cite web|url=http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2001-eng.php |title=Advisories, Warnings and Recalls – 2001 |date=7 January 2009 |access-date=10 January 2011 |publisher=[[Health Canada]] |url-status=dead |archive-url=https://web.archive.org/web/20100503164144/http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2001-eng.php |archive-date=3 May 2010 }}</ref> In India, human use of PPA and its formulations were banned on 10 February 2011.<ref>{{cite web |url=http://www.cdsco.nic.in/html/Drugsbanned.html |title=Drugs Banned in India |publisher=Central Drugs Standard Control Organization |work=Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India |access-date=7 January 2014 |url-status=dead |archive-url=https://web.archive.org/web/20131013222927/http://cdsco.nic.in/html/drugsbanned.html |archive-date=13 October 2013 |df=dmy-all }}</ref> === Lisdexamfetamine === {{Main|Lisdexamfetamine}} Lisdexamfetamine (Vyvanse, etc.) is an amphetamine-type medication, sold for use in treating ADHD.<ref>{{Cite web |title=Lisdexamfetamine: MedlinePlus Drug Information |url=https://medlineplus.gov/druginfo/meds/a607047.html |access-date=2023-08-07 |website=medlineplus.gov |language=en}}</ref> Its effects typically last around 14 hours.<ref name="AHFS20192">{{cite web |title=Lisdexamfetamine Dimesylate Monograph for Professionals |url=https://www.drugs.com/monograph/lisdexamfetamine-dimesylate.html |access-date=15 April 2019 |website=Drugs.com |publisher=American Society of Health-System Pharmacists}}</ref> Lisdexamfetamine is inactive on its own and is metabolized into [[dextroamphetamine]] in the body.<ref>{{Cite journal |last=Dolder |first=Patrick |date=September 7, 2017 |title=Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with d-Amphetamine in Healthy Subjects |journal=Frontiers in Pharmacology |volume=8 |page=617 |doi=10.3389/fphar.2017.00617 |pmid=28936175 |pmc=5594082 |doi-access=free }}</ref> Consequently, it has a lower abuse potential. === Pseudoephedrine === {{Main|Pseudoephedrine}} Pseudoephedrine is a [[sympathomimetic]] [[drug]] of the [[substituted phenethylamine|phenethylamine]] and [[substituted amphetamine|amphetamine]] [[chemical class]]es. It may be used as a [[decongestant|nasal/sinus decongestant]], as a stimulant,<ref>{{cite journal |title=Pseudoephedrine is without ergogenic effects during prolonged exercise |author1=Hunter Gillies |author2=Wayne E. Derman |author3=Timothy D. Noakes |author4=Peter Smith |author5=Alicia Evans |author6=Gary Gabriels |name-list-style=amp |journal=Journal of Applied Physiology |date=1 December 1996 |volume=81 |pages=2611–2617 |issue=6 |pmid=9018513 |df=dmy-all |doi=10.1152/jappl.1996.81.6.2611 |s2cid=15702353 }}</ref> or as a [[wakefulness-promoting agent]].<ref>{{cite journal|last=Hodges |first=K |author2=Hancock S |author3=Currel K |author4=Hamilton B |author5=Jeukendrup AE |title=Pseudoephedrine enhances performance in 1500-m runners |journal=Medicine and Science in Sports and Exercise |date=Feb 2006 |pmid=16531903 |doi=10.1249/01.mss.0000183201.79330.9c |volume=38 |issue=2 |pages=329–33|doi-access=free }}</ref> The [[Salt (chemistry)|salts]] pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many [[over-the-counter drug|over-the-counter]] [[dosage form|preparations]], either as a single ingredient or (more commonly) in combination with [[antihistamine]]s, [[guaifenesin]], [[dextromethorphan]], and/or [[paracetamol]] (acetaminophen) or another [[non-steroidal anti-inflammatory drug|NSAID]] (such as [[aspirin]] or [[ibuprofen]]). It is also used as a precursor chemical in the illegal production of methamphetamine. === ''Catha edulis'' (Khat) === {{Main|Khat}} [[File:Catha edulis.jpg|thumb|200px|right|alt=Photograph of the khat plant|''Catha edulis'']] Khat is a [[flowering plant]] native to the [[Horn of Africa]] and the [[Arabian Peninsula]].<ref name="Tooea">{{cite book|last=Dickens |first=Charles |chapter=The Orsons of East Africa |title=Household Words: A Weekly Journal, Volume 14 |publisher=Bradbury & Evans |year=1856 |orig-year=Digitized 19 February 2010 |page=176 |chapter-url=https://books.google.com/books?id=EdUnAQAAIAAJ&pg=PA176 |access-date=7 January 2014}} {{open access}} {{link note|note=Free eBook}}</ref><ref name="Kciy">{{cite news |url=https://www.who.int/bulletin/volumes/86/10/08-011008/en/ |title=Khat chewing in Yemen: turning over a new leaf – Khat chewing is on the rise in Yemen, raising concerns about the health and social consequences |last=Al-Mugahed |first=Leen |access-date=8 January 2014 |publisher=World Health Organization |date=October 2008 |url-status=dead |archive-url=https://web.archive.org/web/20140108103026/http://www.who.int/bulletin/volumes/86/10/08-011008/en/ |archive-date=8 January 2014 |df=dmy-all }}</ref> Khat contains a [[monoamine]] [[alkaloid]] called [[cathinone]], a "keto-amphetamine", that is said to cause excitement, [[Anorectic|loss of appetite]], and [[euphoria (emotion)|euphoria]]. In 1980, the [[World Health Organization]] (WHO) classified it as a [[drug of abuse]] that can produce mild to moderate [[Substance dependence|psychological dependence]] (less than tobacco or alcohol),<ref name="King">{{cite journal|vauthors=Nutt D, King LA, Blakemore C |title=Development of a rational scale to assess the harm of drugs of potential misuse |journal=Lancet |volume=369 |issue=9566 |pages=1047–53 |date=March 2007 |pmid=17382831 |doi=10.1016/S0140-6736(07)60464-4|s2cid=5903121 }}</ref> although the WHO does not consider khat to be seriously addictive.<ref name="Kciy" /> It is banned in some countries, such as the United States, Canada, and Germany, while its production, sale, and consumption are legal in other nations, including [[Djibouti]], [[Ethiopia]], [[Somalia]], Kenya and [[Yemen]].<ref name="Hafmc">Haight-Ashbury Free Medical Clinic, ''Journal of psychoactive drugs'', Volume 41, (Haight-Ashbury Publications: 2009), p.3.</ref> ===Modafinil=== {{Main article|Modafinil}} [[Modafinil]] is an [[eugeroic]] medication, which means that it promotes wakefulness and alertness. Modafinil is sold under the brand name Provigil among others. Modafinil is used to treat [[excessive daytime sleepiness]] due to [[narcolepsy]], [[shift work sleep disorder]], or [[obstructive sleep apnea]]. While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive.<ref>{{Cite journal|url=https://doi.org/10.1097/JCP.0000000000001085|title=The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis|first1=M Alexandra|last1=Kredlow|first2=Ani|last2=Keshishian|first3=Sarah|last3=Oppenheimer|first4=Michael W|last4=Otto|date=1 September 2019|journal=Journal of Clinical Psychopharmacology|volume=39|issue=5|pages=455–461|via=Europe PMC|doi=10.1097/jcp.0000000000001085|pmid=31433334|s2cid=201119084 }}</ref> Despite being a CNS stimulant, the addiction and [[drug dependence|dependence]] liabilities of modafinil are considered very low.<ref name="pmid23065655">{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–752 | date = October 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 }}</ref><ref name="FDA-2015-Provigil-Prescribing">{{cite web|date=January 2015|title=Provigil: Prescribing information |url= http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|access-date=August 16, 2015|website= FDA.gov| publisher= [[United States Food and Drug Administration]] |agency=Cephalon, Inc|archive-date=February 17, 2017|archive-url= https://web.archive.org/web/20170217165804/https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|url-status=live}}</ref><ref name="pmid33435717">{{cite journal |vauthors= Kakehi S, Tompkins DM |title=A Review of Pharmacologic Neurostimulant Use During Rehabilitation and Recovery After Brain Injury |journal=Ann Pharmacother |volume=55 |issue=10 |pages=1254–1266 |date=October 2021 |pmid=33435717 |doi=10.1177/1060028020983607 |s2cid=231593912 }}</ref> Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have [[Mood elevation|mood-elevating properties]].<ref name="FDA-2015-Provigil-Prescribing"/> The similarities in effects with [[caffeine]] are not clearly established.<ref name="pmid22375280">{{cite journal | vauthors = Kim D | title = Practical use and risk of modafinil, a novel waking drug | journal = Environmental Health and Toxicology | volume = 27 | pages = e2012007 | date = 2012 | pmid = 22375280 | pmc = 3286657 | doi = 10.5620/eht.2012.27.e2012007 }}</ref><ref name="Warot-1993">{{Cite journal|vauthors=Warot D, Corruble E, Payan C, Weil JS, Puech AJ|date=1993|title=Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo|journal=European Psychiatry |volume=8|issue=4|pages=201–208|doi=10.1017/S0924933800002923|s2cid=151797528 }}</ref> Unlike other stimulants, modafinil does not induce a subjective [[Pleasure|feeling of pleasure or reward]], which is commonly associated with [[euphoria]], an intense feeling of well-being. Euphoria is a potential indicator of [[Substance abuse|drug abuse]], which is the compulsive and excessive use of a substance despite adverse consequences. In clinical trials, modafinil has shown no evidence of abuse potential, that is why modafinil is considered to have a low risk of addiction and dependence, however, caution is advised.<ref name="pmid16741217">{{cite journal | vauthors = O'Brien CP, Dackis CA, Kampman K | title = Does modafinil produce euphoria? | journal = The American Journal of Psychiatry | volume = 163 | issue = 6 | pages = 1109 | date = June 2006 | pmid = 16741217 | doi = 10.1176/ajp.2006.163.6.1109 }}</ref><ref name="pmid30285371">{{cite book | vauthors = Greenblatt K, Adams N | chapter = Modafinil | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing | date = February 2022 | pmid = 30285371 | id={{NCBIBook|NBK531476}}}}</ref> == Recreational use and issues of abuse == {{Main|Recreational drug use#Stimulants}} {{See also|Substance abuse}} Stimulants enhance the activity of the [[central nervous system|central]] and [[peripheral nervous system]]s. Common effects may include increased [[alertness]], [[awareness]], [[wakefulness]], [[endurance]], [[productivity]], and [[motivation]], [[arousal]], [[animal locomotion|locomotion]], [[heart rate]], and [[blood pressure]], and a diminished desire for [[food]] and [[sleep]]. Use of stimulants may cause the body to reduce significantly its production of natural body chemicals that fulfill similar functions. Until the body reestablishes its normal state, once the effect of the ingested stimulant has worn off the user may feel depressed, lethargic, confused, and miserable. This is referred to as a "[[Comedown (drugs)|crash]]", and may provoke reuse of the stimulant. [[Drug abuse|Abuse]] of [[central nervous system]] (CNS) stimulants is common. [[Substance use disorder|Addiction]] to some CNS stimulants can quickly lead to [[medical]], [[psychiatric]], and [[psychosocial]] deterioration. [[Drug tolerance]], [[drug dependence|dependence]], and [[Drug sensitization|sensitization]] as well as a [[Drug withdrawal|withdrawal]] syndrome can occur.<ref>{{cite journal|vauthors=Dackis CA, Gold MS |title=Addictiveness of central stimulants |journal=Advances in Alcohol & Substance Abuse |volume=9 |issue=1–2 |pages=9–26 |year=1990 |pmid=1974121 |doi=10.1300/J251v09n01_02}}</ref> Stimulants may be screened for in animal discrimination and self-administration models which have high sensitivity albeit low specificity.<ref>{{cite journal|last1=Huskinson|first1=Sally L.|last2=Naylor|first2=Jennifer E.|last3=Rowlett|first3=James K.|last4=Freeman|first4=Kevin B.|title=Predicting abuse potential of stimulants and other dopaminergic drugs: Overview and recommendations|journal=Neuropharmacology|date=7 January 2017|volume=87|pages=66–80|doi=10.1016/j.neuropharm.2014.03.009|pmc=4171344|issn=0028-3908|pmid=24662599}}</ref> Research on a progressive ratio [[Self-administration]] protocol has found amphetamine, methylphenidate, modafinil, cocaine, and nicotine to all have a higher break point than placebo that scales with dose indicating reinforcing effects.<ref>{{cite journal|last1=Stoops|first1=William W.|title=Reinforcing Effects of Stimulants in Humans: Sensitivity of Progressive-Ratio Schedules|journal=[[Experimental and Clinical Psychopharmacology]]|date=7 January 2017|volume=16|issue=6|pages=503–512|doi=10.1037/a0013657|pmc=2753469|issn=1064-1297|pmid=19086771}}</ref> {| class="wikitable sortable" ! colspan="5" |Dependence potentials of common stimulants<ref name="King" /> |- ! Drug !! Mean !! Pleasure !! Psychological dependence !! Physical dependence |- | [[Cocaine]] || 2.39 || 3.0 || 2.8 || 1.3 |- | [[Tobacco]] || 2.21 || 2.3 || 2.6 || 1.8 |- | [[Amphetamine]] || 1.67 || 2.0 || 1.9 || 1.1 |- | [[Ecstasy (drug)|Ecstasy]] || 1.13 || 1.5 || 1.2 || 0.7 |} ==Treatment for misuse== Psychosocial treatments, such as [[contingency management]], have demonstrated improved effectiveness when added to treatment as usual consisting of counselling and/or case-management. This is demonstrated with a decrease in dropout rates and a lengthening of periods of abstinence.<ref>{{Cite journal|last1=Minozzi|first1=Silvia|last2=Saulle|first2=Rosella|last3=De Crescenzo|first3=Franco|last4=Amato|first4=Laura|date=2016-09-29|title=Psychosocial interventions for psychostimulant misuse|journal=The Cochrane Database of Systematic Reviews|volume=2016|issue=9 |pages=CD011866|doi=10.1002/14651858.CD011866.pub2|issn=1469-493X|pmc=6457581|pmid=27684277}}</ref> == Testing == The presence of stimulants in the body may be tested by a variety of procedures. Serum and urine are the common sources of testing material although saliva is sometimes used. Commonly used tests include chromatography, immunologic assay, and mass spectrometry.<ref>AJ Giannini. ''Drug Abuse''. Los Angeles, Health Information Press, 1999, pp.203–208</ref> == See also == * [[Antidepressant]]s * [[Depressant]]s * [[Hallucinogen]]s * [[Nootropic]]s * [[Psychoanaleptic]]s == Notes == {{Reflist|group=note}} == References == {{Reflist|30em}} == External links == {{Wiktionary|stimulant|upper}} {{Commons category|Stimulants}} * {{cite web|url=http://www.licadd.org/aboutdrugs.htm |title=Long Island Council on Alcohol & Drug Dependence – About Drugs – Stimulants |access-date=4 August 2007 |url-status=unfit |archive-url=https://web.archive.org/web/20080605235801/http://www.licadd.org/aboutdrugs.htm |archive-date=5 June 2008 }} * {{cite web |url=http://ncadistore.samhsa.gov/catalog/results.aspx?h=drugs&topic=68 |title=Online – Publications – Drugs of Abuse – Stimulants |access-date=11 January 2008 |url-status=unfit |archive-url=https://web.archive.org/web/20060922202232/http://ncadistore.samhsa.gov/catalog/results.aspx?h=drugs&topic=68 |archive-date=22 September 2006 }} * [http://www.apaic.org/ Asia & Pacific Amphetamine-Type Stimulants Information Centre (APAIC)] {{Stimulants}} {{Major drug groups}} {{Drug use}} {{Authority control}} [[Category:Stimulants| ]] [[Category:Psychopharmacology]]'
New page wikitext, after the edit (new_wikitext)
'{{Short description|Overarching term covers many drugs that increase activity of the central nervous system}} {{cs1 config|name-list-style=vanc}} {{Use dmy dates|date=January 2021}} {{Use American English|date=January 2014}} [[File:Ritalin-SR-20mg-full.jpg|thumb|right|200px|[[Ritalin]]: 20 mg [[Modified-release dosage|sustained-release]] (SR) tablets]] '''Stimulants''' (also known as '''psychostimulants''' or colloquially as '''uppers''') is an overarching term that covers many [[drug]]s including those that increase the activity of the [[central nervous system]] and the body,<ref>{{cite web|title=stimulant – definition of stimulant in English {{!}} Oxford Dictionaries|url=https://en.oxforddictionaries.com/definition/stimulant|website=Oxford Dictionaries {{!}} English|url-status=dead|archive-url=https://web.archive.org/web/20170226074716/https://en.oxforddictionaries.com/definition/stimulant|archive-date=26 February 2017|df=dmy-all}}</ref> drugs that are pleasurable and invigorating, or drugs that have [[Sympathomimetic drug|sympathomimetic]] effects.<ref name=NBK64328>{{cite book|author1=Center for Substance Abuse Treatment |title=Chapter 2—How Stimulants Affect the Brain and Behavior|publisher=Substance Abuse and Mental Health Services Administration (US)|url=https://www.ncbi.nlm.nih.gov/books/NBK64328/|language=en|url-status=live|archive-url=https://web.archive.org/web/20170219042946/https://www.ncbi.nlm.nih.gov/books/NBK64328/|archive-date=19 February 2017|df=dmy-all|year=1999}}</ref> Stimulants are widely used throughout the world as [[prescription medicine]]s as well as without a prescription (either legally or [[Prohibition (drugs)|illicitly]]) as [[performance-enhancing substance|performance-enhancing]] or [[recreational drug use|recreational]] drugs. Among narcotics, stimulants produce a noticeable crash or ''[[Comedown (drugs)|comedown]]'' at the end of their effects. The most frequently prescribed stimulants as of 2013 were [[lisdexamfetamine]] (Vyvanse), [[methylphenidate]] (Ritalin), and [[amphetamine]] (Adderall).<ref>{{cite web|title=Top 100 Drugs for Q4 2013 by Sales – U.S. Pharmaceutical Statistics|url=https://www.drugs.com/stats/top100/sales|website=www.drugs.com|url-status=live|archive-url=https://web.archive.org/web/20130814232045/http://www.drugs.com/stats/top100/sales|archive-date=14 August 2013|df=dmy-all}}</ref> It was estimated in 2015 that the percentage of the world population that had used [[cocaine]] during a year was 0.4%. For the category "amphetamines and prescription stimulants" (with "amphetamines" including [[amphetamine]] and [[methamphetamine]]) the value was 0.7%, and for [[MDMA]] 0.4%.<ref>{{cite web|title=World Drug Report 2015|url=https://www.unodc.org/documents/wdr2015/World_Drug_Report_2015.pdf|url-status=live|archive-url=https://web.archive.org/web/20160215044543/https://www.unodc.org/documents/wdr2015/World_Drug_Report_2015.pdf|archive-date=15 February 2016|df=dmy-all|page=149}}</ref> == Effects == ===Acute=== Stimulants in therapeutic doses, such as those given to patients with [[Attention deficit hyperactivity disorder|ADHD]], increases ability to focus, vigor, sociability, libido and may elevate mood. However, in higher doses, stimulants may actually decrease the ability to focus, a principle of the [[Yerkes-Dodson Law]]. In higher doses, stimulants may also produce euphoria, vigor, and a decreased need for sleep. Many, but not all, stimulants have [[ergogenic]] effects. Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while cocaine has the opposite effect.<ref>{{cite journal|last1=Avois|first1=L|last2=Robinson|first2=N|last3=Saudan|first3=C|last4=Baume|first4=N|last5=Mangin|first5=P|last6=Saugy|first6=M|title=Central nervous system stimulants and sport practice|journal=British Journal of Sports Medicine|date=7 January 2017|volume=40|issue=Suppl 1|pages=i16–i20|doi=10.1136/bjsm.2006.027557|pmc=2657493|issn=0306-3674|pmid=16799095}}</ref> Neurocognitive enhancing effects of stimulants, specifically [[modafinil]], amphetamine and methylphenidate have been documented in healthy adolescents, and is a commonly cited reason among illicit drug users for use, particularly among college students in the context of studying.<ref>{{cite journal|last1=Bagot|first1=Kara Simone|last2=Kaminer|first2=Yifrah|title=Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review|journal=Addiction |date=1 April 2014|volume=109|issue=4|pages=547–557|pmid=24749160|issn=1360-0443|doi=10.1111/add.12460|pmc=4471173}}</ref> In some cases, psychiatric phenomena may emerge such as [[stimulant psychosis]], [[paranoia]], and [[suicidal ideation]]. Acute toxicity has been reportedly associated with homicide, paranoia, aggressive behavior, motor dysfunction, and [[punding]]. The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia.<ref>{{cite journal|last1=Morton|first1=W. Alexander|last2=Stockton|first2=Gwendolyn G.|title=Methylphenidate Abuse and Psychiatric Side Effects|journal=Primary Care Companion to the Journal of Clinical Psychiatry|date=8 January 2017|volume=2|issue=5|pages=159–164|pmc=181133|issn=1523-5998|pmid=15014637|doi=10.4088/PCC.v02n0502}}</ref> Most drugs classified as stimulants are sympathomimetics, that is they stimulate the sympathetic branch of the autonomic nervous system. This leads to effects such as [[mydriasis]], increased heart rate, blood pressure, respiratory rate and body temperature.<ref name=NBK64328/> When these changes become pathological, they are called [[Heart arrhythmia|arrhythmia]], [[hypertension]], and [[hyperthermia]], and may lead to [[rhabdomyolysis]], [[stroke]], [[cardiac arrest]], or [[seizures]]. However, given the complexity of the mechanisms that underlie these potentially fatal outcomes of acute stimulant toxicity, it is impossible to determine what dose may be lethal.<ref>{{cite book|title=Treatment for Stimulant Use Disorders.Chapter 5—Medical Aspects of Stimulant Use Disorders|chapter=Chapter 5—Medical Aspects of Stimulant Use Disorders |publisher=Center for Substance Abuse Treatment. Treatment for Stimulant Use Disorders. Rockville (MD): Substance Abuse and Mental Health Services Administration (US)|url=https://www.ncbi.nlm.nih.gov/books/NBK64323/|language=en|url-status=live|archive-url=https://web.archive.org/web/20170219043032/https://www.ncbi.nlm.nih.gov/books/NBK64323/|archive-date=19 February 2017|df=dmy-all|year=1999}}</ref> ===Chronic=== Assessment of the effects of stimulants is relevant given the large population currently taking stimulants. A systematic review of cardiovascular effects of prescription stimulants found no association in children, but found a correlation between prescription stimulant use and [[ischemic]] [[heart attack]]s.<ref>{{cite journal|last1=Westover|first1=Arthur N.|last2=Halm|first2=Ethan A.|title=Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review|journal=BMC Cardiovascular Disorders|date=9 June 2012|volume=12|issue=1 |pages=41|doi=10.1186/1471-2261-12-41|pmid=22682429|issn=1471-2261|pmc=3405448 |doi-access=free }}</ref> A review over a four-year period found that there were few negative effects of stimulant treatment, but stressed the need for longer-term studies.<ref>{{cite journal|last1=Fredriksen|first1=Mats|last2=Halmøy|first2=Anne|last3=Faraone|first3=Stephen V.|last4=Haavik|first4=Jan|title=Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies|journal=European Neuropsychopharmacology|date=1 June 2013|volume=23|issue=6|pages=508–527|doi=10.1016/j.euroneuro.2012.07.016|pmid=22917983|issn=1873-7862|hdl=10852/40257|s2cid=20400392|doi-access=free|hdl-access=free}}</ref> A review of a year long period of prescription stimulant use in those with [[Attention deficit hyperactivity disorder|ADHD]] found that cardiovascular side effects were limited to transient increases in blood pressure only.<ref>{{cite journal|last1=Hammerness|first1=Paul G.|last2=Karampahtsis|first2=Chris|last3=Babalola|first3=Ronke|last4=Alexander|first4=Mark E.|title=Attention-deficit/hyperactivity disorder treatment: what are the long-term cardiovascular risks?|journal=Expert Opinion on Drug Safety|date=1 April 2015|volume=14|issue=4|pages=543–551|doi=10.1517/14740338.2015.1011620|pmid=25648243|s2cid=39425997|issn=1744-764X}}</ref> Initiation of stimulant treatment in those with ADHD in early childhood appears to carry benefits into adulthood with regard to social and cognitive functioning, and appears to be relatively safe.<ref>{{cite journal|last1=Hechtman|first1=Lily|last2=Greenfield|first2=Brian|title=Long-term use of stimulants in children with attention deficit hyperactivity disorder: safety, efficacy, and long-term outcome|journal=Paediatric Drugs|date=1 January 2003|volume=5|issue=12|pages=787–794|pmid=14658920|issn=1174-5878|doi=10.2165/00148581-200305120-00002|s2cid=68191253}}</ref> Abuse of prescription stimulants (not following physician instruction) or of illicit stimulants carries many negative health risks. Abuse of cocaine, depending upon route of administration, increases risk of cardiorespiratory disease, [[stroke]], and [[sepsis]].<ref name=Sor2014>{{cite journal|last1=Sordo|first1=L|last2=Indave|first2=BI|last3=Barrio|first3=G|last4=Degenhardt|first4=L|last5=de la Fuente|first5=L|last6=Bravo|first6=MJ|title=Cocaine use and risk of stroke: a systematic review.|journal=Drug and Alcohol Dependence|date=1 September 2014|volume=142|pages=1–13|pmid=25066468|doi=10.1016/j.drugalcdep.2014.06.041|doi-access=free}}</ref> Some effects are dependent upon the route of administration, with intravenous use associated with the transmission of many disease such as [[Hepatitis C]], [[HIV/AIDS]] and potential medical emergencies such as [[infection]], [[thrombosis]] or [[pseudoaneurysm]],<ref>{{cite journal|last=COUGHLIN|first=P|author2=MAVOR, A|title=Arterial Consequences of Recreational Drug Use|journal=European Journal of Vascular and Endovascular Surgery|date=1 October 2006|volume=32|issue=4|pages=389–396|doi=10.1016/j.ejvs.2006.03.003|pmid=16682239|doi-access=free}}</ref> while inhalation may be associated with increased [[lower respiratory tract infection]], [[lung cancer]], and pathological restricting of lung tissue.<ref>{{cite journal|last1=Tashkin|first1=D. P.|title=Airway effects of marijuana, cocaine, and other inhaled illicit agents|journal=Current Opinion in Pulmonary Medicine|date=1 March 2001|volume=7|issue=2|pages=43–61|pmid=11224724|issn=1070-5287|doi=10.1097/00063198-200103000-00001|s2cid=23421796}}</ref> Cocaine may also increase risk for autoimmune disease<ref>{{cite journal|vauthors=Trozak D, Gould W |title = Cocaine abuse and connective tissue disease|journal = J Am Acad Dermatol|volume = 10|issue = 3|page = 525|year = 1984|pmid = 6725666|doi = 10.1016/S0190-9622(84)80112-7|doi-access = free}}</ref><ref>{{cite journal|title=Antiglomerular Basement Membrane Antibody-Mediated Glomerulonephritis after Intranasal Cocaine Use|author=Ramón Peces|journal=Nephron|year=1999|volume=81|issue=4|pages=434–438|pmid=10095180|doi=10.1159/000045328|last2=Navascués|first2=RA|last3=Baltar|first3=J|last4=Seco|first4=M|last5=Alvarez|first5=J|s2cid=26921706}}</ref><ref>{{cite journal |vauthors=Moore PM, Richardson B |title=Neurology of the vasculitides and connective tissue diseases |journal=J. Neurol. Neurosurg. Psychiatry |volume=65 |issue=1 |pages=10–22 |year=1998|pmid=9667555 |pmc=2170162|doi=10.1136/jnnp.65.1.10}}</ref> and damage nasal cartilage. Abuse of methamphetamine produces similar effects as well as marked degeneration of dopaminergic neurons, resulting in an increased risk for [[Parkinson's disease]].<ref name="pmid22392347">{{cite journal |vauthors=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L |title=Toxicity of amphetamines: an update |journal=Arch. Toxicol. |volume=86 |issue=8 |pages=1167–1231 |date=August 2012 |pmid=22392347 |doi=10.1007/s00204-012-0815-5 |s2cid=2873101 }}</ref><ref name="Thrash-">{{cite journal | vauthors = Thrash B, Thiruchelvan K, Ahuja M, Suppiramaniam V, Dhanasekaran M | title = Methamphetamine-induced neurotoxicity: the road to Parkinson's disease | journal = Pharmacol Rep | volume = 61 | issue = 6 | pages = 966–977 | year = 2009 | pmid = 20081231 | doi = 10.1016/s1734-1140(09)70158-6 | s2cid = 4729728 | url = http://www.if-pan.krakow.pl/pjp/pdf/2009/6_966.pdf | url-status = live | archive-url = https://web.archive.org/web/20110716111421/http://www.if-pan.krakow.pl/pjp/pdf/2009/6_966.pdf | archive-date = 16 July 2011 | df = dmy-all }}</ref><ref name="Autoxidation1">{{cite journal |vauthors=Sulzer D, Zecca L | title = Intraneuronal dopamine-quinone synthesis: a review | journal = Neurotox. Res. | volume = 1 | issue = 3 | pages = 181–195 |date=February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289 | 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 Med. Okayama | volume = 62 | issue = 3 | pages = 141–150 |date=June 2008 | pmid = 18596830 | doi = 10.18926/AMO/30942}}</ref> == Medical uses == Stimulants have been used in medicine for many conditions including [[obesity]], [[sleep disorders]], [[mood disorders]], [[impulse control disorders]], [[asthma]], [[nasal congestion]] and, in case of cocaine, as [[local anesthetic]]s.<ref>{{cite journal|last1=Harper|first1=S. J.|last2=Jones|first2=N. S.|title=Cocaine: what role does it have in current ENT practice? A review of the current literature|journal=The Journal of Laryngology and Otology|date=1 October 2006|volume=120|issue=10|pages=808–811|doi=10.1017/S0022215106001459|pmid=16848922|s2cid=28169472|issn=1748-5460}}</ref> Drugs used to treat obesity are called [[anorectic]]s and generally include drugs that follow the general definition of a stimulant, but other drugs such as [[cannabinoid receptor antagonist]]s also belong to this group.<ref>{{cite journal|last1=Kaplan|first1=Lee M.|title=Pharmacological therapies for obesity|journal=Gastroenterology Clinics of North America|date=1 March 2005|volume=34|issue=1|pages=91–104|doi=10.1016/j.gtc.2004.12.002|pmid=15823441|issn=0889-8553}}</ref><ref>{{cite journal|last1=Palamara|first1=Kerri L.|last2=Mogul|first2=Harriette R.|last3=Peterson|first3=Stephen J.|last4=Frishman|first4=William H.|title=Obesity: new perspectives and pharmacotherapies|journal=Cardiology in Review|date=1 October 2016|volume=14|issue=5|pages=238–258|doi=10.1097/01.crd.0000233903.57946.fd|pmid=16924165|issn=1538-4683}}</ref> [[Eugeroic]]s are used in management of sleep disorders characterized by [[excessive daytime sleepiness]], such as [[narcolepsy]], and include stimulants such as [[modafinil]] and [[pitolisant]].<ref>{{cite web|title=The Voice of the Patient A series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative|url=https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|publisher=Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)|url-status=live|archive-url=https://web.archive.org/web/20170505031213/https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|archive-date=5 May 2017|df=dmy-all}}</ref><ref>{{cite journal|last1=Heal|first1=David J|last2=Smith|first2=Sharon L|last3=Gosden|first3=Jane|last4=Nutt|first4=David J|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=Journal of Psychopharmacology |date=7 January 2017|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|issn=0269-8811|pmid=23539642}}</ref> Stimulants are used in impulse control disorders such as [[ADHD]]<ref>{{cite web|last1=Research|first1=Center for Drug Evaluation and|title=Drug Safety and Availability - FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults|url=https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|website=www.fda.gov|language=en|url-status=live|archive-url=https://web.archive.org/web/20131030064843/https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|archive-date=30 October 2013|df=dmy-all|date=26 June 2019}}</ref> and [[off-label use|off-label]] in [[mood disorder]]s such as [[major depressive disorder]] to increase [[mental energy|energy]], focus and elevate mood.<ref>{{cite journal|last1=Stotz|first1=Gabriele|last2=Woggon|first2=Brigitte|last3=Angst|first3=Jules|title=Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients|journal=Dialogues in Clinical Neuroscience|date=1 December 1999|volume=1|issue=3|pages=165–174|doi=10.31887/DCNS.1999.1.3/gstotz |pmc=3181580|issn=1294-8322|pmid=22034135}}</ref> Stimulants such as [[epinephrine]],<ref name="pmid18733372">{{cite journal |author = Doig RL | title = Epinephrin; especially in asthma | journal = California State Journal of Medicine | volume = 3 | issue = 2 | pages = 54–5 |date=February 1905 | pmid = 18733372 | pmc = 1650334 }}</ref> [[theophylline]] and [[salbutamol]]<ref>{{cite journal|last1=Chu|first1=Eric K.|last2=Drazen|first2=Jeffrey M.|title=Asthma|journal=American Journal of Respiratory and Critical Care Medicine|date=1 June 2005|volume=171|issue=11|pages=1202–1208|doi=10.1164/rccm.200502-257OE|pmid=15778490|issn=1073-449X}}</ref> orally have been used to treat asthma, but inhaled adrenergic drugs are now preferred due to less systemic side effects. [[Pseudoephedrine]] is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection.<ref name="Bicopoulos">Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.</ref><ref>{{cite web|title=Pseudoephedrine (By mouth) – National Library of Medicine|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|website=PubMed Health|url-status=live|archive-url=https://web.archive.org/web/20140214034938/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|archive-date=14 February 2014|df=dmy-all}}</ref> ===Depression=== Stimulants were one of the first classes of drugs to be used in the treatment of depression, beginning after the introduction of the amphetamines in the 1930s.<ref name="pmid18321627">{{cite journal | vauthors = Moncrieff J | title = The creation of the concept of an antidepressant: an historical analysis | journal = Soc Sci Med | volume = 66 | issue = 11 | pages = 2346–55 | date = June 2008 | pmid = 18321627 | doi = 10.1016/j.socscimed.2008.01.047 | url = }}</ref><ref name="Moncrieff2016">{{cite book | author = J. Moncrieff | date = 13 April 2016 | title = The Myth of the Chemical Cure: A Critique of Psychiatric Drug Treatment | publisher = Springer | pages = 121– | isbn = 978-0-230-58944-5 | oclc = 1047624331 | url = https://books.google.com/books?id=2tD7CwAAQBAJ&pg=PA121 | quote = A well-known textbook of physical treatments described stimulants as having 'limited value in depression' because the euphoria they induce quickly wears off and 'the patient slips back' (Sargant & Slater 1944).}}</ref><ref name="pmid34000249">{{cite journal | vauthors = Morelli M, Tognotti E | title = Brief history of the medical and non-medical use of amphetamine-like psychostimulants | journal = Exp Neurol | volume = 342 | issue = | pages = 113754 | date = August 2021 | pmid = 34000249 | doi = 10.1016/j.expneurol.2021.113754 | s2cid = 234768496 | url = }}</ref> However, they were largely abandoned for treatment of depression following the introduction of conventional [[antidepressant]]s in the 1950s.<ref name="pmid18321627"/><ref name="Moncrieff2016"/> Subsequent to this, there has been a resurgence in interest in stimulants for depression in recent years.<ref name="pmid26906078">{{cite journal | vauthors = Malhi GS, Byrow Y, Bassett D, Boyce P, Hopwood M, Lyndon W, Mulder R, Porter R, Singh A, Murray G | title = Stimulants for depression: On the up and up? | journal = Aust N Z J Psychiatry | volume = 50 | issue = 3 | pages = 203–7 | date = March 2016 | pmid = 26906078 | doi = 10.1177/0004867416634208 | s2cid = 45341424 | url = }}</ref><ref name="pmid17338594">{{cite journal | vauthors = Orr K, Taylor D | title = Psychostimulants in the treatment of depression : a review of the evidence | journal = CNS Drugs | volume = 21 | issue = 3 | pages = 239–57 | date = 2007 | pmid = 17338594 | doi = 10.2165/00023210-200721030-00004 | s2cid = 35761979 | url = }}</ref> Stimulants produce a fast-acting and pronounced but transient and short-lived mood lift.<ref name="pmid36009115">{{cite journal | vauthors = Pallikaras V, Shizgal P | title = Dopamine and Beyond: Implications of Psychophysical Studies of Intracranial Self-Stimulation for the Treatment of Depression | journal = Brain Sci | volume = 12 | issue = 8 | date = August 2022 | page = 1052 | pmid = 36009115 | doi = 10.3390/brainsci12081052 | pmc = 9406029 | url = | doi-access = free }}</ref><ref name="pmid35431828">{{cite journal | vauthors = Pallikaras V, Shizgal P | title = The Convergence Model of Brain Reward Circuitry: Implications for Relief of Treatment-Resistant Depression by Deep-Brain Stimulation of the Medial Forebrain Bundle | journal = Front Behav Neurosci | volume = 16 | issue = | pages = 851067 | date = 2022 | pmid = 35431828 | pmc = 9011331 | doi = 10.3389/fnbeh.2022.851067 | url = | doi-access = free }}</ref><ref name="pmid26906078" /><ref name="Moncrieff2016" /> In relation to this, they are minimally effective in the treatment of depression when administered continuously.<ref name="pmid36009115" /><ref name="pmid35431828" /> In addition, tolerance to the mood-lifting effects of amphetamine has led to dose escalation and [[drug dependence|dependence]].