Stimulant

A stimulant is an overarching term that covers many drugs including those that increase the activity of the central nervous system and the body,{{cite web|title=stimulant – definition of stimulant in English {{!}} Oxford Dictionaries|url=https://en.oxforddictionaries.com/definition/stimulant|website=Oxford Dictionaries {{!}} English|archive-url=https://web.archive.org/web/20170226074716/https://en.oxforddictionaries.com/definition/stimulant|archive-date=26 February 2017}} drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects.{{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|year=1999}} Sympathomimetic effects are those effects that mimic or copy the actions of the sympathetic nervous system. The sympathetic nervous system is a part of the nervous system that prepares the body for action, such as increasing the heart rate, blood pressure, and breathing rate. Stimulants can activate the same receptors as the natural chemicals released by the sympathetic nervous system (namely epinephrine and norepinephrine) and cause similar effects.{{cite journal |vauthors=Costa VM, Grando LG, Milandri E, Nardi J, Teixeira P, Mladěnka P, Remião F |collaboration=OEMONOM |title=Natural Sympathomimetic Drugs: From Pharmacology to Toxicology |journal=Biomolecules |volume=12 |issue=12 |date=November 2022 |page=1793 |pmid=36551221 |pmc=9775352 |doi=10.3390/biom12121793 |doi-access=free}}

Stimulants in therapeutic doses, such as those given to patients with attention deficit hyperactivity disorder (ADHD), increase 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.{{cite journal |vauthors=Rozenek EB, Górska M, Wilczyńska K, Waszkiewicz N |title=In search of optimal psychoactivation: stimulants as cognitive performance enhancers |journal=Arh Hig Rada Toksikol |volume=70 |issue=3 |pages=150–159 |date=September 2019 |pmid=32597132 |doi=10.2478/aiht-2019-70-3298 |url=https://hrcak.srce.hr/file/328740 |access-date=2 February 2024 |archive-date=19 March 2023 |archive-url=https://web.archive.org/web/20230319182915/https://hrcak.srce.hr/file/328740 |url-status=live }} In higher doses, stimulants may also produce euphoria, vigor, and a decreased need for sleep.

Many, but not all, stimulants have ergogenic effects; that is, they enhance physical performance. Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while cocaine has the opposite effect.{{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}}

Neurocognitive enhancing effects of stimulants, specifically modafinil, amphetamine and methylphenidate have been reported in healthy adolescents by some studies, and is a commonly cited reason among illicit drug users for use, particularly among college students in the context of studying.{{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}} Still, results of these studies is inconclusive: assessing the potential overall neurocognitive benefits of stimulants among healthy youth is challenging due to the diversity within the population, the variability in cognitive task characteristics, and the absence of replication of studies. Research on the cognitive enhancement effects of modafinil in healthy non-sleep-deprived individuals has yielded mixed results, with some studies suggesting modest improvements in attention and executive functions while others show no significant benefits or even a decline in cognitive functions.{{cite journal | vauthors = Zamanian MY, Karimvandi MN, Nikbakhtzadeh M, Zahedi E, Bokov DO, Kujawska M, Heidari M, Rahmani MR | display-authors = 6 | title = Effects of Modafinil (Provigil) on Memory and Learning in Experimental and Clinical Studies: From Molecular Mechanisms to Behaviour Molecular Mechanisms and Behavioural Effects | journal = Current Molecular Pharmacology | volume = 16 | issue = 4 | pages = 507–516 | date = 2023 | pmid = 36056861 | doi = 10.2174/1874467215666220901122824 | s2cid = 252046371 }}{{cite journal | vauthors = Hashemian SM, Farhadi T | title = A review on modafinil: the characteristics, function, and use in critical care | journal = Journal of Drug Assessment | volume = 9 | issue = 1 | pages = 82–86 | date = 2020 | pmid = 32341841 | pmc = 7170336 | doi = 10.1080/21556660.2020.1745209 }}{{cite book | vauthors = Meulen R, Hall W, Mohammed A |title=Rethinking Cognitive Enhancement |date=2017 |publisher=Oxford University Press |isbn=978-0-19-872739-2 |page=116 |url=https://books.google.com/books?id=aAIXDgAAQBAJ&pg=PA116 }}