<ref name="pmid17338594"/> Although the efficacy for depression with continuous administration is modest, it may still reach [[statistical significance]] over [[placebo]] and provide benefits similar in magnitude to those of conventional antidepressants.<ref name="pmid29028590">{{cite journal | vauthors = Giacobbe P, Rakita U, Lam R, Milev R, Kennedy SH, McIntyre RS | title = Efficacy and tolerability of lisdexamfetamine as an antidepressant augmentation strategy: A meta-analysis of randomized controlled trials | journal = J Affect Disord | volume = 226 | issue = | pages = 294–300 | date = January 2018 | pmid = 29028590 | doi = 10.1016/j.jad.2017.09.041 | url = }}</ref><ref name="pmid28590365">{{cite journal | vauthors = McIntyre RS, Lee Y, Zhou AJ, Rosenblat JD, Peters EM, Lam RW, Kennedy SH, Rong C, Jerrell JM | title = The Efficacy of Psychostimulants in Major Depressive Episodes: A Systematic Review and Meta-Analysis | journal = J Clin Psychopharmacol | volume = 37 | issue = 4 | pages = 412–418 | date = August 2017 | pmid = 28590365 | doi = 10.1097/JCP.0000000000000723 | s2cid = 27622964 | url = }}</ref><ref name="pmid34144366">{{cite journal | vauthors = Bahji A, Mesbah-Oskui L | title = Comparative efficacy and safety of stimulant-type medications for depression: A systematic review and network meta-analysis | journal = J Affect Disord | volume = 292 | issue = | pages = 416–423 | date = September 2021 | pmid = 34144366 | doi = 10.1016/j.jad.2021.05.119 | url = }}</ref><ref name="pmid34986373">{{cite journal | vauthors = Nuñez NA, Joseph B, Pahwa M, Kumar R, Resendez MG, Prokop LJ, Veldic M, Seshadri A, Biernacka JM, Frye MA, Wang Z, Singh B | title = Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis | journal = J Affect Disord | volume = 302 | issue = | pages = 385–400 | date = April 2022 | pmid = 34986373 | pmc = 9328668 | doi = 10.1016/j.jad.2021.12.134 | url = }}</ref> The reasons for the short-term mood-improving effects of stimulants are unclear, but may relate to rapid [[drug tolerance|tolerance]].<ref name="pmid36009115" /><ref name="pmid35431828" /><ref name="Moncrieff2016" /><ref name="pmid15893821" /> Tolerance to the effects of stimulants has been studied and characterized both in animals<ref name="pmid15893821" /><ref name="pmid30768951">{{cite journal | vauthors = Folgering JH, Choi M, Schlumbohm C, van Gaalen MM, Stratford RE | title = Development of a non-human primate model to support CNS translational research: Demonstration with D-amphetamine exposure and dopamine response | journal = J Neurosci Methods | volume = 317 | issue = | pages = 71–81 | date = April 2019 | pmid = 30768951 | doi = 10.1016/j.jneumeth.2019.02.005 | s2cid = 72333922 | url = | doi-access = free }}</ref><ref name="pmid30733244">{{cite journal | vauthors = van Gaalen MM, Schlumbohm C, Folgering JH, Adhikari S, Bhattacharya C, Steinbach D, Stratford RE | title = Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine | journal = J Pharmacol Exp Ther | volume = 369 | issue = 1 | pages = 107–120 | date = April 2019 | pmid = 30733244 | doi = 10.1124/jpet.118.254508 | s2cid = 73441294 | url = | doi-access = free }}</ref><ref name="vanGaalenSchlumbohm2019">{{cite journal | last1=van Gaalen | first1=Marcel M. | last2=Schlumbohm | first2=Christina | last3=Folgering | first3=Joost H. | last4=Adhikari | first4=Saugat | last5=Bhattacharya | first5=Chandrali | last6=Steinbach | first6=Douglas | last7=Stratford | first7=Robert E. | title=Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine | journal=Journal of Pharmacology and Experimental Therapeutics | publisher=American Society for Pharmacology & Experimental Therapeutics (ASPET) | volume=369 | issue=1 | date=7 February 2019 | issn=0022-3565 | doi=10.1124/jpet.118.254508 | pages=107–120| pmid=30733244 | s2cid=73441294 | doi-access=free }}</ref> and humans.<ref name="pmid27021968">{{cite journal | vauthors = Ermer JC, Pennick M, Frick G | title = Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy | journal = Clin Drug Investig | volume = 36 | issue = 5 | pages = 341–56 | date = May 2016 | pmid = 27021968 | pmc = 4823324 | doi = 10.1007/s40261-015-0354-y | url = }}</ref><ref name="pmid28936175">{{cite journal | vauthors = Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME | title = Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects | journal = Front Pharmacol | volume = 8 | issue = | pages = 617 | date = 2017 | pmid = 28936175 | pmc = 5594082 | doi = 10.3389/fphar.2017.00617 | url = | doi-access = free }}</ref><ref name="pmid8834422">{{cite journal | vauthors = Brauer LH, Ambre J, De Wit H | title = Acute tolerance to subjective but not cardiovascular effects of d-amphetamine in normal, healthy men | journal = J Clin Psychopharmacol | volume = 16 | issue = 1 | pages = 72–6 | date = February 1996 | pmid = 8834422 | doi = 10.1097/00004714-199602000-00012 | url = }}</ref><ref name="pmid11441429">{{cite journal | vauthors = Comer SD, Hart CL, Ward AS, Haney M, Foltin RW, Fischman MW | title = Effects of repeated oral methamphetamine administration in humans | journal = Psychopharmacology (Berl) | volume = 155 | issue = 4 | pages = 397–404 | date = June 2001 | pmid = 11441429 | doi = 10.1007/s002130100727 | s2cid = 19103494 | url = }}</ref> Stimulant [[drug withdrawal|withdrawal]] is remarkably similar in its symptoms to those of major depressive disorder.<ref name="pmid12368072">{{cite journal | vauthors = Barr AM, Markou A, Phillips AG | title = A 'crash' course on psychostimulant withdrawal as a model of depression | journal = Trends Pharmacol Sci | volume = 23 | issue = 10 | pages = 475–82 | date = October 2002 | pmid = 12368072 | doi = 10.1016/s0165-6147(02)02086-2 | url = }}</ref><ref name="pmid15893821">{{cite journal | vauthors = Barr AM, Markou A | title = Psychostimulant withdrawal as an inducing condition in animal models of depression | journal = Neurosci Biobehav Rev | volume = 29 | issue = 4–5 | pages = 675–706 | date = 2005 | pmid = 15893821 | doi = 10.1016/j.neubiorev.2005.03.012 | s2cid = 23653608 | url = }}</ref><ref name="pmid21161752">{{cite journal | vauthors = D'Souza MS, Markou A | title = Neural substrates of psychostimulant withdrawal-induced anhedonia | journal = Curr Top Behav Neurosci | series = Current Topics in Behavioral Neurosciences | volume = 3 | issue = | pages = 119–78 | date = 2010 | location = Berlin, Heidelberg | pmid = 21161752 | doi = 10.1007/7854_2009_20 | isbn = 978-3-642-03000-0 | url = }}</ref><ref name="pmid16140055">{{cite journal | vauthors = Baicy K, Bearden CE, Monterosso J, Brody AL, Isaacson AJ, London ED | title = Common substrates of dysphoria in stimulant drug abuse and primary depression: therapeutic targets | journal = Int Rev Neurobiol | series = International Review of Neurobiology | volume = 65 | issue = | pages = 117–45 | date = 2005 | pmid = 16140055 | doi = 10.1016/S0074-7742(04)65005-7 | isbn = 9780123668660 | url = }}</ref> == Chemistry == {{For|details on stimulant classes|Substituted phenethylamine|Substituted amphetamine|Substituted phenylmorpholine|Substituted cathinone}} [[File:Methamphetamines.PNG|thumb|A chart comparing the chemical structures of different [[Template:Amphetamines|amphetamine derivatives]]]] Classifying stimulants is difficult, because of the large number of classes the drugs occupy, and the fact that they may belong to multiple classes; for example, [[MDMA|ecstasy]] can be classified as a [[substituted methylenedioxyphenethylamine]], a [[substituted amphetamine]] and consequently, a [[substituted phenethylamine]].{{Citation needed|reason=who says they are hard to classify?|date=January 2017}} When referring to stimulants, the parent drug (e.g., ''amphetamine'') will always be expressed in the singular{{According to whom|date=January 2017}}; with the word "substituted" placed before the parent drug ([[substituted amphetamine|''substituted amphetamines'']]).<!--Referring to the class as "amphetamines" is an abuse of language. Racemic, levo-, and dextro-amphetamine are "amphetamines"; methamphetamine and the like are substituted amphetamines or "amphetamine-type" compounds.--> Major stimulant classes include [[substituted phenethylamine|phenethylamines]] and their daughter class [[substituted amphetamines]].{{According to whom|date=January 2017}} === Amphetamines (class) === {{Main|Substituted amphetamines}} [[Substituted amphetamines]] are a [[chemical class|class of compounds]] based upon the [[amphetamine]] structure;<ref name="Amphetamine - a substituted amphetamine" /> it includes all [[derivative (chemistry)|derivative]] compounds which are formed by replacing, or [[substitution reaction|substituting]], one or more [[hydrogen atom]]s in the amphetamine core structure with [[substituent]]s.<ref name="Amphetamine - a substituted amphetamine">{{cite journal | vauthors = Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ | title = Biosynthesis of amphetamine analogs in plants | journal = Trends Plant Sci. | volume = 17 | issue = 7 | pages = 404–412 | date = 2012 | pmid = 22502775 | doi = 10.1016/j.tplants.2012.03.004 | quote = Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). Countless variation in functional group substitutions has yielded a collection of synthetic drugs with diverse pharmacological properties as stimulants, empathogens and hallucinogens [3].&nbsp;... Beyond (1''R'',2''S'')-ephedrine and (1''S'',2''S'')-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. The stereochemistry at the α-carbon is often a key determinant of pharmacological activity, with (''S'')-enantiomers being more potent. For example, (''S'')-amphetamine, commonly known as d-amphetamine or dextroamphetamine, displays five times greater psychostimulant activity compared with its (''R'')-isomer [78]. Most such molecules are produced exclusively through chemical syntheses and many are prescribed widely in modern medicine. For example, (''S'')-amphetamine (Figure 4b), a key ingredient in Adderall and Dexedrine, is used to treat attention deficit hyperactivity disorder (ADHD) [79].&nbsp;... <br />[Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.}}</ref><ref name="Substituted amphetamines">{{cite book | author = Glennon RA |veditors=Lemke TL, Williams DA, Roche VF, Zito W | title=Foye's principles of medicinal chemistry | date=2013 | publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins | location=Philadelphia, USA | isbn=9781609133450 | pages=646–648 | edition=7th | section-url=https://books.google.com/books?id=Sd6ot9ul-bUC&q=substituted%20derivatives%20substituents%20amphetamine%20substitution&pg=PA646 | section=Phenylisopropylamine stimulants: amphetamine-related agents | quote = The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39).}}</ref><ref name="pmid1855720">{{cite journal | vauthors = Lillsunde P, Korte T | title = Determination of ring- and N-substituted amphetamines as heptafluorobutyryl derivatives | journal = Forensic Sci. Int. | volume = 49 | issue = 2 | pages = 205–213 | date = March 1991 | pmid = 1855720 | doi=10.1016/0379-0738(91)90081-s}}</ref> Examples of substituted amphetamines are amphetamine (itself),<ref name="Amphetamine - a substituted amphetamine" /><ref name="Substituted amphetamines" /> [[methamphetamine]],<ref name="Amphetamine - a substituted amphetamine" /> [[ephedrine]],<ref name="Amphetamine - a substituted amphetamine" /> [[cathinone]],<ref name="Amphetamine - a substituted amphetamine" /> [[phentermine]],<ref name="Amphetamine - a substituted amphetamine" /> [[mephentermine]],<ref name="Amphetamine - a substituted amphetamine" /> [[bupropion]],<ref name="Amphetamine - a substituted amphetamine" /> [[methoxyphenamine]],<ref name="Amphetamine - a substituted amphetamine" /> [[selegiline]],<ref name="Amphetamine - a substituted amphetamine" /> [[amfepramone]],<ref name="Amphetamine - a substituted amphetamine" /> [[pyrovalerone]],<ref name="Amphetamine - a substituted amphetamine" /> [[MDMA]] (ecstasy), and [[2,5-dimethoxy-4-methylamphetamine|DOM]] (STP). Many drugs in this class work primarily by activating [[trace amine-associated receptor 1]] (TAAR1);<ref name="Miller" /> in turn, this causes [[reuptake inhibition]] and effluxion, or release, of [[dopamine]], [[norepinephrine]], and [[serotonin]].<ref name="Miller" /> An additional mechanism of some substituted amphetamines is the release of [[synaptic vesicle|vesicular stores]] of [[monoamine neurotransmitter]]s through [[VMAT2]], thereby increasing the concentration of these neurotransmitters in the [[cytosol]], or intracellular fluid, of the [[presynaptic neuron]].<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> Amphetamines-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treat [[major depression]], where subjects do not respond well to traditional [[selective serotonin reuptake inhibitor|SSRI]] medications,{{Citation needed|date=May 2015}} but evidence supporting this use is poor/mixed.<ref>{{cite journal |vauthors=Orr K, Taylor D | title = Psychostimulants in the Treatment of Depression | journal = CNS Drugs | volume = 21 | issue = 3 | pages = 239–57 | year = 2007 | pmid = 17338594 | doi = 10.2165/00023210-200721030-00004 | s2cid = 35761979 }}</ref> Notably, two recent large [[Phase III clinical trials|phase III]] studies of [[lisdexamfetamine]] (a [[prodrug]] to amphetamine) as an adjunct to an SSRI or SNRI in the treatment of [[major depressive disorder]] showed no further benefit relative to [[placebo]] in effectiveness.<ref name="DaleBang-Andersen2015">{{cite journal|last1=Dale|first1=Elena|last2=Bang-Andersen|first2=Benny|last3=Sánchez|first3=Connie|title=Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs|journal=Biochemical Pharmacology|volume=95|issue=2|year=2015|pages=81–97|issn=0006-2952|doi=10.1016/j.bcp.2015.03.011|pmid=25813654|doi-access=free}}</ref> Numerous studies have demonstrated the effectiveness of drugs such as [[Adderall]] (a mixture of [[salt (chemistry)|salts]] of [[amphetamine]] and [[dextroamphetamine]]) in controlling symptoms associated with [[ADHD]]. Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse.<ref>[http://www.drugabuse.gov/Testimony/7-26-06Testimony.html Efforts of the National Institute on Drug Abuse to Prevent and Treat Prescription Drug Abuse] {{webarchive|url=https://web.archive.org/web/20070929083259/http://www.drugabuse.gov/Testimony/7-26-06Testimony.html |date=29 September 2007 }}, Testimony Before the Subcommittee on Criminal Justice, Drug Policy, and Human Resources Committee on Government Reform, United States House of Representatives, 26 July 2006</ref> ===Cocaine analogues=== {{Main|List of cocaine analogues}} Hundreds of cocaine analogues have been created, all of them usually maintaining a benzyloxy connected to the 3 carbon of a tropane. Various modifications include substitutions on the benzene ring, as well as additions or substitutions in place of the normal carboxylate on the tropane 2 carbon. Various compound with similar structure activity relationships to cocaine that aren't technically analogues have been developed as well. ==Mechanisms of action== Most stimulants exert their activating effects by enhancing [[catecholamine]] neurotransmission. Catecholamine neurotransmitters are employed in regulatory pathways implicated in attention, arousal, motivation, task salience and reward anticipation. Classical stimulants either [[Monoamine reuptake inhibitor|block the reuptake]] or [[Monoamine releasing agent|stimulate the efflux]] of these catecholamines, resulting in increased activity of their circuits. Some stimulants, specifically those with [[empathogen]]ic and [[hallucinogen]]ic effects, also affect [[Serotonin|serotonergic]] transmission. Some stimulants, such as some amphetamine derivatives and, notably, [[yohimbine]], can decrease [[negative feedback]] by antagonizing regulatory autoreceptors.<ref>{{cite journal|last1=Docherty|first1=J R|title=Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)|journal=British Journal of Pharmacology|date=7 January 2017|volume=154|issue=3|pages=606–622|doi=10.1038/bjp.2008.124|pmc=2439527|issn=0007-1188|pmid=18500382}}</ref> [[Adrenergic agonist]]s, such as, in part, [[ephedrine]], act by directly binding to and activating [[adrenergic receptor]]s, producing sympathomimetic effects. There are also more indirect mechanisms a drug can elicit activating effects. Caffeine is an [[adenosine receptor antagonist]], and only indirectly increases catecholamine transmission in the brain.<ref>{{cite book|title=Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations.|publisher=National Academies Press (US)|location=Washington (DC)|url=https://www.ncbi.nlm.nih.gov/books/NBK223808/|language=en|url-status=live|archive-url=https://web.archive.org/web/20171009140913/https://www.ncbi.nlm.nih.gov/books/NBK223808/|archive-date=9 October 2017|df=dmy-all|year=2001}}</ref> [[Pitolisant]] is an [[H3 receptor antagonist|H3-receptor inverse agonist]]. As H3 receptors mainly act as autoreceptors, pitolisant decreases negative feedback to [[histamine]]rgic neurons, enhancing histaminergic transmission. == Notable stimulants == === Amphetamine === {{Main|Amphetamine}} Amphetamine is a potent [[central nervous system]] (CNS) stimulant of the [[substituted phenethylamine|phenethylamine class]] that is approved for the treatment of [[attention deficit hyperactivity disorder]] (ADHD) and [[narcolepsy]].<ref name="FDA Abuse & OD">{{cite web |title=Adderall XR Prescribing Information |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s024lbl.pdf |page=11 |work=United States Food and Drug Administration |date=June 2013 |access-date=7 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20141006101218/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s024lbl.pdf |archive-date=6 October 2014 |df=dmy-all }}</ref> Amphetamine is also used off-label as a [[performance enhancer|performance]] and [[Nootropic|cognitive enhancer]], and recreationally as an [[aphrodisiac]] and [[euphoriant]].