In some cases, psychiatric phenomena may emerge such as stimulant psychosis, paranoia, and suicidal ideation. Acute toxicity has been reportedly associated with hyperhydrosis, panic attacks, severe anxiety, mydriasis, paranoia, aggressive behavior, excessive motor activity, psychosis, rhabdomyolysis, and punding. The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia.{{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}} Most drugs classified as stimulants are sympathomimetic, meaning that they stimulate the sympathetic branch of the autonomic nervous system. This leads to effects such as mydriasis (dilation of the pupils), increased heart rate, blood pressure, respiratory rate and body temperature. When these changes become pathological, they are called 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.{{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|year=1999}}

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 attacks.{{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 |page=41|doi=10.1186/1471-2261-12-41|pmid=22682429|issn=1471-2261|pmc=3405448 |doi-access=free }} 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.{{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}} A review of a year long period of prescription stimulant use in those with ADHD found that cardiovascular side effects were limited to transient increases in blood pressure only.{{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}} However, a 2024 systematic review of the evidence found that stimulants overall improve ADHD symptoms and broadband behavioral measures in children and adolescents, though they carry risks of side effects like appetite suppression and other adverse events.{{Cite journal |last1=Peterson |first1=Bradley S. |last2=Trampush |first2=Joey |last3=Maglione |first3=Margaret |last4=Bolshakova |first4=Maria |last5=Rozelle |first5=Mary |last6=Miles |first6=Jeremy |last7=Pakdaman |first7=Sheila |last8=Brown |first8=Morah |last9=Yagyu |first9=Sachi |last10=Motala |first10=Aneesa |last11=Hempel |first11=Susanne |date=2024-04-01 |title=Treatments for ADHD in Children and Adolescents: A Systematic Review |url=https://publications.aap.org/pediatrics/article/153/4/e2024065787/196922/Treatments-for-ADHD-in-Children-and-Adolescents-A |journal=Pediatrics |language=en |volume=153 |issue=4 |doi=10.1542/peds.2024-065787 |pmid=38523592 |issn=0031-4005 |access-date=23 July 2024 |archive-date=12 July 2024 |archive-url=https://web.archive.org/web/20240712143559/https://publications.aap.org/pediatrics/article/153/4/e2024065787/196922/Treatments-for-ADHD-in-Children-and-Adolescents-A |url-status=live }} 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.{{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}}

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.{{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}} 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,{{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}} while inhalation may be associated with increased lower respiratory tract infection, lung cancer, and pathological restricting of lung tissue.{{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}} Cocaine may also increase risk for autoimmune disease{{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}}{{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}}{{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}} 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.{{cite journal |vauthors=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L |title=Toxicity of amphetamines: an update |journal=Arch. Toxicol. |volume=86 |issue=8 |pages=1167–1231 |date=August 2012 |pmid=22392347 |doi=10.1007/s00204-012-0815-5 |bibcode=2012ArTox..86.1167C |s2cid=2873101 }}{{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 }}{{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 }}{{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}}

Stimulants are widely used throughout the world as prescription medicines as well as without a prescription (either legally or illicitly) as performance-enhancing or recreational drugs. Among narcotics, stimulants produce a noticeable crash or comedown at the end of their effects. In the US, the most frequently prescribed stimulants as of 2013 were lisdexamfetamine (Vyvanse), methylphenidate (Ritalin), and amphetamine (Adderall).{{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}} 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%.{{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|page=149}}

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 anesthetics.{{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}} Drugs used to treat obesity are called anorectics and generally include drugs that follow the general definition of a stimulant, but other drugs such as cannabinoid receptor antagonists also belong to this group.{{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}}{{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}} Eugeroics are used in management of sleep disorders characterized by excessive daytime sleepiness, such as narcolepsy, and include stimulants such as modafinil and pitolisant.{{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}}{{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}} Stimulants are used in impulse control disorders such as ADHD{{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|date=26 June 2019}} and off-label in mood disorders such as major depressive disorder to increase energy, focus and elevate mood.{{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}} Stimulants such as epinephrine,{{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 }} theophylline and salbutamol{{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}} 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.Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.{{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}}

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.{{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 = https://discovery.ucl.ac.uk/id/eprint/10193706/1/Moncrieff_1-s2.0-S0277953608000129-main.pdf | access-date = 3 July 2024 | archive-date = 20 June 2024 | archive-url = https://web.archive.org/web/20240620144633/https://discovery.ucl.ac.uk/id/eprint/10193706/1/Moncrieff_1-s2.0-S0277953608000129-main.pdf | url-status = live }}{{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). | access-date = 29 August 2022 | archive-date = 29 August 2022 | archive-url = https://web.archive.org/web/20220829225107/https://books.google.com/books?id=2tD7CwAAQBAJ&pg=PA121 | url-status = live }}{{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 = | page = 113754 | date = August 2021 | pmid = 34000249 | doi = 10.1016/j.expneurol.2021.113754 | s2cid = 234768496 | url = }} However, they were largely abandoned for treatment of depression following the introduction of conventional antidepressants in the 1950s. Subsequent to this, there has been a resurgence in interest in stimulants for depression in recent years.{{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 = }}{{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 = }}

Stimulants produce a fast-acting and pronounced but transient and short-lived mood lift.{{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 }}{{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 = | page = 851067 | date = 2022 | pmid = 35431828 | pmc = 9011331 | doi = 10.3389/fnbeh.2022.851067 | url = | doi-access = free }} In relation to this, they are minimally effective in the treatment of depression when administered continuously. In addition, tolerance to the mood-lifting effects of amphetamine has led to dose escalation and dependence. 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.{{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 = }}{{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 = }}{{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 = }}{{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 = }} The reasons for the short-term mood-improving effects of stimulants are unclear, but may relate to rapid tolerance. Tolerance to the effects of stimulants has been studied and characterized both in animals{{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 }}{{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 }}{{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 }} and humans.{{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 = }}{{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 = | page = 617 | date = 2017 | pmid = 28936175 | pmc = 5594082 | doi = 10.3389/fphar.2017.00617 | url = | doi-access = free }}{{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 = }}{{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 = }} Stimulant withdrawal is remarkably similar in its symptoms to those of major depressive disorder.{{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 = }}{{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 = }}{{cite book | vauthors = D'Souza MS, Markou A | title = Behavioral Neuroscience of Drug Addiction | chapter = Neural substrates of psychostimulant withdrawal-induced anhedonia | series = Current Topics in Behavioral Neurosciences | volume = 3 | pages = 119–78 | date = 2010 | location = Berlin, Heidelberg | pmid = 21161752 | doi = 10.1007/7854_2009_20 | isbn = 978-3-642-03000-0 | chapter-url = }}{{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 = 978-0-12-366866-0 | url = }}

{{For|details on stimulant classes|Substituted phenethylamine|Substituted amphetamine|Substituted phenylmorpholine|Substituted cathinone}}

File:Methamphetamines.PNG]]

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, 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}}

Major stimulant classes include phenethylamines and their daughter class substituted amphetamines.{{cite journal |vauthors=Gallardo-Godoy A, Fierro A, McLean TH, Castillo M, Cassels BK, Reyes-Parada M, Nichols DE |title=Sulfur-substituted alpha-alkyl phenethylamines as selective and reversible MAO-A inhibitors: biological activities, CoMFA analysis, and active site modeling |journal=J Med Chem |volume=48 |issue=7 |pages=2407–19 |date=April 2005 |pmid=15801832 |doi=10.1021/jm0493109}}{{cite journal |vauthors=Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE |title=Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones |journal=Neuropharmacology |volume=245 |page=109827 |date=March 2024 |pmid=38154512 |doi=10.1016/j.neuropharm.2023.109827|pmc=10842458 |s2cid=266558677 }}

{{Main|Substituted amphetamines}}

Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents.{{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 | bibcode = 2012TPS....17..404H | 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]. ... Beyond (1R,2S)-ephedrine and (1S,2S)-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]. ...
[Figure 4](b) Examples of synthetic, pharmaceutically important 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=978-1-60913-345-0 | 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). | access-date=25 October 2020 | archive-date=25 March 2024 | archive-url=https://web.archive.org/web/20240325205904/https://books.google.com/books?id=Sd6ot9ul-bUC&q=substituted%20derivatives%20substituents%20amphetamine%20substitution&pg=PA646#v=snippet&q=substituted%20derivatives%20substituents%20amphetamine%20substitution&f=false | url-status=live }}{{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}} Examples of substituted amphetamines are amphetamine (itself), methamphetamine, ephedrine, cathinone, phentermine, mephentermine, bupropion, methoxyphenamine, selegiline, amfepramone, pyrovalerone, MDMA (ecstasy), and DOM (STP). Many drugs in this class work primarily by activating trace amine-associated receptor 1 (TAAR1); in turn, this causes reuptake inhibition and effluxion, or release, of dopamine, norepinephrine, and serotonin. An additional mechanism of some substituted amphetamines is the release of vesicular stores of monoamine neurotransmitters through VMAT2, thereby increasing the concentration of these neurotransmitters in the cytosol, or intracellular fluid, of the presynaptic neuron.{{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 }}