<ref name="Ergogenics" /><ref name="Malenka_2009">{{cite book|vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |year=2009 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-148127-4 |page=318 |edition=2nd |chapter=Chapter 13: Higher Cognitive Function and Behavioral Control |quote=Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in individuals with ADHD and in normal subjects...it is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control, as will be discussed below. It is important to recognize, however, that stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks...through indirect stimulation of dopamine and norepinephrine receptors.}}</ref><ref name="Libido">{{cite journal|author=Montgomery KA |title=Sexual desire disorders |journal=Psychiatry |volume=5 |issue=6 |pages=50–55 |date=June 2008 |pmid=19727285 |pmc=2695750 }}</ref><ref name="Nonmedical">{{cite journal|vauthors=Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S |title=Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature |journal=J. Am. Acad. Child Adolesc. Psychiatry |volume=47 |issue=1 |pages=21–31 |date=January 2008 |pmid=18174822 |doi=10.1097/chi.0b013e31815a56f1 |quote=Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile)...<br /><br />Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.}}</ref> Although it is a prescription medication in many countries, unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use.<ref name="UN Convention">{{cite web |title=Convention on psychotropic substances |url=http://treaties.un.org/Pages/ViewDetails.aspx?src=TREATY&mtdsg_no=VI-16&chapter=6&lang=en |work=United Nations Treaty Collection |publisher=United Nations |access-date=7 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20160331074842/https://treaties.un.org/pages/ViewDetails.aspx?src=TREATY&mtdsg_no=VI-16&chapter=6&lang=en |archive-date=31 March 2016 |df=dmy-all }}</ref><ref name="drugpolicy">{{cite web |title=Methamphetamine facts |url=http://www.drugpolicy.org/drug-facts/methamphetamine-facts |work=DrugPolicy.org |access-date=7 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20180417185214/https://www.drugpolicy.org/drug-facts/methamphetamine-facts |archive-date=17 April 2018 |df=dmy-all }}</ref> As a consequence, amphetamine is illegally manufactured in [[clandestine chemistry|clandestine labs]] to be trafficked and sold to users.<ref name="World Drug Report" /> Based upon drug and [[drug precursor]] seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of [[methamphetamine]].<ref name="World Drug Report">{{cite web |vauthors=Chawla S, Le Pichon T |title=World Drug Report 2006 |year=2006 |pages=128–135 |work=United Nations Office on Drugs and Crime |url=http://www.unodc.org/pdf/WDR_2006/wdr2006_volume1.pdf |access-date=7 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20130530231143/http://www.unodc.org/pdf/WDR_2006/wdr2006_volume1.pdf |archive-date=30 May 2013 |df=dmy-all }}</ref> The first pharmaceutical amphetamine was [[Benzedrine]], a brand of inhalers used to treat a variety of conditions.<ref name="Amph Uses">{{cite journal|vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ|date=June 2013|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=J. Psychopharmacol.|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|pmid=23539642}}</ref><ref name="Benzedrine">{{cite journal|author=Rasmussen N |title=Making the first anti-depressant: amphetamine in American medicine, 1929–1950 |journal=J. Hist. Med. Allied Sci. |volume=61 |issue=3 |pages=288–323 |date=July 2006 |pmid=16492800 |doi=10.1093/jhmas/jrj039|s2cid=24974454 }}</ref> Because the dextrorotary isomer has greater stimulant properties, Benzedrine was gradually discontinued in favor of formulations containing all or mostly dextroamphetamine. Presently, it is typically prescribed as [[Adderall|mixed amphetamine salts]], [[dextroamphetamine]], and [[lisdexamfetamine]].<ref name="Amph Uses" /><ref name="Adderall IR">{{cite web |title=Adderall IR Prescribing Information |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf |work=United States Food and Drug Administration |date=March 2007 |access-date=2 November 2013 |page=5 |url-status=live |archive-url=https://web.archive.org/web/20130926063018/http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf |archive-date=26 September 2013 |df=dmy-all }}</ref> Amphetamine is a [[Norepinephrine–dopamine releasing agent|norepinephrine-dopamine releasing agent]] (NDRA). It enters neurons through [[Dopamine transporter|dopamine]] and [[norepinephrine transporter]]s and facilitates neurotransmitter efflux by activating [[TAAR1]] and inhibiting [[Vesicular monoamine transporter 2|VMAT2]].<ref name="Miller">{{cite journal|author=Miller GM |title=The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity |journal=J. Neurochem. |volume=116 |issue=2 |pages=164–176 |date=January 2011 |pmid=21073468 |pmc=3005101 |doi=10.1111/j.1471-4159.2010.07109.x}}</ref> At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved [[cognitive control]].<ref name="Malenka_2009" /><ref name="Libido" /><ref name="FDA Effects">{{cite web |title=Adderall XR Prescribing Information |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s024lbl.pdf |pages=4–8 |work=United States Food and Drug Administration |date=June 2013 |access-date=7 October 2013 |url-status=live |archive-url=https://web.archive.org/web/20141006101218/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s024lbl.pdf |archive-date=6 October 2014 |df=dmy-all }}</ref> Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.<ref name="Ergogenics">{{cite journal|vauthors=Liddle DG, Connor DJ |title=Nutritional supplements and ergogenic AIDS |journal=Prim. Care |volume=40 |issue=2 |pages=487–505 |date=June 2013 |pmid=23668655 |doi=10.1016/j.pop.2013.02.009 |quote=Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training...<br />Physiologic and performance effects<br />{{bull}}Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation<br />{{bull}}Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40<br />{{bull}}Improved reaction time<br />{{bull}}Increased muscle strength and delayed muscle fatigue<br />{{bull}}Increased acceleration<br />{{bull}}Increased alertness and attention to task}}</ref> In contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapid [[rhabdomyolysis|muscle breakdown]].<ref name="FDA Abuse & OD" /><ref name="Malenka_2009" /><ref name="Westfall">{{cite book|veditors=Brunton LL, Chabner BA, Knollmann BC |title=Goodman & Gilman's Pharmacological Basis of Therapeutics |year=2010 |publisher=McGraw-Hill |location=New York |isbn=978-0-07-162442-8 |vauthors=Westfall DP, Westfall TC |section=Miscellaneous Sympathomimetic Agonists |section-url=http://www.accessmedicine.com/content.aspx?aID=16661601 |edition=12th}}</ref> Very high doses can result in [[Stimulant psychosis#Amphetamines|psychosis]] (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use.<ref name="Cochrane">{{cite journal|vauthors=Shoptaw SJ, Kao U, Ling W |title=Treatment for amphetamine psychosis (Review) |journal=Cochrane Database of Systematic Reviews |year=2009 |volume=2009 |issue=1|doi=10.1002/14651858.CD003026.pub3 |pmid=19160215 |pmc=7004251 |pages=CD003026}}</ref><ref name="Stimulant Misuse">{{cite web |author=Greydanus D |title=Stimulant Misuse: Strategies to Manage a Growing Problem |type=Review Article |url=http://www.acha.org/prof_dev/ADHD_docs/ADHD_PDprogram_Article2.pdf |work=American College Health Association |publisher=ACHA Professional Development Program |access-date=2 November 2013 |page=20 |url-status=dead |archive-url=https://web.archive.org/web/20131103155156/http://www.acha.org/prof_dev/ADHD_docs/ADHD_PDprogram_Article2.pdf |archive-date=3 November 2013 |df=dmy-all }}</ref> As recreational doses are generally much larger than prescribed therapeutic doses, recreational use carries a far greater risk of serious side effects, such as dependence, which only rarely arises with therapeutic amphetamine use.<ref name="FDA Abuse & OD" /><ref name="Westfall" /><ref name="Cochrane" /> === Caffeine === {{Main|Caffeine}} [[File:Roasted coffee beans.jpg|180px|right|thumb|Roasted coffee beans, a common source of caffeine.]] Caffeine is a stimulant compound belonging to the [[xanthine]] class of chemicals naturally found in [[coffee]], [[tea]], and (to a lesser degree) [[Cocoa solids|cocoa]] or [[chocolate]]. It is included in many [[soft drink]]s, as well as a larger amount in [[energy drink]]s. Caffeine is the world's most widely used psychoactive drug and by far the most common stimulant. In North America, 90% of adults consume caffeine daily.<ref name="demon drink">{{cite journal |author=Lovett R |title=Coffee: The demon drink? |journal=New Scientist |issue=2518 |date=24 September 2005 |url=https://www.newscientist.com/article.ns?id=mg18725181.700 |access-date=3 August 2009 |url-status=live |archive-url=https://web.archive.org/web/20071024030810/http://www.newscientist.com/article.ns?id=mg18725181.700 |archive-date=24 October 2007 |df=dmy-all }} {{subscription required}}</ref> A few jurisdictions restrict its sale and use.{{Citation needed|date=November 2020|reason=This claim needs a reliable source; There may be a few jurisdictions that restrict its sale and use, but this needs to be verifiable.}} Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient, or reducing one of its side-effects (especially drowsiness). Tablets containing standardized doses of caffeine are also widely available. Caffeine's mechanism of action differs from many stimulants, as it produces stimulant effects by inhibiting adenosine receptors.<ref>{{cite journal|last1=Nehlig|first1=A.|last2=Daval|first2=J. L.|last3=Debry|first3=G.|title=Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects|journal=Brain Research. Brain Research Reviews|date=1 August 2016|volume=17|issue=2|pages=139–170|pmid=1356551|doi=10.1016/0165-0173(92)90012-b|s2cid=14277779}}</ref> Adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness.<ref>{{cite journal|last1=Bjorness|first1=Theresa E|last2=Greene|first2=Robert W|title=Adenosine and Sleep|journal=Current Neuropharmacology|date=8 January 2017|volume=7|issue=3|pages=238–245|doi=10.2174/157015909789152182|pmc=2769007|issn=1570-159X|pmid=20190965}}</ref> Caffeine has been found to increase striatal dopamine in animal models,<ref>{{cite journal|last1=Solinas|first1=Marcello|last2=Ferré|first2=Sergi|last3=You|first3=Zhi-Bing|last4=Karcz-Kubicha|first4=Marzena|last5=Popoli|first5=Patrizia|last6=Goldberg|first6=Steven R.|title=Caffeine Induces Dopamine and Glutamate Release in the Shell of the Nucleus Accumbens|journal=Journal of Neuroscience|date=1 August 2002|volume=22|issue=15|pages=6321–6324|language=en|issn=0270-6474|df=dmy-all|doi=10.1523/JNEUROSCI.22-15-06321.2002|pmid=12151508|pmc=6758129}}</ref> as well as inhibit the inhibitory effect of adenosine receptors on dopamine receptors,<ref name="pmid12804599">{{cite journal | vauthors = Kamiya T, Saitoh O, Yoshioka K, Nakata H | title = Oligomerization of adenosine A2A and dopamine D2 receptors in living cells | journal = Biochemical and Biophysical Research Communications | volume = 306 | issue = 2 | pages = 544–9 | date = Jun 2003 | pmid = 12804599 | doi = 10.1016/S0006-291X(03)00991-4 }}</ref> however the implications for humans are unknown. Unlike most stimulants, caffeine has no addictive potential. Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, per a study on drug abuse liability published in an NIDA research monograph that described a group preferring placebo over caffeine.<ref>{{cite book|last1=Fishchman|first1=N|last2=Mello|first2=N|title=Testing for Abuse Liability of Drugs in Humans|publisher=U.S. Department of Health and Human Services Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse |location=Rockville, MD |page=179|url=http://ww1.drugabuse.gov/pdf/monographs/92.pdf|url-status=dead|archive-url=https://web.archive.org/web/20161222041641/http://ww1.drugabuse.gov/pdf/monographs/92.pdf|archive-date=22 December 2016|df=dmy-all}}</ref> In large telephone surveys only 11% reported dependence symptoms. However, when people were tested in labs, only half of those who claim dependence actually experienced it, casting doubt on caffeine's ability to produce dependence and putting societal pressures in the spotlight.<ref name="pmid19428492">{{cite journal | vauthors = Temple JL | title = Caffeine use in children: what we know, what we have left to learn, and why we should worry | journal = Neuroscience and Biobehavioral Reviews | volume = 33 | issue = 6 | pages = 793–806 | year = 2009 | pmid = 19428492 | pmc = 2699625 | doi = 10.1016/j.neubiorev.2009.01.001 }}</ref> Coffee consumption is associated with a lower overall risk of [[cancer]].<ref name="pmid18834663">{{cite journal | author = Nkondjock A | title = Coffee consumption and the risk of cancer: an overview | journal = Cancer Lett. | volume = 277 | issue = 2 | pages = 121–5 | date = May 2009 | pmid = 18834663 | doi = 10.1016/j.canlet.2008.08.022 }}</ref> This is primarily due to a decrease in the risks of [[hepatocellular carcinoma|hepatocellular]] and [[endometrial cancer]], but it may also have a modest effect on colorectal cancer.<ref name=Cancer10/> There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of [[bladder cancer]].<ref name=Cancer10>{{cite journal | author = Arab L | title = Epidemiologic evidence on coffee and cancer | journal = Nutrition and Cancer | volume = 62 | issue = 3 | pages = 271–83 | year = 2010 | pmid = 20358464 | doi = 10.1080/01635580903407122 | s2cid = 44949233 }}</ref> A protective effect of caffeine against [[Alzheimer's disease]] is possible, but the evidence is inconclusive.<ref name="pmid20182026">{{cite journal |vauthors=Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N | title = Caffeine intake and dementia: systematic review and meta-analysis | journal = J. Alzheimers Dis. | volume = 20 |issue=Suppl 1 | pages = S187–204 | year = 2010 | pmid = 20182026 | doi = 10.3233/JAD-2010-091387 | doi-access = free }}</ref><ref name="pmid21427489">{{cite journal |vauthors=Marques S, Batalha VL, Lopes LV, Outeiro TF | title = Modulating Alzheimer's disease through caffeine: a putative link to epigenetics | journal = J. Alzheimers Dis. | volume = 24 | issue = 2 | pages = 161–71 | year = 2011 | pmid = 21427489 | doi = 10.3233/JAD-2011-110032 }}</ref><ref name="pmid20182037">{{cite journal |vauthors=Arendash GW, Cao C | title = Caffeine and coffee as therapeutics against Alzheimer's disease | journal = J. Alzheimers Dis. | volume = 20 |issue=Suppl 1 | pages = S117–26 | year = 2010 | pmid = 20182037 | doi = 10.3233/JAD-2010-091249 | doi-access = free }}</ref> Moderate coffee consumption may decrease the risk of [[cardiovascular disease]],<ref name=Ding2014>{{cite journal |vauthors=Ding M, Bhupathiraju SN, Satija A, van Dam RM, Hu FB | title = Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies. | journal = Circulation | volume = 129 | issue = 6 | pages = 643–59 | date = 11 February 2014 | pmid = 24201300 | pmc = 3945962 | doi = 10.1161/circulationaha.113.005925 }}</ref> and it may somewhat reduce the risk of [[Diabetes mellitus type 2|type 2 diabetes]].<ref name=Dam08>{{cite journal | author = van Dam RM | title = Coffee consumption and risk of type 2 diabetes, cardiovascular diseases, and cancer | journal = Applied Physiology, Nutrition, and Metabolism | volume = 33 | issue = 6 | pages = 1269–1283 | year = 2008 | pmid = 19088789 | doi = 10.1139/H08-120 }}</ref> Drinking 1-3 cups of coffee per day does not affect the risk of [[hypertension]] compared to drinking little or no coffee. However those who drink 2–4 cups per day may be at a slightly increased risk.<ref name="pmid21450934">{{cite journal |vauthors=Zhang Z, Hu G, Caballero B, Appel L, Chen L | title = Habitual coffee consumption and risk of hypertension: a systematic review and meta-analysis of prospective observational studies | journal = Am. J. Clin. Nutr. | volume = 93 | issue = 6 | pages = 1212–9 | date = June 2011 | pmid = 21450934 | doi = 10.3945/ajcn.110.004044 | doi-access = free }}</ref> Caffeine increases [[intraocular pressure]] in those with [[glaucoma]] but does not appear to affect normal individuals.<ref name="pmid20706731">{{cite journal |vauthors=Li M, Wang M, Guo W, Wang J, Sun X | title = The effect of caffeine on intraocular pressure: a systematic review and meta-analysis | journal = Graefes Arch. Clin. Exp. Ophthalmol. | volume = 249 | issue = 3 | pages = 435–42 | date = March 2011 | pmid = 20706731 | doi = 10.1007/s00417-010-1455-1 | s2cid = 668498 }}</ref> It may protect people from [[liver cirrhosis]].<ref name="pmid19825397">{{cite journal |vauthors=Muriel P, Arauz J | title = Coffee and liver diseases | journal = Fitoterapia | volume = 81 | issue = 5 | pages = 297–305 | year = 2010 | pmid = 19825397 | doi = 10.1016/j.fitote.2009.10.003 }}</ref> There is no evidence that coffee stunts a child's growth.<ref>{{cite book|author=O'Connor A |title=Never shower in a thunderstorm : surprising facts and misleading myths about our health and the world we live in |year=2007 |publisher=Times Books |location=New York |isbn=978-0-8050-8312-5 |page=144 |edition=1st |url=https://books.google.com/books?id=neuEbVUZik0C&pg=PA144 |access-date=15 January 2014}}</ref> Caffeine may increase the effectiveness of some medications including ones used to treat [[headaches]].<ref name="pmid21302868">{{cite journal |vauthors=Gilmore B, Michael M | title = Treatment of acute migraine headache | journal = Am Fam Physician | volume = 83 | issue = 3 | pages = 271–80 | date = February 2011 | pmid = 21302868 }}</ref> Caffeine may lessen the severity of [[acute mountain sickness]] if taken a few hours prior to attaining a high altitude.<ref name="pmid20367483">{{cite journal | author = Hackett PH | title = Caffeine at high altitude: java at base Camp | journal = High Alt. Med. Biol. | volume = 11 | issue = 1 | pages = 13–7 | year = 2010 | pmid = 20367483 | doi = 10.1089/ham.2009.1077 | s2cid = 8820874 }}</ref> === Ephedrine === {{Main|Ephedrine}} Ephedrine is a [[sympathomimetic]] [[amine]] similar in molecular structure to the well-known drugs [[phenylpropanolamine]] and [[methamphetamine]], as well as to the important [[neurotransmitter]] [[epinephrine]] (adrenaline). Ephedrine is commonly used as a stimulant, [[appetite suppressant]], concentration aid, and [[decongestant]], and to treat [[hypotension]] associated with anaesthesia. In chemical terms, it is an [[alkaloid]] with a [[phenethylamine]] skeleton found in various plants in the genus ''[[Ephedra (genus)|Ephedra]]'' (family [[Ephedraceae]]). It works mainly by increasing the activity of [[norepinephrine]] (noradrenaline) on [[adrenergic receptors]].<ref name=merck>[http://www.merckmanuals.com/professional/lexicomp/ephedrine.html Merck Manuals EPHEDrine] {{webarchive|url=https://web.archive.org/web/20110324031411/http://www.merckmanuals.com/professional/lexicomp/ephedrine.html |date=24 March 2011 }} Last full review/revision January 2010</ref> It is most usually marketed as the ''hydrochloride'' or ''sulfate'' salt. The herb ''má huáng'' (''[[Ephedra sinica]]''), used in [[traditional Chinese medicine]] (TCM), contains ephedrine and [[pseudoephedrine]] as its principal active constituents. The same may be true of other herbal products containing extracts from other ''Ephedra'' species. === MDMA === [[File:Ecstasy monogram.jpg|thumb|240px|Tablets containing MDMA]] {{Main|MDMA}} {{See also|Substituted methylenedioxyphenethylamines|l1=Its parent class|3,4-methylenedioxyamphetamine|l2=MDA}} 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, or molly) is a euphoriant, [[empathogen]], and stimulant of the amphetamine class.<ref>{{cite journal|last1=Meyer|first1=Jerrold S|title=3,4-methylenedioxymethamphetamine (MDMA): current perspectives|journal=Substance Abuse and Rehabilitation|date=21 November 2013|volume=4|pages=83–99|doi=10.2147/SAR.S37258|pmc=3931692|issn=1179-8467|pmid=24648791 |doi-access=free }}</ref> Briefly used by some psychotherapists as an adjunct to therapy, the drug became popular recreationally and the [[Drug Enforcement Administration|DEA]] listed MDMA as a [[Controlled substances act#Schedule I controlled substances|Schedule I controlled substance]], prohibiting most medical studies and applications. MDMA is known for its [[entactogen]]ic properties. The stimulant effects of MDMA include [[hypertension]], [[anorexia (symptom)|anorexia]] (appetite loss), [[euphoria]], social disinhibition, [[insomnia]] (enhanced wakefulness/inability to sleep), improved [[mental energy|energy]], increased arousal, and increased [[perspiration]], among others. Relative to catecholaminergic transmission, MDMA enhances serotonergic transmission significantly more, when compared to classical stimulants like amphetamine. MDMA does not appear to be significantly addictive or dependence forming.<ref>{{cite journal|last1=Nutt|first1=David|last2=King|first2=Leslie A.|last3=Saulsbury|first3=William|last4=Blakemore|first4=Colin|title=Development of a rational scale to assess the harm of drugs of potential misuse|journal=Lancet |date=24 March 2007|volume=369|issue=9566|pages=1047–1053|doi=10.1016/S0140-6736(07)60464-4|pmid=17382831|s2cid=5903121|issn=1474-547X}}</ref> Due to the relative safety of MDMA, some researchers such as [[David Nutt]] have criticized the scheduling level, writing a satirical article finding MDMA to be 28 times less dangerous than horseriding, a condition he termed "equasy" or "Equine Addiction Syndrome".<ref>{{Cite news|title = Ecstasy 'no more dangerous than horse riding'|url = https://www.telegraph.co.uk/news/uknews/law-and-order/4537874/Ecstasy-no-more-dangerous-than-horse-riding.html|website = Telegraph.co.uk |access-date = 4 December 2015|url-status = live|archive-url = https://web.archive.org/web/20151210201615/http://www.telegraph.co.uk/news/uknews/law-and-order/4537874/Ecstasy-no-more-dangerous-than-horse-riding.html|archive-date = 10 December 2015|df = dmy-all|date = 2009-02-07|editor-last1 = Hope |editor-first1 = Christopher }}</ref> === MDPV === {{Main|Methylenedioxypyrovalerone|l1=MDPV}} Methylenedioxypyrovalerone (MDPV) is a [[psychoactive drug]] with stimulant properties that acts as a [[norepinephrine-dopamine reuptake inhibitor]] (NDRI).<ref name="SimmlerBuser2012">{{cite journal|last1=Simmler |first1=L. D. |last2=Buser |first2=T. A. |last3=Donzelli |first3=M. |last4=Schramm |first4=Y |last5=Dieu |first5=L-H. |last6=Huwyler |first6=J. |last7=Chaboz |first7=S. |last8=Hoener |first8=M. C. |last9=Liechti |first9=M. E. |title=Pharmacological characterization of designer cathinones in vitro |journal=[[British Journal of Pharmacology]] |year=2012 |pages=458–470 |issn=0007-1188 |doi=10.1111/j.1476-5381.2012.02145.x |volume=168 |issue=2 |pmid=22897747 |pmc=3572571}}</ref> It was first developed in the 1960s by a team at Boehringer Ingelheim.<ref>US Patent 3478050 – 1-(3,4-methylenedioxy-phenyl)-2-pyrrolidino-alkanones</ref> MDPV remained an obscure stimulant until around 2004, when it was reported to be sold as a [[designer drug]]. Products labeled as [[Bath salts (drug)|bath salts]] containing MDPV were previously sold as recreational drugs in gas stations and convenience stores in the United States, similar to the marketing for [[Spice (drug)|Spice]] and [[K2 (drug)|K2]] as incense.<ref>{{cite news |url=http://www.kmbc.com/news/26256067/detail.html |title=Abuse Of Fake 'Bath Salts' Sends Dozens To ER |date=23 December 2010 |work=KMBC.com |url-status=dead |archive-url=https://web.archive.org/web/20110713161635/http://www.kmbc.com/news/26256067/detail.html |archive-date=13 July 2011 |df=dmy-all }}</ref><ref>{{cite web |url=http://healthybodydaily.com/dr-oz-in-case-you-missed-it/dr-oz-bath-salts-mdpv-bath-salts-drug-over-the-counter |title=MDPV Bath Salts Drug Over The Counter |url-status=dead |archive-url=https://web.archive.org/web/20110310193146/http://healthybodydaily.com/dr-oz-in-case-you-missed-it/dr-oz-bath-salts-mdpv-bath-salts-drug-over-the-counter |archive-date=10 March 2011 |df=dmy-all }}</ref> Incidents of psychological and physical harm have been attributed to MDPV use.<ref>{{cite news |access-date=16 May 2011 |url=http://www.nbc33tv.com/consumer-alert/parents-cautioned-against-over-the-counter-synthetic-speed |title=Parents cautioned against over the counter synthetic speed |date=9 November 2010 |publisher=NBC 33 News |author=Samantha Morgan |url-status=live |archive-url=https://web.archive.org/web/20110928084237/http://www.nbc33tv.com/consumer-alert/parents-cautioned-against-over-the-counter-synthetic-speed |archive-date=28 September 2011 |df=dmy-all }}</ref><ref>{{cite news |access-date=16 May 2011 |url=http://www.nbc33tv.com/news/bath-salts-used-to-get-high |title=Bath Salts Used to Get High |date=6 January 2011 |publisher=NBC 33 News |author=Kelsey Scram |url-status=live |archive-url=https://web.archive.org/web/20110928084244/http://www.nbc33tv.com/news/bath-salts-used-to-get-high |archive-date=28 September 2011 |df=dmy-all }}</ref> === Mephedrone === {{Main|Mephedrone}} Mephedrone is a [[Organic compound#Synthetic compounds|synthetic]] stimulant drug of the [[substituted amphetamine|amphetamine]] and [[substituted cathinone|cathinone]] classes. Slang names include drone<ref name=Cumming>{{cite news|last=Cumming |first=E. |url=https://www.telegraph.co.uk/health/7614099/Mephedrone-Chemistry-lessons.html |title=Mephedrone: Chemistry lessons |newspaper=The Daily Telegraph |date=22 April 2010 |access-date=14 September 2010 |location=London |archive-url=https://web.archive.org/web/20140107033621/http://news.bbc.co.uk/2/hi/uk_news/scotland/north_east/8555872.stm |archive-date=7 January 2014 |url-status=dead}}</ref> and MCAT.<ref name=bbc0803>{{cite news|url=http://news.bbc.co.uk/1/hi/scotland/north_east/8555872.stm |title=Drugs crackdown hailed a success |work=BBC News |date=8 March 2010 |access-date=31 March 2010 |archive-url=https://web.archive.org/web/20120826231758/http://www.telegraph.co.uk/health/7614099/Mephedrone-Chemistry-lessons.html |archive-date=26 August 2012 |url-status=live}}</ref> It is reported to be manufactured in China and is chemically similar to the cathinone compounds found in the [[khat]] plant of [[eastern Africa]]. It comes in the form of tablets or a powder, which users can swallow, snort, or inject, producing similar effects to [[MDMA]], [[amphetamine]]s, and [[cocaine]]. Mephedrone was first synthesized in 1929, but did not become widely known until it was rediscovered in 2003. By 2007, mephedrone was reported to be available for sale on the Internet; by 2008 law enforcement agencies had become aware of the compound; and, by 2010, it had been reported in most of Europe, becoming particularly prevalent in the United Kingdom. Mephedrone was first made illegal in Israel in 2008, followed by Sweden later that year. In 2010, it was made illegal in many European countries, and, in December 2010, the EU ruled it illegal. In Australia, New Zealand, and the US, it is considered an [[structural analog|analog]] of other illegal drugs and can be controlled by laws similar to the [[Federal Analog Act]]. In September 2011, the USA temporarily classified mephedrone as illegal, in effect from October 2011. === Methamphetamine === {{Main|Methamphetamine}} Methamphetamine (contracted from {{nowrap|[[Methyl group|''N''-'''meth'''yl]]-[[amphetamine|'''a'''lpha-'''m'''ethyl'''ph'''en'''et'''hyl'''amine''']]}}) is a potent psychostimulant of the [[phenethylamine]] and [[substituted amphetamine|amphetamine]] [[chemical classification|classes]] that is used to treat [[attention deficit hyperactivity disorder]] (ADHD) and [[obesity]].<ref name = "Malenka">{{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 |isbn=9780071481274 |page=370 |edition=2nd |chapter=15 |quote=Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.}}</ref><ref name="Desoxyn">{{cite web |title=Desoxyn Prescribing Information |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/005378s028lbl.pdf |date=December 2013 |work=United States Food and Drug Administration |access-date=6 January 2014 |url-status=live |archive-url=https://web.archive.org/web/20140102192621/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/005378s028lbl.pdf |archive-date=2 January 2014 |df=dmy-all }}</ref><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> Methamphetamine exists as two [[enantiomer]]s, [[dextrorotary]] and [[levorotary]].<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 |doi=10.1523/JNEUROSCI.15-02-01308.1995|pmc=6577819 }}</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> Dextromethamphetamine is a stronger CNS stimulant than [[levomethamphetamine]];<ref name="Westfall" /><ref name="Kuczenski" /><ref name="Mendelson" /> however, both are addictive and produce the same toxicity symptoms at high doses.<ref name="Mendelson" /> Although rarely prescribed due to the potential risks, methamphetamine hydrochloride is approved by the [[United States Food and Drug Administration]] (USFDA) under the trade name ''Desoxyn''.<ref name="Desoxyn" /> Recreationally, methamphetamine is used to [[aphrodisiac|increase sexual desire]], [[euphoriant|lift the mood]], and increase [[mental energy|energy]], allowing some users to engage in sexual activity continuously for several days straight.<ref name="Desoxyn" />{{not in citation|date=December 2021}}<ref name="SF Meth" />{{unreliable source|date=December 2021}} Methamphetamine may be sold illicitly, either as pure dextromethamphetamine or in an [[racemate|equal parts]] mixture of the right- and left-handed molecules (i.e., 50%&nbsp;levomethamphetamine and 50%&nbsp;dextromethamphetamine).<ref name="SF Meth">{{cite episode |date=11 August 2013 |title=San Francisco Meth Zombies |url=http://channel.nationalgeographic.com/drugs-inc/episodes/san-francisco-meth-zombies/ |series=Drugs, Inc. |series-link=Drugs, Inc. |season=4 |number=1 |network=National Geographic Channel |minutes=43 |asin=B00EHAOBAO |url-status=dead |archive-url=https://web.archive.org/web/20160708142916/http://channel.nationalgeographic.com/drugs-inc/episodes/san-francisco-meth-zombies/ |archive-date=8 July 2016 |df=dmy-all }}</ref> Both dextromethamphetamine and racemic methamphetamine are [[Schedule II Controlled Substance|schedule II]] controlled substances in the United States.<ref name="Desoxyn" /> Also, the production, distribution, sale, and possession of methamphetamine is restricted or illegal in many other countries due to its placement in schedule II of the [[Convention on Psychotropic Substances|United Nations Convention on Psychotropic Substances]] treaty.<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=9789211482232 |url=http://www.unodc.org/pdf/youthnet/ATS.pdf |access-date=11 November 2013 |url-status=live |archive-url=https://web.archive.org/web/20131016082310/http://www.unodc.org/pdf/youthnet/ATS.pdf |archive-date=16 October 2013 |df=dmy-all }}</ref><ref name="incb">{{cite web|title=List of psychotropic substances under international control |work=International Narcotics Control Board |publisher=United Nations |url=http://www.incb.org/pdf/e/list/green.pdf |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 contrast, [[levomethamphetamine]] is an [[over-the-counter drug]] in the United States.{{#tag:ref|The active ingredient in some OTC inhalers in the United States is listed as ''levmetamfetamine'', the [[International Nonproprietary Name|INN]] and [[United States Adopted Name|USAN]] of levomethamphetamine.<ref name="FDA levmetamfetamine">{{cite web|title=CFR TITLE 21: 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|access-date=7 March 2016|date=April 2015|quote=Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in each 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.|url-status=live|archive-url=https://web.archive.org/web/20150918190451/http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=341.80|archive-date=18 September 2015|df=dmy-all}}</ref><ref>{{cite encyclopedia | title=Levomethamphetamine| section=Identification | section-url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604#section=Identification | work=Pubchem Compound| publisher=National Center for Biotechnology Information }}</ref>|name="OTC levmetamfetamine"|group = "note"}} In low doses, methamphetamine can cause an [[euphoria|elevated mood]] and increase alertness, concentration, and energy in fatigued individuals.<ref name="Westfall" /><ref name="Desoxyn" /> At higher doses, it can induce [[methamphetamine psychosis|psychosis]], [[rhabdomyolysis]], and [[cerebral hemorrhage]].<ref name="Westfall" /><ref name="Desoxyn" /> Methamphetamine is known to have a high potential for [[substance abuse|abuse]] and [[substance dependence|addiction]].<ref name="Westfall" /><ref name="Desoxyn" /> Recreational use of methamphetamine may result in psychosis or lead to [[post-withdrawal syndrome]], a withdrawal syndrome that can persist for months beyond the typical withdrawal period.<ref name="Cruickshank-2009">{{cite journal|vauthors=Cruickshank CC, Dyer KR |title=A review of the clinical pharmacology of methamphetamine |journal=Addiction |volume=104 |issue=7 |pages=1085–1099 |date=July 2009 |pmid=19426289 |doi=10.1111/j.1360-0443.2009.02564.x|s2cid=37079117 |doi-access=free }}</ref> Unlike [[amphetamine]] and [[cocaine]], methamphetamine is [[neurotoxic]] to humans, damaging both [[dopamine]] and [[serotonin]] neurons in the [[central nervous system]] (CNS).<ref name = "Malenka" /><ref name="pmid19328213" /> Unlike the long-term use of amphetamine in prescription doses, which may improve certain brain regions in individuals with ADHD, there is evidence that methamphetamine causes brain damage from long-term use in humans;<ref name = "Malenka" /><ref name="pmid19328213" /> this damage includes adverse changes in brain structure and function, such as reductions in [[gray matter]] volume in several brain regions and adverse changes in markers of metabolic integrity.<ref name="Neuroplasticity 1">{{cite journal|vauthors=Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K |title=Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects |journal=JAMA Psychiatry |volume=70 |issue=2 |pages=185–198 |date=February 2013 |pmid=23247506 |doi=10.1001/jamapsychiatry.2013.277 }}</ref><ref name="Neuroplasticity 2">{{cite journal|vauthors=Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J |title=Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies |journal=J. Clin. Psychiatry |volume=74 |issue=9 |pages=902–917 |date=September 2013 |pmid=24107764 |doi=10.4088/JCP.12r08287 |pmc=3801446}}</ref><ref name="pmid19328213" /> However, recreational amphetamine doses may also be neurotoxic. <ref>{{Cite journal|url=https://www.cambridge.org/core/journals/psychological-medicine/article/continuous-amphetamine-intoxication-an-animal-model-of-the-acute-psychotic-episode/7DEB3BCC38395608F1C4FE87529D4C8F|doi=10.1017/S003329170005145X|title=Continuous amphetamine intoxication: An animal model of the acute psychotic episode|year=1983|last1=Ellison|first1=Gaylord D.|last2=Eison|first2=Michael S.|journal=Psychological Medicine|volume=13|issue=4|pages=751–761|pmid=6320247|s2cid=2337423 }}</ref> === Methylphenidate === {{Main|Methylphenidate}} Methylphenidate is a stimulant drug that is often used in the treatment of ADHD and narcolepsy and occasionally to treat obesity in combination with diet restraints and exercise. Its effects at therapeutic doses include increased focus, increased alertness, decreased appetite, decreased need for sleep and decreased impulsivity. Methylphenidate is not usually used recreationally, but when it is used, its effects are very similar to those of amphetamines. Methylphenidate acts as a norepinephrine-dopamine reuptake inhibitor, by blocking the [[norepinephrine transporter]] (NET) and the [[dopamine transporter]] (DAT). Methylphenidate has a higher affinity for the dopamine transporter than for the norepinephrine transporter, and so its effects are mainly due to elevated dopamine levels caused by the inhibited reuptake of dopamine, however increased norepinephrine levels also contribute to various of the effects caused by the drug. Methylphenidate is sold under a number of brand names including Ritalin. Other versions include the long lasting tablet Concerta and the long lasting transdermal patch Daytrana. === Cocaine === [[File:Cocaine lines 2.jpg|thumb|180px|right|Lines of illicit [[cocaine]], used as a [[recreational drug|recreational]] stimulant]] {{Main|Cocaine}} Cocaine is an [[SNDRI]]. Cocaine is made from the leaves of the [[coca]] shrub, which grows in the mountain regions of South American countries such as [[Bolivia]], [[Colombia]], and [[Peru]], regions in which it was cultivated and used for centuries mainly by the [[Aymara people]]. In Europe, North America, and some parts of Asia, the most common form of cocaine is a white crystalline powder. Cocaine is a stimulant but is not normally prescribed therapeutically for its stimulant properties, although it sees clinical use as a local anesthetic, in particular in [[ophthalmology]].