Amphetamine-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treat major depressive disorder, 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 mixed. Two large phase III studies of lisdexamfetamine (a prodrug to amphetamine) as an adjunct to an SSRI or serotonin–norepinephrine reuptake inhibitor (SNRI) in the treatment of major depressive disorder showed no further benefit relative to placebo in effectiveness.{{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}} Numerous studies have demonstrated the effectiveness of drugs like Adderall (a mixture of salts of amphetamine and dextroamphetamine) in controlling symptoms associated with ADHD. Non-stimulants such as atomoxetine have also found to be effective.{{Cite report |url=https://effectivehealthcare.ahrq.gov/products/attention-deficit-hyperactivity-disorder/research |title=ADHD Diagnosis and Treatment in Children and Adolescents |last1=Peterson |first1=Bradley S. |last2=Trampush |first2=Joey |last3=Maglione |first3=Margaret |last4=Bolshakova |first4=Maria |last5=Brown |first5=Morah |last6=Rozelle |first6=Mary |last7=Motala |first7=Aneesa |last8=Yagyu |first8=Sachi |last9=Miles |first9=Jeremy |date=2024-03-25 |publisher=Agency for Healthcare Research and Quality (AHRQ) |doi=10.23970/ahrqepccer267}} Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse.[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

{{Main|List of cocaine analogs}}

Hundreds of cocaine analogs 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 analogs have been developed as well.

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 block the reuptake or stimulate the efflux of these catecholamines, resulting in increased activity of their circuits. Some stimulants, specifically those with empathogenic and hallucinogenic effects, also affect serotonergic transmission. Some stimulants, such as some amphetamine derivatives{{which|date=May 2024}} and, notably, yohimbine, can decrease negative feedback by antagonizing regulatory autoreceptors.{{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}} Adrenergic agonists, such as, in part, ephedrine, act by directly binding to and activating adrenergic receptors, producing sympathomimetic effects.{{citation needed |date=May 2024}}

There are also more indirect mechanisms of action by which a drug can elicit activating effects. Caffeine is an adenosine receptor antagonist, and only indirectly increases catecholamine transmission in the brain.{{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|year=2001}} Pitolisant is an histamine 3 (H₃)-receptor inverse agonist. As histamine 3 (H₃) receptors mainly act as autoreceptors, pitolisant decreases negative feedback to histaminergic neurons, enhancing histaminergic transmission.

The precise mechanism of action of some stimulants, such as modafinil, for treating symptoms of narcolepsy and other sleep disorders, remains unknown.{{cite web |title=Modafinil Monograph for Professionals |url=https://www.drugs.com/monograph/modafinil.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=24 June 2018 |archive-date=30 March 2019 |archive-url=https://web.archive.org/web/20190330181813/https://www.drugs.com/monograph/modafinil.html |url-status=live }}{{cite journal | vauthors = Thorpy MJ, Bogan RK | title = Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications | journal = Sleep Medicine | volume = 68 | issue = | pages = 97–109 | date = April 2020 | pmid = 32032921 | doi = 10.1016/j.sleep.2019.09.001 | s2cid = 203405397 }}{{cite book | vauthors=Stahl SM | title=Prescriber's Guide: Stahl's Essential Psychopharmacology | date=March 2017 | publisher=Cambridge University Press | location=Cambridge, United Kingdom | isbn=978-1-108-22874-9 | pages=491–495 | edition=6th | chapter=Modafinil }}{{cite journal | vauthors = Gerrard P, Malcolm R | title = Mechanisms of modafinil: A review of current research | journal = Neuropsychiatric Disease and Treatment | volume = 3 | issue = 3 | pages = 349–364 | date = June 2007 | pmid = 19300566 | pmc = 2654794 }}{{cite journal | vauthors = Lazarus M, Chen JF, Huang ZL, Urade Y, Fredholm BB | title = Adenosine and Sleep | journal = Handbook of Experimental Pharmacology | volume = 253 | issue = | pages = 359–381 | date = 2019 | pmid = 28646346 | doi = 10.1007/164_2017_36 | isbn = 978-3-030-11270-7 }}

{{Main|Amphetamine}}

Amphetamine is a potent central nervous system (CNS) stimulant of the phenethylamine class that is approved for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.{{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 }} Amphetamine is also used off-label as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant.{{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.}}{{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 }}{{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)...

Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.}} 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.{{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 }}{{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 }} As a consequence, amphetamine is illegally manufactured in clandestine labs to be trafficked and sold to users. Based upon drug and drug precursor seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of methamphetamine.{{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 }}

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions.{{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}}{{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 }} 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 mixed amphetamine salts, dextroamphetamine, and lisdexamfetamine.{{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 }}

Amphetamine is a norepinephrine-dopamine releasing agent (NDRA). It enters neurons through dopamine and norepinephrine transporters and facilitates neurotransmitter efflux by activating TAAR1 and inhibiting VMAT2.{{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}} At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved cognitive control.{{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 }} Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.{{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...
Physiologic and performance effects
{{bull}}Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
{{bull}}Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
{{bull}}Improved reaction time
{{bull}}Increased muscle strength and delayed muscle fatigue
{{bull}}Increased acceleration
{{bull}}Increased alertness and attention to task}} In contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown.{{cite book |veditors=Brunton LL, Chabner BA, Knollmann BC |title=Goodman & Gilman's Pharmacological Basis of Therapeutics |year=2010 |publisher=McGraw-Hill |location=New York |isbn=978-0-07-162442-8 |vauthors=Westfall DP, Westfall TC |section=Miscellaneous Sympathomimetic Agonists |section-url=http://www.accessmedicine.com/content.aspx?aID=16661601 |edition=12th |access-date=18 December 2013 |archive-date=10 November 2013 |archive-url=https://web.archive.org/web/20131110094145/http://www.accessmedicine.com/content.aspx?aID=16661601 |url-status=live }} Very high doses can result in psychosis (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use.{{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}}{{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 |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 }} 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.

{{Main|Caffeine}}

File:Roasted coffee beans.jpg

Caffeine is a stimulant compound belonging to the xanthine class of chemicals naturally found in coffee, tea, and (to a lesser degree) cocoa or chocolate. It is included in many soft drinks, as well as a larger amount in energy drinks. 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.{{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 }} {{subscription required}}

A few jurisdictions restrict the sale and use of caffeine. In the United States, the FDA has banned the sale of pure and highly concentrated caffeine products for personal consumption, due to the risk of overdose and death.{{cite web|url=https://www.fda.gov/news-events/press-announcements/fda-warns-companies-stop-selling-dangerous-and-illegal-pure-and-highly-concentrated-caffeine|title=FDA warns companies to stop selling dangerous and illegal pure and highly concentrated caffeine products|first=Office of the|last=Commissioner|date=24 March 2020|website=FDA|access-date=24 January 2024|archive-date=24 January 2024|archive-url=https://web.archive.org/web/20240124074601/https://www.fda.gov/news-events/press-announcements/fda-warns-companies-stop-selling-dangerous-and-illegal-pure-and-highly-concentrated-caffeine|url-status=live}} The Australian Government has announced a ban on the sale of pure and highly concentrated caffeine food products for personal consumption, following the death of a young man from acute caffeine toxicity.{{Cite web |url=https://www.tga.gov.au/resources/publication/scheduling-decisions-interim/interim-decisions-and-invitation-further-comment-substances-referred-november-2019-acmsaccs-meetings/31-interim-decision-relation-caffeine |title=3.1 Interim decision in relation to caffeine | Therapeutic Goods Administration (TGA) |access-date=24 January 2024 |archive-date=24 January 2024 |archive-url=https://web.archive.org/web/20240124074604/https://www.tga.gov.au/resources/publication/scheduling-decisions-interim/interim-decisions-and-invitation-further-comment-substances-referred-november-2019-acmsaccs-meetings/31-interim-decision-relation-caffeine |url-status=live }}{{Cite web |url=https://www.health.gov.au/ministers/senator-the-hon-richard-colbeck/media/australia-to-protect-consumers-by-banning-sale-of-pure-caffeine-powder |title=Australia to protect consumers by banning sale of pure caffeine powder | Health Portfolio Ministers | Australian Government Department of Health and Aged Care |access-date=24 January 2024 |archive-date=24 January 2024 |archive-url=https://web.archive.org/web/20240124074603/https://www.health.gov.au/ministers/senator-the-hon-richard-colbeck/media/australia-to-protect-consumers-by-banning-sale-of-pure-caffeine-powder |url-status=live }} In Canada, Health Canada has proposed to limit the amount of caffeine in energy drinks to 180 mg per serving, and to require warning labels and other safety measures on these products.

Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient,{{cite journal |vauthors=Lipton RB, Diener HC, Robbins MS, Garas SY, Patel K |title=Caffeine in the management of patients with headache |journal=J Headache Pain |volume=18 |issue=1 |page=107 |date=October 2017 |pmid=29067618 |pmc=5655397 |doi=10.1186/s10194-017-0806-2 |doi-access=free |url=}} or reducing one of its side-effects (especially drowsiness).{{cite journal |title=Caffeine: Psychological Effects, Use and Abuse |journal=Orthomolecular Psychiatry |volume=10 |issue=3 |date=1981 |pages=202–211 |first1=S. |last1=Bolton |first2=G. |last2=Null |url=http://orthomolecular.org/library/jom/1981/pdf/1981-v10n03-p202.pdf |access-date=24 January 2024 |archive-date=6 October 2008 |archive-url=https://web.archive.org/web/20081006073801/http://orthomolecular.org/library/jom/1981/pdf/1981-v10n03-p202.pdf |url-status=live }} Tablets containing standardized doses of caffeine are also widely available.{{cite journal |vauthors=Cappelletti S, Piacentino D, Fineschi V, Frati P, Cipolloni L, Aromatario M |title=Caffeine-Related Deaths: Manner of Deaths and Categories at Risk |journal=Nutrients |volume=10 |issue=5 |date=May 2018 |page=611 |pmid=29757951 |pmc=5986491 |doi=10.3390/nu10050611 |doi-access=free |url=}}

Caffeine's mechanism of action differs from many stimulants, as it produces stimulant effects by inhibiting adenosine receptors.{{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}} Adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness.{{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}} Caffeine has been found to increase striatal dopamine in animal models,{{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|doi=10.1523/JNEUROSCI.22-15-06321.2002|pmid=12151508|pmc=6758129}} as well as inhibit the inhibitory effect of adenosine receptors on dopamine receptors,{{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 }} 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.{{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|archive-url=https://web.archive.org/web/20161222041641/http://ww1.drugabuse.gov/pdf/monographs/92.pdf|archive-date=22 December 2016}} 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.{{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 }}

Coffee consumption is associated with a lower overall risk of cancer.{{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 }} This is primarily due to a decrease in the risks of hepatocellular and endometrial cancer, but it may also have a modest effect on colorectal cancer. 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.{{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 }} A protective effect of caffeine against Alzheimer's disease is possible, but the evidence is inconclusive.{{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 | hdl = 10216/160619 | hdl-access = free }}{{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 }}{{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 }} Moderate coffee consumption may decrease the risk of cardiovascular disease,{{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 }} and it may somewhat reduce the risk of type 2 diabetes.{{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 }} 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.{{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 }} Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.{{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 }} It may protect people from liver cirrhosis.{{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 }} There is no evidence that coffee stunts a child's growth.{{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 |archive-date=25 March 2024 |archive-url=https://web.archive.org/web/20240325205644/https://books.google.com/books?id=neuEbVUZik0C&pg=PA144#v=onepage&q&f=false |url-status=live }} Caffeine may increase the effectiveness of some medications including ones used to treat headaches.{{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 }} Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.{{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 }}

{{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 anesthesia.{{citation needed|date=May 2024}}

In chemical terms, it is an alkaloid with a phenethylamine skeleton found in various plants in the genus Ephedra (family Ephedraceae). It works mainly by increasing the activity of norepinephrine (noradrenaline) on adrenergic receptors.[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 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.

File:Ecstasy monogram.jpg

{{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.{{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 }} Briefly used by some psychotherapists as an adjunct to therapy, the drug became popular recreationally and the DEA listed MDMA as a Schedule I controlled substance, prohibiting most medical studies and applications. MDMA is known for its entactogenic properties. The stimulant effects of MDMA include hypertension, anorexia (appetite loss), euphoria, social disinhibition, insomnia (enhanced wakefulness/inability to sleep), improved 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.{{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}}

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".{{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 = 7 February 2009|editor-last1 = Hope |editor-first1 = Christopher }}