<ref>{{Cite web|date=2020|title=Efectos psicológicos del consumo de la cocaína|url=https://www.avancepsicologos.com/efectos-psicologicos-del-consumo-de-la-cocaina/|website=Avance Psicólogos|language=es}}</ref> Most cocaine use is recreational and its abuse potential is high (higher than amphetamine), and so its sale and possession are strictly controlled in most jurisdictions. Other [[tropane]] derivative drugs related to cocaine are also known such as [[troparil]] and [[lometopane]] but have not been widely sold or used recreationally.<ref>{{cite journal|author1=AJ Giannini |author2=WC Price |title=Contemporary drugs of abuse |journal=American Family Physician |volume=33 |pages=207–213 |year=1986}}</ref> === Nicotine === {{Main|Nicotine}} [[Nicotine]] is the active chemical constituent in [[tobacco]], which is available in many forms, including [[cigarette]]s, [[cigar]]s, [[chewing tobacco]], and [[smoking cessation]] aids such as [[nicotine patch]]es, [[nicotine gum]], and [[electronic cigarette]]s. Nicotine is used widely throughout the world for its stimulating and relaxing effects. Nicotine exerts its effects through the agonism of [[nicotinic acetylcholine receptors]], resulting in multiple downstream effects such as increase in activity of dopaminergic neurons in the midbrain [[reward system]], and acetaldehyde one of the tobacco constituent decreased the expression of [[monoamine oxidase]] in the brain.<ref>{{cite journal|last1=Talhouth|first1=Reinskje|last2=Opperhuizen|first2=Antoon|last3=van Amsterdam G. C.|first3=Jan|title=Role of acetaldehyde in tobacco smoke addiction|journal=European Neuropsychopharmacology|date=October 2007|volume=17|issue=10|pages=627–636|doi=10.1016/j.euroneuro.2007.02.013|pmid=17382522|s2cid=25866206}}</ref> Nicotine is addictive and dependence forming. Tobacco, the most common source of nicotine, has an overall harm to user and self score 3 percent below cocaine, and 13 percent above amphetamines, ranking 6th most harmful of the 20 drugs assessed, as determined by a multi-criteria decision analysis.<ref>{{cite journal|last1=Nutt|first1=David J.|last2=King|first2=Leslie A.|last3=Phillips|first3=Lawrence D.|title=Drug harms in the UK: a multicriteria decision analysis|journal=Lancet |date=6 November 2010|volume=376|issue=9752|pages=1558–1565|doi=10.1016/S0140-6736(10)61462-6|pmid=21036393|issn=1474-547X|citeseerx=10.1.1.690.1283|s2cid=5667719}}</ref> === Phenylpropanolamine === {{Main|Phenylpropanolamine}} Phenylpropanolamine (PPA; Accutrim; β-hydroxyamphetamine), also known as the [[stereoisomerism|stereoisomers]] norephedrine and norpseudoephedrine, is a [[psychoactive drug]] of the [[phenethylamine]] and [[amphetamine]] [[chemical class]]es that is used as a stimulant, [[decongestant]], and [[anorectic]] agent.<ref name="pmid15608085">{{cite journal|author=Flavahan NA |title=Phenylpropanolamine constricts mouse and human blood vessels by preferentially activating alpha2-adrenoceptors |journal=Journal of Pharmacology and Experimental Therapeutics |volume=313 |issue=1 |pages=432–9 |date=April 2005 |pmid=15608085 |doi=10.1124/jpet.104.076653 |s2cid=41470513 }}</ref> It is commonly used in [[prescription drug|prescription]] and [[over-the-counter drug|over-the-counter]] [[cough and cold preparation]]s. In [[veterinary medicine]], it is used to control [[urinary incontinence]] in dogs under [[trade name]]s Propalin and Proin. In the United States, PPA is no longer sold without a prescription due to a proposed increased risk of [[stroke]] in younger women. In a few countries in Europe, however, it is still available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001.<ref>{{cite web|url=http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2001-eng.php |title=Advisories, Warnings and Recalls – 2001 |date=7 January 2009 |access-date=10 January 2011 |publisher=[[Health Canada]] |url-status=dead |archive-url=https://web.archive.org/web/20100503164144/http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2001-eng.php |archive-date=3 May 2010 }}</ref> In India, human use of PPA and its formulations were banned on 10 February 2011.<ref>{{cite web |url=http://www.cdsco.nic.in/html/Drugsbanned.html |title=Drugs Banned in India |publisher=Central Drugs Standard Control Organization |work=Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India |access-date=7 January 2014 |url-status=dead |archive-url=https://web.archive.org/web/20131013222927/http://cdsco.nic.in/html/drugsbanned.html |archive-date=13 October 2013 |df=dmy-all }}</ref> === Lisdexamfetamine === {{Main|Lisdexamfetamine}} Lisdexamfetamine (Vyvanse, etc.) is an amphetamine-type medication, sold for use in treating ADHD.<ref>{{Cite web |title=Lisdexamfetamine: MedlinePlus Drug Information |url=https://medlineplus.gov/druginfo/meds/a607047.html |access-date=2023-08-07 |website=medlineplus.gov |language=en}}</ref> Its effects typically last around 14 hours.<ref name="AHFS20192">{{cite web |title=Lisdexamfetamine Dimesylate Monograph for Professionals |url=https://www.drugs.com/monograph/lisdexamfetamine-dimesylate.html |access-date=15 April 2019 |website=Drugs.com |publisher=American Society of Health-System Pharmacists}}</ref> Lisdexamfetamine is inactive on its own and is metabolized into [[dextroamphetamine]] in the body.<ref>{{Cite journal |last=Dolder |first=Patrick |date=September 7, 2017 |title=Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with d-Amphetamine in Healthy Subjects |journal=Frontiers in Pharmacology |volume=8 |page=617 |doi=10.3389/fphar.2017.00617 |pmid=28936175 |pmc=5594082 |doi-access=free }}</ref> Consequently, it has a lower abuse potential. === Pseudoephedrine === {{Main|Pseudoephedrine}} Pseudoephedrine is a [[sympathomimetic]] [[drug]] of the [[substituted phenethylamine|phenethylamine]] and [[substituted amphetamine|amphetamine]] [[chemical class]]es. It may be used as a [[decongestant|nasal/sinus decongestant]], as a stimulant,<ref>{{cite journal |title=Pseudoephedrine is without ergogenic effects during prolonged exercise |author1=Hunter Gillies |author2=Wayne E. Derman |author3=Timothy D. Noakes |author4=Peter Smith |author5=Alicia Evans |author6=Gary Gabriels |name-list-style=amp |journal=Journal of Applied Physiology |date=1 December 1996 |volume=81 |pages=2611–2617 |issue=6 |pmid=9018513 |df=dmy-all |doi=10.1152/jappl.1996.81.6.2611 |s2cid=15702353 }}</ref> or as a [[wakefulness-promoting agent]].<ref>{{cite journal|last=Hodges |first=K |author2=Hancock S |author3=Currel K |author4=Hamilton B |author5=Jeukendrup AE |title=Pseudoephedrine enhances performance in 1500-m runners |journal=Medicine and Science in Sports and Exercise |date=Feb 2006 |pmid=16531903 |doi=10.1249/01.mss.0000183201.79330.9c |volume=38 |issue=2 |pages=329–33|doi-access=free }}</ref> The [[Salt (chemistry)|salts]] pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many [[over-the-counter drug|over-the-counter]] [[dosage form|preparations]], either as a single ingredient or (more commonly) in combination with [[antihistamine]]s, [[guaifenesin]], [[dextromethorphan]], and/or [[paracetamol]] (acetaminophen) or another [[non-steroidal anti-inflammatory drug|NSAID]] (such as [[aspirin]] or [[ibuprofen]]). It is also used as a precursor chemical in the illegal production of methamphetamine. === ''Catha edulis'' (Khat) === {{Main|Khat}} [[File:Catha edulis.jpg|thumb|200px|right|alt=Photograph of the khat plant|''Catha edulis'']] Khat is a [[flowering plant]] native to the [[Horn of Africa]] and the [[Arabian Peninsula]].<ref name="Tooea">{{cite book|last=Dickens |first=Charles |chapter=The Orsons of East Africa |title=Household Words: A Weekly Journal, Volume 14 |publisher=Bradbury & Evans |year=1856 |orig-year=Digitized 19 February 2010 |page=176 |chapter-url=https://books.google.com/books?id=EdUnAQAAIAAJ&pg=PA176 |access-date=7 January 2014}} {{open access}} {{link note|note=Free eBook}}</ref><ref name="Kciy">{{cite news |url=https://www.who.int/bulletin/volumes/86/10/08-011008/en/ |title=Khat chewing in Yemen: turning over a new leaf – Khat chewing is on the rise in Yemen, raising concerns about the health and social consequences |last=Al-Mugahed |first=Leen |access-date=8 January 2014 |publisher=World Health Organization |date=October 2008 |url-status=dead |archive-url=https://web.archive.org/web/20140108103026/http://www.who.int/bulletin/volumes/86/10/08-011008/en/ |archive-date=8 January 2014 |df=dmy-all }}</ref> Khat contains a [[monoamine]] [[alkaloid]] called [[cathinone]], a "keto-amphetamine", that is said to cause excitement, [[Anorectic|loss of appetite]], and [[euphoria (emotion)|euphoria]]. In 1980, the [[World Health Organization]] (WHO) classified it as a [[drug of abuse]] that can produce mild to moderate [[Substance dependence|psychological dependence]] (less than tobacco or alcohol),<ref name="King">{{cite journal|vauthors=Nutt D, King LA, Blakemore C |title=Development of a rational scale to assess the harm of drugs of potential misuse |journal=Lancet |volume=369 |issue=9566 |pages=1047–53 |date=March 2007 |pmid=17382831 |doi=10.1016/S0140-6736(07)60464-4|s2cid=5903121 }}</ref> although the WHO does not consider khat to be seriously addictive.<ref name="Kciy" /> It is banned in some countries, such as the United States, Canada, and Germany, while its production, sale, and consumption are legal in other nations, including [[Djibouti]], [[Ethiopia]], [[Somalia]], Kenya and [[Yemen]].<ref name="Hafmc">Haight-Ashbury Free Medical Clinic, ''Journal of psychoactive drugs'', Volume 41, (Haight-Ashbury Publications: 2009), p.3.</ref> ===Modafinil=== {{Main article|Modafinil}} [[Modafinil]] is an [[eugeroic]] medication, which means that it promotes wakefulness and alertness. Modafinil is sold under the brand name Provigil among others. Modafinil is used to treat [[excessive daytime sleepiness]] due to [[narcolepsy]], [[shift work sleep disorder]], or [[obstructive sleep apnea]]. While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive.<ref>{{Cite journal|url=https://doi.org/10.1097/JCP.0000000000001085|title=The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis|first1=M Alexandra|last1=Kredlow|first2=Ani|last2=Keshishian|first3=Sarah|last3=Oppenheimer|first4=Michael W|last4=Otto|date=1 September 2019|journal=Journal of Clinical Psychopharmacology|volume=39|issue=5|pages=455–461|via=Europe PMC|doi=10.1097/jcp.0000000000001085|pmid=31433334|s2cid=201119084 }}</ref> Despite being a CNS stimulant, the addiction and [[drug dependence|dependence]] liabilities of modafinil are considered very low.<ref name="pmid23065655">{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–752 | date = October 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 }}</ref><ref name="FDA-2015-Provigil-Prescribing">{{cite web|date=January 2015|title=Provigil: Prescribing information |url= http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|access-date=August 16, 2015|website= FDA.gov| publisher= [[United States Food and Drug Administration]] |agency=Cephalon, Inc|archive-date=February 17, 2017|archive-url= https://web.archive.org/web/20170217165804/https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|url-status=live}}</ref><ref name="pmid33435717">{{cite journal |vauthors= Kakehi S, Tompkins DM |title=A Review of Pharmacologic Neurostimulant Use During Rehabilitation and Recovery After Brain Injury |journal=Ann Pharmacother |volume=55 |issue=10 |pages=1254–1266 |date=October 2021 |pmid=33435717 |doi=10.1177/1060028020983607 |s2cid=231593912 }}</ref> Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have [[Mood elevation|mood-elevating properties]].<ref name="FDA-2015-Provigil-Prescribing"/> The similarities in effects with [[caffeine]] are not clearly established.<ref name="pmid22375280">{{cite journal | vauthors = Kim D | title = Practical use and risk of modafinil, a novel waking drug | journal = Environmental Health and Toxicology | volume = 27 | pages = e2012007 | date = 2012 | pmid = 22375280 | pmc = 3286657 | doi = 10.5620/eht.2012.27.e2012007 }}</ref><ref name="Warot-1993">{{Cite journal|vauthors=Warot D, Corruble E, Payan C, Weil JS, Puech AJ|date=1993|title=Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo|journal=European Psychiatry |volume=8|issue=4|pages=201–208|doi=10.1017/S0924933800002923|s2cid=151797528 }}</ref> Unlike other stimulants, modafinil does not induce a subjective [[Pleasure|feeling of pleasure or reward]], which is commonly associated with [[euphoria]], an intense feeling of well-being. Euphoria is a potential indicator of [[Substance abuse|drug abuse]], which is the compulsive and excessive use of a substance despite adverse consequences. In clinical trials, modafinil has shown no evidence of abuse potential, that is why modafinil is considered to have a low risk of addiction and dependence, however, caution is advised.<ref name="pmid16741217">{{cite journal | vauthors = O'Brien CP, Dackis CA, Kampman K | title = Does modafinil produce euphoria? | journal = The American Journal of Psychiatry | volume = 163 | issue = 6 | pages = 1109 | date = June 2006 | pmid = 16741217 | doi = 10.1176/ajp.2006.163.6.1109 }}</ref><ref name="pmid30285371">{{cite book | vauthors = Greenblatt K, Adams N | chapter = Modafinil | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing | date = February 2022 | pmid = 30285371 | id={{NCBIBook|NBK531476}}}}</ref> ===Pitolisant=== {{Main article|Pitolisant}} Pitolisant, an [[eugeroic]] medication, is an inverse agonist (antagonist) of the [[Histamine H3 receptor|histamine 3 (H<sub>3</sub>) autoreceptor]], that belongs to the class of [[CNS stimulant]]s.<ref>https://www.ncbi.nlm.nih.gov/books/NBK573784/</ref><ref>{{Cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK548702/|title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|date=22 January 2012|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|via=PubMed|pmid=31644012}}</ref><ref>{{Cite web|url=https://www.drugs.com/mtm/pitolisant.html|title=Pitolisant Uses, Side Effects & Warnings|website=Drugs.com}}</ref><ref>{{Cite web|url=https://www.drugs.com/drug-class/cns-stimulants.html|title=List of CNS stimulants + Uses & Side Effects|website=Drugs.com}}</ref> Pitolisant is also considered a medication of class "[[eugeroic]]", which means that it promotes wakefulness and alertness. Pitolisant is the first eugeroic drug that acts by blocking the [[Histamine H3 receptor|histamine 3 (H<sub>3</sub>) autoreceptor]], which increases the activity of histamine neurons in the brain. Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.<ref>{{Cite journal|url=https://doi.org/10.1001/jama.2021.1349|title=Pitolisant (Wakix) for Narcolepsy|date=21 September 2021|journal=JAMA|volume=326|issue=11|pages=1060–1061|via=Silverchair|doi=10.1001/jama.2021.1349|pmid=34546302 |s2cid=237583921 }}</ref><ref>{{Cite journal|url=https://doi.org/10.1016/j.sleep.2017.01.002|title=The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use|first1=Marta|last1=Kollb-Sielecka|first2=Pierre|last2=Demolis|first3=Joseph|last3=Emmerich|first4=Greg|last4=Markey|first5=Tomas|last5=Salmonson|first6=Manuel|last6=Haas|date=1 May 2017|journal=Sleep Medicine|volume=33|pages=125–129|via=Europe PMC|doi=10.1016/j.sleep.2017.01.002|pmid=28449891}}</ref><ref>{{Cite journal|url=https://doi.org/10.1007/s40263-020-00703-x|title=Pitolisant: A Review in Narcolepsy with or without Cataplexy|first=Yvette N|last=Lamb|date=1 February 2020|journal=CNS Drugs|volume=34|issue=2|pages=207–218|via=Europe PMC|doi=10.1007/s40263-020-00703-x|pmid=31997137|s2cid=210949049 }}</ref> The H<sub>3</sub> autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine synthesis and release upon binding to endogenous histamine.<ref>{{cite journal | vauthors = West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA | title = Identification of two H3-histamine receptor subtypes | journal = Molecular Pharmacology | volume = 38 | issue = 5 | pages = 610–613 | date = November 1990 | pmid = 2172771 | url = https://molpharm.aspetjournals.org/content/38/5/610 }}</ref> By preventing the binding of endogenous histamine at the H<sub>3</sub>, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.<ref>{{cite journal | vauthors = Sarfraz N, Okuampa D, Hansen H, Alvarez M, Cornett EM, Kakazu J, Kaye AM, Kaye AD | display-authors = 6 | title = pitolisant, a novel histamine-3 receptor competitive antagonist, and inverse agonist, in the treatment of excessive daytime sleepiness in adult patients with narcolepsy | journal = Health Psychology Research | volume = 10 | issue = 3 | pages = 34222 | date = 30 May 2022 | pmid = 35774905 | pmc = 9239364 | doi = 10.52965/001c.34222 }}</ref> Pitolisant is the only non-controlled anti-narcoleptic drug in the US.<ref name="pmid31997137" /> Pitolisant has shown minimal abuse risk in studies.<ref name="pmid31997137">{{cite journal |vauthors=Lamb YN |title=Pitolisant: A Review in Narcolepsy with or without Cataplexy |journal=CNS Drugs |volume=34 |issue=2 |pages=207–218 |date=February 2020 |pmid=31997137 |doi=10.1007/s40263-020-00703-x |s2cid=210949049 }}</ref><ref name="pmid32941089">{{cite journal |vauthors=de Biase S, Pellitteri G, Gigli GL, Valente M |title=Evaluating pitolisant as a narcolepsy treatment option |journal=Expert Opinion on Pharmacotherapy |volume=22 |issue=2 |pages=155–162 |date=February 2021 |pmid=32941089 |doi=10.1080/14656566.2020.1817387 |s2cid=221788777}}</ref> == Recreational use and issues of abuse == {{Main|Recreational drug use#Stimulants}} {{See also|Substance abuse}} Stimulants enhance the activity of the [[central nervous system|central]] and [[peripheral nervous system]]s. Common effects may include increased [[alertness]], [[awareness]], [[wakefulness]], [[endurance]], [[productivity]], and [[motivation]], [[arousal]], [[animal locomotion|locomotion]], [[heart rate]], and [[blood pressure]], and a diminished desire for [[food]] and [[sleep]]. Use of stimulants may cause the body to reduce significantly its production of natural body chemicals that fulfill similar functions. Until the body reestablishes its normal state, once the effect of the ingested stimulant has worn off the user may feel depressed, lethargic, confused, and miserable. This is referred to as a "[[Comedown (drugs)|crash]]", and may provoke reuse of the stimulant. [[Drug abuse|Abuse]] of [[central nervous system]] (CNS) stimulants is common. [[Substance use disorder|Addiction]] to some CNS stimulants can quickly lead to [[medical]], [[psychiatric]], and [[psychosocial]] deterioration. [[Drug tolerance]], [[drug dependence|dependence]], and [[Drug sensitization|sensitization]] as well as a [[Drug withdrawal|withdrawal]] syndrome can occur.<ref>{{cite journal|vauthors=Dackis CA, Gold MS |title=Addictiveness of central stimulants |journal=Advances in Alcohol & Substance Abuse |volume=9 |issue=1–2 |pages=9–26 |year=1990 |pmid=1974121 |doi=10.1300/J251v09n01_02}}</ref> Stimulants may be screened for in animal discrimination and self-administration models which have high sensitivity albeit low specificity.<ref>{{cite journal|last1=Huskinson|first1=Sally L.|last2=Naylor|first2=Jennifer E.|last3=Rowlett|first3=James K.|last4=Freeman|first4=Kevin B.|title=Predicting abuse potential of stimulants and other dopaminergic drugs: Overview and recommendations|journal=Neuropharmacology|date=7 January 2017|volume=87|pages=66–80|doi=10.1016/j.neuropharm.2014.03.009|pmc=4171344|issn=0028-3908|pmid=24662599}}</ref> Research on a progressive ratio [[Self-administration]] protocol has found amphetamine, methylphenidate, modafinil, cocaine, and nicotine to all have a higher break point than placebo that scales with dose indicating reinforcing effects.<ref>{{cite journal|last1=Stoops|first1=William W.|title=Reinforcing Effects of Stimulants in Humans: Sensitivity of Progressive-Ratio Schedules|journal=[[Experimental and Clinical Psychopharmacology]]|date=7 January 2017|volume=16|issue=6|pages=503–512|doi=10.1037/a0013657|pmc=2753469|issn=1064-1297|pmid=19086771}}</ref> {| class="wikitable sortable" ! colspan="5" |Dependence potentials of common stimulants<ref name="King" /> |- ! Drug !! Mean !! Pleasure !! Psychological dependence !! Physical dependence |- | [[Cocaine]] || 2.39 || 3.0 || 2.8 || 1.3 |- | [[Tobacco]] || 2.21 || 2.3 || 2.6 || 1.8 |- | [[Amphetamine]] || 1.67 || 2.0 || 1.9 || 1.1 |- | [[Ecstasy (drug)|Ecstasy]] || 1.13 || 1.5 || 1.2 || 0.7 |} ==Treatment for misuse== Psychosocial treatments, such as [[contingency management]], have demonstrated improved effectiveness when added to treatment as usual consisting of counselling and/or case-management. This is demonstrated with a decrease in dropout rates and a lengthening of periods of abstinence.<ref>{{Cite journal|last1=Minozzi|first1=Silvia|last2=Saulle|first2=Rosella|last3=De Crescenzo|first3=Franco|last4=Amato|first4=Laura|date=2016-09-29|title=Psychosocial interventions for psychostimulant misuse|journal=The Cochrane Database of Systematic Reviews|volume=2016|issue=9 |pages=CD011866|doi=10.1002/14651858.CD011866.pub2|issn=1469-493X|pmc=6457581|pmid=27684277}}</ref> == Testing == The presence of stimulants in the body may be tested by a variety of procedures. Serum and urine are the common sources of testing material although saliva is sometimes used. Commonly used tests include chromatography, immunologic assay, and mass spectrometry.<ref>AJ Giannini. ''Drug Abuse''. Los Angeles, Health Information Press, 1999, pp.203–208</ref> == See also == * [[Antidepressant]]s * [[Depressant]]s * [[Hallucinogen]]s * [[Nootropic]]s * [[Psychoanaleptic]]s == Notes == {{Reflist|group=note}} == References == {{Reflist|30em}} == External links == {{Wiktionary|stimulant|upper}} {{Commons category|Stimulants}} * {{cite web|url=http://www.licadd.org/aboutdrugs.htm |title=Long Island Council on Alcohol & Drug Dependence – About Drugs – Stimulants |access-date=4 August 2007 |url-status=unfit |archive-url=https://web.archive.org/web/20080605235801/http://www.licadd.org/aboutdrugs.htm |archive-date=5 June 2008 }} * {{cite web |url=http://ncadistore.samhsa.gov/catalog/results.aspx?h=drugs&topic=68 |title=Online – Publications – Drugs of Abuse – Stimulants |access-date=11 January 2008 |url-status=unfit |archive-url=https://web.archive.org/web/20060922202232/http://ncadistore.samhsa.gov/catalog/results.aspx?h=drugs&topic=68 |archive-date=22 September 2006 }} * [http://www.apaic.org/ Asia & Pacific Amphetamine-Type Stimulants Information Centre (APAIC)] {{Stimulants}} {{Major drug groups}} {{Drug use}} {{Authority control}} [[Category:Stimulants| ]] [[Category:Psychopharmacology]]'
Unified diff of changes made by edit (edit_diff)
'@@ -18,5 +18,5 @@ == Medical uses == -Stimulants have been used in medicine for many conditions including [[obesity]], [[sleep disorders]], [[mood disorders]], [[impulse control disorders]], [[asthma]], [[nasal congestion]] and, in case of cocaine, as [[local anesthetic]]s.<ref>{{cite journal|last1=Harper|first1=S. J.|last2=Jones|first2=N. S.|title=Cocaine: what role does it have in current ENT practice? A review of the current literature|journal=The Journal of Laryngology and Otology|date=1 October 2006|volume=120|issue=10|pages=808–811|doi=10.1017/S0022215106001459|pmid=16848922|s2cid=28169472|issn=1748-5460}}</ref> Drugs used to treat obesity are called [[anorectic]]s and generally include drugs that follow the general definition of a stimulant, but other drugs such as [[cannabinoid receptor antagonist]]s also belong to this group.<ref>{{cite journal|last1=Kaplan|first1=Lee M.|title=Pharmacological therapies for obesity|journal=Gastroenterology Clinics of North America|date=1 March 2005|volume=34|issue=1|pages=91–104|doi=10.1016/j.gtc.2004.12.002|pmid=15823441|issn=0889-8553}}</ref><ref>{{cite journal|last1=Palamara|first1=Kerri L.|last2=Mogul|first2=Harriette R.|last3=Peterson|first3=Stephen J.|last4=Frishman|first4=William H.|title=Obesity: new perspectives and pharmacotherapies|journal=Cardiology in Review|date=1 October 2016|volume=14|issue=5|pages=238–258|doi=10.1097/01.crd.0000233903.57946.fd|pmid=16924165|issn=1538-4683}}</ref> [[Eugeroic]]s are used in management of sleep disorders characterized by [[excessive daytime sleepiness]], such as [[narcolepsy]], and include stimulants such as [[modafinil]].<ref>{{cite web|title=The Voice of the Patient A series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative|url=https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|publisher=Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)|url-status=live|archive-url=https://web.archive.org/web/20170505031213/https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|archive-date=5 May 2017|df=dmy-all}}</ref><ref>{{cite journal|last1=Heal|first1=David J|last2=Smith|first2=Sharon L|last3=Gosden|first3=Jane|last4=Nutt|first4=David J|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=Journal of Psychopharmacology |date=7 January 2017|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|issn=0269-8811|pmid=23539642}}</ref> Stimulants are used in impulse control disorders such as [[ADHD]]<ref>{{cite web|last1=Research|first1=Center for Drug Evaluation and|title=Drug Safety and Availability - FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults|url=https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|website=www.fda.gov|language=en|url-status=live|archive-url=https://web.archive.org/web/20131030064843/https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|archive-date=30 October 2013|df=dmy-all|date=26 June 2019}}</ref> and [[off-label use|off-label]] in [[mood disorder]]s such as [[major depressive disorder]] to increase [[mental energy|energy]], focus and elevate mood.<ref>{{cite journal|last1=Stotz|first1=Gabriele|last2=Woggon|first2=Brigitte|last3=Angst|first3=Jules|title=Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients|journal=Dialogues in Clinical Neuroscience|date=1 December 1999|volume=1|issue=3|pages=165–174|doi=10.31887/DCNS.1999.1.3/gstotz |pmc=3181580|issn=1294-8322|pmid=22034135}}</ref> Stimulants such as [[epinephrine]],<ref name="pmid18733372">{{cite journal |author = Doig RL | title = Epinephrin; especially in asthma | journal = California State Journal of Medicine | volume = 3 | issue = 2 | pages = 54–5 |date=February 1905 | pmid = 18733372 | pmc = 1650334 }}</ref> [[theophylline]] and [[salbutamol]]<ref>{{cite journal|last1=Chu|first1=Eric K.|last2=Drazen|first2=Jeffrey M.|title=Asthma|journal=American Journal of Respiratory and Critical Care Medicine|date=1 June 2005|volume=171|issue=11|pages=1202–1208|doi=10.1164/rccm.200502-257OE|pmid=15778490|issn=1073-449X}}</ref> orally have been used to treat asthma, but inhaled adrenergic drugs are now preferred due to less systemic side effects. [[Pseudoephedrine]] is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection.<ref name="Bicopoulos">Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.</ref><ref>{{cite web|title=Pseudoephedrine (By mouth) – National Library of Medicine|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|website=PubMed Health|url-status=live|archive-url=https://web.archive.org/web/20140214034938/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|archive-date=14 February 2014|df=dmy-all}}</ref> +Stimulants have been used in medicine for many conditions including [[obesity]], [[sleep disorders]], [[mood disorders]], [[impulse control disorders]], [[asthma]], [[nasal congestion]] and, in case of cocaine, as [[local anesthetic]]s.<ref>{{cite journal|last1=Harper|first1=S. J.|last2=Jones|first2=N. S.|title=Cocaine: what role does it have in current ENT practice? A review of the current literature|journal=The Journal of Laryngology and Otology|date=1 October 2006|volume=120|issue=10|pages=808–811|doi=10.1017/S0022215106001459|pmid=16848922|s2cid=28169472|issn=1748-5460}}</ref> Drugs used to treat obesity are called [[anorectic]]s and generally include drugs that follow the general definition of a stimulant, but other drugs such as [[cannabinoid receptor antagonist]]s also belong to this group.<ref>{{cite journal|last1=Kaplan|first1=Lee M.|title=Pharmacological therapies for obesity|journal=Gastroenterology Clinics of North America|date=1 March 2005|volume=34|issue=1|pages=91–104|doi=10.1016/j.gtc.2004.12.002|pmid=15823441|issn=0889-8553}}</ref><ref>{{cite journal|last1=Palamara|first1=Kerri L.|last2=Mogul|first2=Harriette R.|last3=Peterson|first3=Stephen J.|last4=Frishman|first4=William H.|title=Obesity: new perspectives and pharmacotherapies|journal=Cardiology in Review|date=1 October 2016|volume=14|issue=5|pages=238–258|doi=10.1097/01.crd.0000233903.57946.fd|pmid=16924165|issn=1538-4683}}</ref> [[Eugeroic]]s are used in management of sleep disorders characterized by [[excessive daytime sleepiness]], such as [[narcolepsy]], and include stimulants such as [[modafinil]] and [[pitolisant]].<ref>{{cite web|title=The Voice of the Patient A series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative|url=https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|publisher=Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)|url-status=live|archive-url=https://web.archive.org/web/20170505031213/https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|archive-date=5 May 2017|df=dmy-all}}</ref><ref>{{cite journal|last1=Heal|first1=David J|last2=Smith|first2=Sharon L|last3=Gosden|first3=Jane|last4=Nutt|first4=David J|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=Journal of Psychopharmacology |date=7 January 2017|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|issn=0269-8811|pmid=23539642}}</ref> Stimulants are used in impulse control disorders such as [[ADHD]]<ref>{{cite web|last1=Research|first1=Center for Drug Evaluation and|title=Drug Safety and Availability - FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults|url=https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|website=www.fda.gov|language=en|url-status=live|archive-url=https://web.archive.org/web/20131030064843/https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|archive-date=30 October 2013|df=dmy-all|date=26 June 2019}}</ref> and [[off-label use|off-label]] in [[mood disorder]]s such as [[major depressive disorder]] to increase [[mental energy|energy]], focus and elevate mood.<ref>{{cite journal|last1=Stotz|first1=Gabriele|last2=Woggon|first2=Brigitte|last3=Angst|first3=Jules|title=Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients|journal=Dialogues in Clinical Neuroscience|date=1 December 1999|volume=1|issue=3|pages=165–174|doi=10.31887/DCNS.1999.1.3/gstotz |pmc=3181580|issn=1294-8322|pmid=22034135}}</ref> Stimulants such as [[epinephrine]],<ref name="pmid18733372">{{cite journal |author = Doig RL | title = Epinephrin; especially in asthma | journal = California State Journal of Medicine | volume = 3 | issue = 2 | pages = 54–5 |date=February 1905 | pmid = 18733372 | pmc = 1650334 }}</ref> [[theophylline]] and [[salbutamol]]<ref>{{cite journal|last1=Chu|first1=Eric K.|last2=Drazen|first2=Jeffrey M.|title=Asthma|journal=American Journal of Respiratory and Critical Care Medicine|date=1 June 2005|volume=171|issue=11|pages=1202–1208|doi=10.1164/rccm.200502-257OE|pmid=15778490|issn=1073-449X}}</ref> orally have been used to treat asthma, but inhaled adrenergic drugs are now preferred due to less systemic side effects. [[Pseudoephedrine]] is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection.<ref name="Bicopoulos">Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.</ref><ref>{{cite web|title=Pseudoephedrine (By mouth) – National Library of Medicine|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|website=PubMed Health|url-status=live|archive-url=https://web.archive.org/web/20140214034938/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|archive-date=14 February 2014|df=dmy-all}}</ref> ===Depression=== @@ -158,4 +158,10 @@ {{Main article|Modafinil}} [[Modafinil]] is an [[eugeroic]] medication, which means that it promotes wakefulness and alertness. Modafinil is sold under the brand name Provigil among others. Modafinil is used to treat [[excessive daytime sleepiness]] due to [[narcolepsy]], [[shift work sleep disorder]], or [[obstructive sleep apnea]]. While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive.<ref>{{Cite journal|url=https://doi.org/10.1097/JCP.0000000000001085|title=The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis|first1=M Alexandra|last1=Kredlow|first2=Ani|last2=Keshishian|first3=Sarah|last3=Oppenheimer|first4=Michael W|last4=Otto|date=1 September 2019|journal=Journal of Clinical Psychopharmacology|volume=39|issue=5|pages=455–461|via=Europe PMC|doi=10.1097/jcp.0000000000001085|pmid=31433334|s2cid=201119084 }}</ref> Despite being a CNS stimulant, the addiction and [[drug dependence|dependence]] liabilities of modafinil are considered very low.<ref name="pmid23065655">{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–752 | date = October 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 }}</ref><ref name="FDA-2015-Provigil-Prescribing">{{cite web|date=January 2015|title=Provigil: Prescribing information |url= http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|access-date=August 16, 2015|website= FDA.gov| publisher= [[United States Food and Drug Administration]] |agency=Cephalon, Inc|archive-date=February 17, 2017|archive-url= https://web.archive.org/web/20170217165804/https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|url-status=live}}</ref><ref name="pmid33435717">{{cite journal |vauthors= Kakehi S, Tompkins DM |title=A Review of Pharmacologic Neurostimulant Use During Rehabilitation and Recovery After Brain Injury |journal=Ann Pharmacother |volume=55 |issue=10 |pages=1254–1266 |date=October 2021 |pmid=33435717 |doi=10.1177/1060028020983607 |s2cid=231593912 }}</ref> Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have [[Mood elevation|mood-elevating properties]].<ref name="FDA-2015-Provigil-Prescribing"/> The similarities in effects with [[caffeine]] are not clearly established.<ref name="pmid22375280">{{cite journal | vauthors = Kim D | title = Practical use and risk of modafinil, a novel waking drug | journal = Environmental Health and Toxicology | volume = 27 | pages = e2012007 | date = 2012 | pmid = 22375280 | pmc = 3286657 | doi = 10.5620/eht.2012.27.e2012007 }}</ref><ref name="Warot-1993">{{Cite journal|vauthors=Warot D, Corruble E, Payan C, Weil JS, Puech AJ|date=1993|title=Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo|journal=European Psychiatry |volume=8|issue=4|pages=201–208|doi=10.1017/S0924933800002923|s2cid=151797528 }}</ref> Unlike other stimulants, modafinil does not induce a subjective [[Pleasure|feeling of pleasure or reward]], which is commonly associated with [[euphoria]], an intense feeling of well-being. Euphoria is a potential indicator of [[Substance abuse|drug abuse]], which is the compulsive and excessive use of a substance despite adverse consequences. In clinical trials, modafinil has shown no evidence of abuse potential, that is why modafinil is considered to have a low risk of addiction and dependence, however, caution is advised.