{{Main|Methylenedioxypyrovalerone|l1=MDPV}}

Methylenedioxypyrovalerone (MDPV) is a psychoactive drug with stimulant properties that acts as a norepinephrine-dopamine reuptake inhibitor (NDRI).{{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}} It was first developed in the 1960s by a team at Boehringer Ingelheim.US Patent 3478050 – 1-(3,4-methylenedioxy-phenyl)-2-pyrrolidino-alkanones MDPV remained an obscure stimulant until around 2004, when it was reported to be sold as a designer drug. Products labeled as 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 and K2 as incense.{{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 |archive-url=https://web.archive.org/web/20110713161635/http://www.kmbc.com/news/26256067/detail.html |archive-date=13 July 2011 }}{{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 |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 }}

Incidents of psychological and physical harm have been attributed to MDPV use.{{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 }}{{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 }}

{{Main|Mephedrone}}

Mephedrone is a synthetic stimulant drug of the amphetamine and cathinone classes. Slang names include drone{{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 }} and MCAT.{{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}} 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, amphetamines, 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 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.

Mephedrone is neurotoxic and has abuse potential, predominantly exerted on 5-hydroxytryptamine (5-HT) terminals, mimicking that of MDMA with which it shares the same subjective sensations on abusers.{{cite journal |vauthors=Karch SB |title=Cathinone neurotoxicity ("The "3Ms") |journal=Curr Neuropharmacol |volume=13 |issue=1 |pages=21–5 |date=January 2015 |pmid=26074741 |pmc=4462040 |doi=10.2174/1570159X13666141210225009 |url=}}{{cite journal |vauthors=Pantano F, Tittarelli R, Mannocchi G, Pacifici R, di Luca A, Busardò FP, Marinelli E |title=Neurotoxicity Induced by Mephedrone: An up-to-date Review |journal=Curr Neuropharmacol |volume=15 |issue=5 |pages=738–749 |date=2017 |pmid=27908258 |pmc=5771050 |doi=10.2174/1570159X14666161130130718 |url=}}{{cite journal |vauthors=Mead J, Parrott A |title=Mephedrone and MDMA: A comparative review |journal=Brain Res |volume=1735 |issue= |pages=146740 |date=May 2020 |pmid=32087112 |doi=10.1016/j.brainres.2020.146740 |s2cid=211199225 |url=}}

{{Main|Methamphetamine}}

Methamphetamine (contracted from {{nowrap|N-methyl-alpha-methylphenethylamine}}) is a potent psychostimulant of the phenethylamine and amphetamine classes that is used to treat attention deficit hyperactivity disorder (ADHD) and obesity.{{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=370 |edition=2nd |chapter=15 |quote=Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.}}{{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 }}{{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) ...
Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ...
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 ...
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).}} Methamphetamine exists as two enantiomers, dextrorotary and levorotary.{{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 }}{{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 }} Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine; however, both are addictive and produce the same toxicity symptoms at high doses. 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. Recreationally, methamphetamine is used to increase sexual desire, lift the mood, and increase energy, allowing some users to engage in sexual activity continuously for several days straight.{{failed verification|date=December 2021}}{{unreliable source?|date=December 2021}}

Methamphetamine may be sold illicitly, either as pure dextromethamphetamine or in an equal parts mixture of the right- and left-handed molecules (i.e., 50% levomethamphetamine and 50% dextromethamphetamine).{{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 |archive-url=https://web.archive.org/web/20160708142916/http://channel.nationalgeographic.com/drugs-inc/episodes/san-francisco-meth-zombies/ |archive-date=8 July 2016 }} Both dextromethamphetamine and racemic methamphetamine are schedule II controlled substances in the United States. 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 United Nations Convention on Psychotropic Substances treaty.{{cite book |author=United Nations Office on Drugs and Crime |title=Preventing Amphetamine-type Stimulant Use Among Young People: A Policy and Programming Guide |publisher=United Nations |location=New York |year=2007 |isbn=978-92-1-148223-2 |url=http://www.unodc.org/pdf/youthnet/ATS.pdf |access-date=11 November 2013 |url-status=live |archive-url=https://web.archive.org/web/20131016082310/http://www.unodc.org/pdf/youthnet/ATS.pdf |archive-date=16 October 2013 }}{{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}} 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 INN and USAN of levomethamphetamine.{{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}}{{cite web |title=Levomethamphetamine |url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604#section=Identification |website=PubChem |access-date=15 September 2017 |archive-date=6 October 2014 |archive-url=https://web.archive.org/web/20141006215922/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604#section=Identification |url-status=live }}|name="OTC levmetamfetamine"|group = "note"}}