<ref name="pmid16741217">{{cite journal | vauthors = O'Brien CP, Dackis CA, Kampman K | title = Does modafinil produce euphoria? | journal = The American Journal of Psychiatry | volume = 163 | issue = 6 | pages = 1109 | date = June 2006 | pmid = 16741217 | doi = 10.1176/ajp.2006.163.6.1109 }}</ref><ref name="pmid30285371">{{cite book | vauthors = Greenblatt K, Adams N | chapter = Modafinil | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing | date = February 2022 | pmid = 30285371 | id={{NCBIBook|NBK531476}}}}</ref> + +===Pitolisant=== +{{Main article|Pitolisant}} +Pitolisant, an [[eugeroic]] medication, is an inverse agonist (antagonist) of the [[Histamine H3 receptor|histamine 3 (H<sub>3</sub>) autoreceptor]], that belongs to the class of [[CNS stimulant]]s.<ref>https://www.ncbi.nlm.nih.gov/books/NBK573784/</ref><ref>{{Cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK548702/|title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|date=22 January 2012|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|via=PubMed|pmid=31644012}}</ref><ref>{{Cite web|url=https://www.drugs.com/mtm/pitolisant.html|title=Pitolisant Uses, Side Effects & Warnings|website=Drugs.com}}</ref><ref>{{Cite web|url=https://www.drugs.com/drug-class/cns-stimulants.html|title=List of CNS stimulants + Uses & Side Effects|website=Drugs.com}}</ref> Pitolisant is also considered a medication of class "[[eugeroic]]", which means that it promotes wakefulness and alertness. Pitolisant is the first eugeroic drug that acts by blocking the [[Histamine H3 receptor|histamine 3 (H<sub>3</sub>) autoreceptor]], which increases the activity of histamine neurons in the brain. Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.<ref>{{Cite journal|url=https://doi.org/10.1001/jama.2021.1349|title=Pitolisant (Wakix) for Narcolepsy|date=21 September 2021|journal=JAMA|volume=326|issue=11|pages=1060–1061|via=Silverchair|doi=10.1001/jama.2021.1349|pmid=34546302 |s2cid=237583921 }}</ref><ref>{{Cite journal|url=https://doi.org/10.1016/j.sleep.2017.01.002|title=The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use|first1=Marta|last1=Kollb-Sielecka|first2=Pierre|last2=Demolis|first3=Joseph|last3=Emmerich|first4=Greg|last4=Markey|first5=Tomas|last5=Salmonson|first6=Manuel|last6=Haas|date=1 May 2017|journal=Sleep Medicine|volume=33|pages=125–129|via=Europe PMC|doi=10.1016/j.sleep.2017.01.002|pmid=28449891}}</ref><ref>{{Cite journal|url=https://doi.org/10.1007/s40263-020-00703-x|title=Pitolisant: A Review in Narcolepsy with or without Cataplexy|first=Yvette N|last=Lamb|date=1 February 2020|journal=CNS Drugs|volume=34|issue=2|pages=207–218|via=Europe PMC|doi=10.1007/s40263-020-00703-x|pmid=31997137|s2cid=210949049 }}</ref> The H<sub>3</sub> autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine synthesis and release upon binding to endogenous histamine.<ref>{{cite journal | vauthors = West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA | title = Identification of two H3-histamine receptor subtypes | journal = Molecular Pharmacology | volume = 38 | issue = 5 | pages = 610–613 | date = November 1990 | pmid = 2172771 | url = https://molpharm.aspetjournals.org/content/38/5/610 }}</ref> By preventing the binding of endogenous histamine at the H<sub>3</sub>, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.<ref>{{cite journal | vauthors = Sarfraz N, Okuampa D, Hansen H, Alvarez M, Cornett EM, Kakazu J, Kaye AM, Kaye AD | display-authors = 6 | title = pitolisant, a novel histamine-3 receptor competitive antagonist, and inverse agonist, in the treatment of excessive daytime sleepiness in adult patients with narcolepsy | journal = Health Psychology Research | volume = 10 | issue = 3 | pages = 34222 | date = 30 May 2022 | pmid = 35774905 | pmc = 9239364 | doi = 10.52965/001c.34222 }}</ref> + +Pitolisant is the only non-controlled anti-narcoleptic drug in the US.<ref name="pmid31997137" /> Pitolisant has shown minimal abuse risk in studies.<ref name="pmid31997137">{{cite journal |vauthors=Lamb YN |title=Pitolisant: A Review in Narcolepsy with or without Cataplexy |journal=CNS Drugs |volume=34 |issue=2 |pages=207–218 |date=February 2020 |pmid=31997137 |doi=10.1007/s40263-020-00703-x |s2cid=210949049 }}</ref><ref name="pmid32941089">{{cite journal |vauthors=de Biase S, Pellitteri G, Gigli GL, Valente M |title=Evaluating pitolisant as a narcolepsy treatment option |journal=Expert Opinion on Pharmacotherapy |volume=22 |issue=2 |pages=155–162 |date=February 2021 |pmid=32941089 |doi=10.1080/14656566.2020.1817387 |s2cid=221788777}}</ref> == Recreational use and issues of abuse == '
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[ 0 => 'Stimulants have been used in medicine for many conditions including [[obesity]], [[sleep disorders]], [[mood disorders]], [[impulse control disorders]], [[asthma]], [[nasal congestion]] and, in case of cocaine, as [[local anesthetic]]s.<ref>{{cite journal|last1=Harper|first1=S. J.|last2=Jones|first2=N. S.|title=Cocaine: what role does it have in current ENT practice? A review of the current literature|journal=The Journal of Laryngology and Otology|date=1 October 2006|volume=120|issue=10|pages=808–811|doi=10.1017/S0022215106001459|pmid=16848922|s2cid=28169472|issn=1748-5460}}</ref> Drugs used to treat obesity are called [[anorectic]]s and generally include drugs that follow the general definition of a stimulant, but other drugs such as [[cannabinoid receptor antagonist]]s also belong to this group.<ref>{{cite journal|last1=Kaplan|first1=Lee M.|title=Pharmacological therapies for obesity|journal=Gastroenterology Clinics of North America|date=1 March 2005|volume=34|issue=1|pages=91–104|doi=10.1016/j.gtc.2004.12.002|pmid=15823441|issn=0889-8553}}</ref><ref>{{cite journal|last1=Palamara|first1=Kerri L.|last2=Mogul|first2=Harriette R.|last3=Peterson|first3=Stephen J.|last4=Frishman|first4=William H.|title=Obesity: new perspectives and pharmacotherapies|journal=Cardiology in Review|date=1 October 2016|volume=14|issue=5|pages=238–258|doi=10.1097/01.crd.0000233903.57946.fd|pmid=16924165|issn=1538-4683}}</ref> [[Eugeroic]]s are used in management of sleep disorders characterized by [[excessive daytime sleepiness]], such as [[narcolepsy]], and include stimulants such as [[modafinil]] and [[pitolisant]].<ref>{{cite web|title=The Voice of the Patient A series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative|url=https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|publisher=Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)|url-status=live|archive-url=https://web.archive.org/web/20170505031213/https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|archive-date=5 May 2017|df=dmy-all}}</ref><ref>{{cite journal|last1=Heal|first1=David J|last2=Smith|first2=Sharon L|last3=Gosden|first3=Jane|last4=Nutt|first4=David J|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=Journal of Psychopharmacology |date=7 January 2017|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|issn=0269-8811|pmid=23539642}}</ref> Stimulants are used in impulse control disorders such as [[ADHD]]<ref>{{cite web|last1=Research|first1=Center for Drug Evaluation and|title=Drug Safety and Availability - FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults|url=https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|website=www.fda.gov|language=en|url-status=live|archive-url=https://web.archive.org/web/20131030064843/https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|archive-date=30 October 2013|df=dmy-all|date=26 June 2019}}</ref> and [[off-label use|off-label]] in [[mood disorder]]s such as [[major depressive disorder]] to increase [[mental energy|energy]], focus and elevate mood.<ref>{{cite journal|last1=Stotz|first1=Gabriele|last2=Woggon|first2=Brigitte|last3=Angst|first3=Jules|title=Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients|journal=Dialogues in Clinical Neuroscience|date=1 December 1999|volume=1|issue=3|pages=165–174|doi=10.31887/DCNS.1999.1.3/gstotz |pmc=3181580|issn=1294-8322|pmid=22034135}}</ref> Stimulants such as [[epinephrine]],<ref name="pmid18733372">{{cite journal |author = Doig RL | title = Epinephrin; especially in asthma | journal = California State Journal of Medicine | volume = 3 | issue = 2 | pages = 54–5 |date=February 1905 | pmid = 18733372 | pmc = 1650334 }}</ref> [[theophylline]] and [[salbutamol]]<ref>{{cite journal|last1=Chu|first1=Eric K.|last2=Drazen|first2=Jeffrey M.|title=Asthma|journal=American Journal of Respiratory and Critical Care Medicine|date=1 June 2005|volume=171|issue=11|pages=1202–1208|doi=10.1164/rccm.200502-257OE|pmid=15778490|issn=1073-449X}}</ref> orally have been used to treat asthma, but inhaled adrenergic drugs are now preferred due to less systemic side effects. [[Pseudoephedrine]] is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection.<ref name="Bicopoulos">Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.</ref><ref>{{cite web|title=Pseudoephedrine (By mouth) – National Library of Medicine|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|website=PubMed Health|url-status=live|archive-url=https://web.archive.org/web/20140214034938/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|archive-date=14 February 2014|df=dmy-all}}</ref>', 1 => '', 2 => '===Pitolisant===', 3 => '{{Main article|Pitolisant}}', 4 => 'Pitolisant, an [[eugeroic]] medication, is an inverse agonist (antagonist) of the [[Histamine H3 receptor|histamine 3 (H<sub>3</sub>) autoreceptor]], that belongs to the class of [[CNS stimulant]]s.<ref>https://www.ncbi.nlm.nih.gov/books/NBK573784/</ref><ref>{{Cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK548702/|title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|date=22 January 2012|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|via=PubMed|pmid=31644012}}</ref><ref>{{Cite web|url=https://www.drugs.com/mtm/pitolisant.html|title=Pitolisant Uses, Side Effects & Warnings|website=Drugs.com}}</ref><ref>{{Cite web|url=https://www.drugs.com/drug-class/cns-stimulants.html|title=List of CNS stimulants + Uses & Side Effects|website=Drugs.com}}</ref> Pitolisant is also considered a medication of class "[[eugeroic]]", which means that it promotes wakefulness and alertness. Pitolisant is the first eugeroic drug that acts by blocking the [[Histamine H3 receptor|histamine 3 (H<sub>3</sub>) autoreceptor]], which increases the activity of histamine neurons in the brain. Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.<ref>{{Cite journal|url=https://doi.org/10.1001/jama.2021.1349|title=Pitolisant (Wakix) for Narcolepsy|date=21 September 2021|journal=JAMA|volume=326|issue=11|pages=1060–1061|via=Silverchair|doi=10.1001/jama.2021.1349|pmid=34546302 |s2cid=237583921 }}</ref><ref>{{Cite journal|url=https://doi.org/10.1016/j.sleep.2017.01.002|title=The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use|first1=Marta|last1=Kollb-Sielecka|first2=Pierre|last2=Demolis|first3=Joseph|last3=Emmerich|first4=Greg|last4=Markey|first5=Tomas|last5=Salmonson|first6=Manuel|last6=Haas|date=1 May 2017|journal=Sleep Medicine|volume=33|pages=125–129|via=Europe PMC|doi=10.1016/j.sleep.2017.01.002|pmid=28449891}}</ref><ref>{{Cite journal|url=https://doi.org/10.1007/s40263-020-00703-x|title=Pitolisant: A Review in Narcolepsy with or without Cataplexy|first=Yvette N|last=Lamb|date=1 February 2020|journal=CNS Drugs|volume=34|issue=2|pages=207–218|via=Europe PMC|doi=10.1007/s40263-020-00703-x|pmid=31997137|s2cid=210949049 }}</ref> The H<sub>3</sub> autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine synthesis and release upon binding to endogenous histamine.<ref>{{cite journal | vauthors = West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA | title = Identification of two H3-histamine receptor subtypes | journal = Molecular Pharmacology | volume = 38 | issue = 5 | pages = 610–613 | date = November 1990 | pmid = 2172771 | url = https://molpharm.aspetjournals.org/content/38/5/610 }}</ref> By preventing the binding of endogenous histamine at the H<sub>3</sub>, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.<ref>{{cite journal | vauthors = Sarfraz N, Okuampa D, Hansen H, Alvarez M, Cornett EM, Kakazu J, Kaye AM, Kaye AD | display-authors = 6 | title = pitolisant, a novel histamine-3 receptor competitive antagonist, and inverse agonist, in the treatment of excessive daytime sleepiness in adult patients with narcolepsy | journal = Health Psychology Research | volume = 10 | issue = 3 | pages = 34222 | date = 30 May 2022 | pmid = 35774905 | pmc = 9239364 | doi = 10.52965/001c.34222 }}</ref>', 5 => '', 6 => 'Pitolisant is the only non-controlled anti-narcoleptic drug in the US.<ref name="pmid31997137" /> Pitolisant has shown minimal abuse risk in studies.<ref name="pmid31997137">{{cite journal |vauthors=Lamb YN |title=Pitolisant: A Review in Narcolepsy with or without Cataplexy |journal=CNS Drugs |volume=34 |issue=2 |pages=207–218 |date=February 2020 |pmid=31997137 |doi=10.1007/s40263-020-00703-x |s2cid=210949049 }}</ref><ref name="pmid32941089">{{cite journal |vauthors=de Biase S, Pellitteri G, Gigli GL, Valente M |title=Evaluating pitolisant as a narcolepsy treatment option |journal=Expert Opinion on Pharmacotherapy |volume=22 |issue=2 |pages=155–162 |date=February 2021 |pmid=32941089 |doi=10.1080/14656566.2020.1817387 |s2cid=221788777}}</ref>' ]
Lines removed in edit (removed_lines)
[ 0 => 'Stimulants have been used in medicine for many conditions including [[obesity]], [[sleep disorders]], [[mood disorders]], [[impulse control disorders]], [[asthma]], [[nasal congestion]] and, in case of cocaine, as [[local anesthetic]]s.<ref>{{cite journal|last1=Harper|first1=S. J.|last2=Jones|first2=N. S.|title=Cocaine: what role does it have in current ENT practice? A review of the current literature|journal=The Journal of Laryngology and Otology|date=1 October 2006|volume=120|issue=10|pages=808–811|doi=10.1017/S0022215106001459|pmid=16848922|s2cid=28169472|issn=1748-5460}}</ref> Drugs used to treat obesity are called [[anorectic]]s and generally include drugs that follow the general definition of a stimulant, but other drugs such as [[cannabinoid receptor antagonist]]s also belong to this group.<ref>{{cite journal|last1=Kaplan|first1=Lee M.|title=Pharmacological therapies for obesity|journal=Gastroenterology Clinics of North America|date=1 March 2005|volume=34|issue=1|pages=91–104|doi=10.1016/j.gtc.2004.12.002|pmid=15823441|issn=0889-8553}}</ref><ref>{{cite journal|last1=Palamara|first1=Kerri L.|last2=Mogul|first2=Harriette R.|last3=Peterson|first3=Stephen J.|last4=Frishman|first4=William H.|title=Obesity: new perspectives and pharmacotherapies|journal=Cardiology in Review|date=1 October 2016|volume=14|issue=5|pages=238–258|doi=10.1097/01.crd.0000233903.57946.fd|pmid=16924165|issn=1538-4683}}</ref> [[Eugeroic]]s are used in management of sleep disorders characterized by [[excessive daytime sleepiness]], such as [[narcolepsy]], and include stimulants such as [[modafinil]].<ref>{{cite web|title=The Voice of the Patient A series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative|url=https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|publisher=Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)|url-status=live|archive-url=https://web.archive.org/web/20170505031213/https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM402907.pdf|archive-date=5 May 2017|df=dmy-all}}</ref><ref>{{cite journal|last1=Heal|first1=David J|last2=Smith|first2=Sharon L|last3=Gosden|first3=Jane|last4=Nutt|first4=David J|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=Journal of Psychopharmacology |date=7 January 2017|volume=27|issue=6|pages=479–496|doi=10.1177/0269881113482532|pmc=3666194|issn=0269-8811|pmid=23539642}}</ref> Stimulants are used in impulse control disorders such as [[ADHD]]<ref>{{cite web|last1=Research|first1=Center for Drug Evaluation and|title=Drug Safety and Availability - FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults|url=https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|website=www.fda.gov|language=en|url-status=live|archive-url=https://web.archive.org/web/20131030064843/https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm|archive-date=30 October 2013|df=dmy-all|date=26 June 2019}}</ref> and [[off-label use|off-label]] in [[mood disorder]]s such as [[major depressive disorder]] to increase [[mental energy|energy]], focus and elevate mood.<ref>{{cite journal|last1=Stotz|first1=Gabriele|last2=Woggon|first2=Brigitte|last3=Angst|first3=Jules|title=Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients|journal=Dialogues in Clinical Neuroscience|date=1 December 1999|volume=1|issue=3|pages=165–174|doi=10.31887/DCNS.1999.1.3/gstotz |pmc=3181580|issn=1294-8322|pmid=22034135}}</ref> Stimulants such as [[epinephrine]],<ref name="pmid18733372">{{cite journal |author = Doig RL | title = Epinephrin; especially in asthma | journal = California State Journal of Medicine | volume = 3 | issue = 2 | pages = 54–5 |date=February 1905 | pmid = 18733372 | pmc = 1650334 }}</ref> [[theophylline]] and [[salbutamol]]<ref>{{cite journal|last1=Chu|first1=Eric K.|last2=Drazen|first2=Jeffrey M.|title=Asthma|journal=American Journal of Respiratory and Critical Care Medicine|date=1 June 2005|volume=171|issue=11|pages=1202–1208|doi=10.1164/rccm.200502-257OE|pmid=15778490|issn=1073-449X}}</ref> orally have been used to treat asthma, but inhaled adrenergic drugs are now preferred due to less systemic side effects. [[Pseudoephedrine]] is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection.<ref name="Bicopoulos">Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.</ref><ref>{{cite web|title=Pseudoephedrine (By mouth) – National Library of Medicine|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|website=PubMed Health|url-status=live|archive-url=https://web.archive.org/web/20140214034938/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011888/|archive-date=14 February 2014|df=dmy-all}}</ref>' ]
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Unix timestamp of change (timestamp)
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Retrieved from "https://en.wikipedia.org/wiki/Special:AbuseLog/36833631"