In low doses, methamphetamine can cause an elevated mood and increase alertness, concentration, and energy in fatigued individuals. At higher doses, it can induce psychosis, rhabdomyolysis, and cerebral hemorrhage. Methamphetamine is known to have a high potential for abuse and addiction. 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.{{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 }} Unlike amphetamine and cocaine, methamphetamine is neurotoxic to humans, damaging both dopamine and serotonin neurons in the central nervous system (CNS). 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; 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.{{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 }}{{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}} However, recreational amphetamine doses may also be neurotoxic.{{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|url-access=subscription|access-date=23 July 2021|archive-date=3 June 2020|archive-url=https://web.archive.org/web/20200603170616/https://www.cambridge.org/core/journals/psychological-medicine/article/continuous-amphetamine-intoxication-an-animal-model-of-the-acute-psychotic-episode/7DEB3BCC38395608F1C4FE87529D4C8F|url-status=live}}

{{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 (NDRI), 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.

File:Cocaine lines 2.jpg, a popular 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.{{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|access-date=9 December 2020|archive-date=3 December 2020|archive-url=https://web.archive.org/web/20201203170129/https://www.avancepsicologos.com/efectos-psicologicos-del-consumo-de-la-cocaina/|url-status=live}} 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.{{cite journal|author1=AJ Giannini |author2=WC Price |title=Contemporary drugs of abuse |journal=American Family Physician |volume=33 |pages=207–213 |year=1986}}

{{Main|Nicotine}}

Nicotine is the active chemical constituent in tobacco, which is available in many forms, including cigarettes, cigars, chewing tobacco, and smoking cessation aids such as nicotine patches, nicotine gum, and electronic cigarettes. 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.{{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}} 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.{{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}}

{{Main|Phenylpropanolamine}}

Phenylpropanolamine (PPA; Accutrim; β-hydroxyamphetamine), also known as the stereoisomers norephedrine and norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine chemical classes that is used as a stimulant, decongestant, and anorectic agent.{{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 }} It is commonly used in prescription and over-the-counter cough and cold preparations. In veterinary medicine, it is used to control urinary incontinence in dogs under trade names Propalin and Proin.

In the United States, PPA is no longer sold without a prescription due to a possible 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.{{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 |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 }} In India, human use of PPA and its formulations were banned on 10 February 2011.{{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 |archive-url=https://web.archive.org/web/20131013222927/http://cdsco.nic.in/html/drugsbanned.html |archive-date=13 October 2013 }}

{{Main|Lisdexamfetamine}}

Lisdexamfetamine (Vyvanse, etc.) is an amphetamine-type medication, sold for use in treating ADHD.{{cite web |title=Lisdexamfetamine: MedlinePlus Drug Information |url=https://medlineplus.gov/druginfo/meds/a607047.html |access-date=7 August 2023 |website=medlineplus.gov |language=en |archive-date=7 August 2023 |archive-url=https://web.archive.org/web/20230807022247/https://medlineplus.gov/druginfo/meds/a607047.html |url-status=live }} Its effects typically last around 14 hours.{{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 |archive-date=8 June 2019 |archive-url=https://web.archive.org/web/20190608192642/https://www.drugs.com/monograph/lisdexamfetamine-dimesylate.html |url-status=live }} Lisdexamfetamine is inactive on its own and is metabolized into dextroamphetamine in the body. Consequently, it has a lower abuse potential.

{{Main|Pseudoephedrine}}

Pseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant,{{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 |journal=Journal of Applied Physiology |date=1 December 1996 |volume=81 |pages=2611–2617 |issue=6 |pmid=9018513 |doi=10.1152/jappl.1996.81.6.2611 |s2cid=15702353 }} or as a wakefulness-promoting agent.{{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 }}

The salts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many over-the-counter preparations, either as a single ingredient or (more commonly) in combination with antihistamines, guaifenesin, dextromethorphan, and/or paracetamol (acetaminophen) or another NSAID (such as aspirin or ibuprofen). It is also used as a precursor chemical in the illegal production of methamphetamine.

{{Main|Khat}}

File:Catha edulis.jpg

Khat is a flowering plant native to the Horn of Africa and the Arabian Peninsula.{{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-date=Digitized 19 February 2010 |page=176 |chapter-url=https://books.google.com/books?id=EdUnAQAAIAAJ&pg=PA176 |access-date=7 January 2014 |archive-date=25 March 2024 |archive-url=https://web.archive.org/web/20240325205905/https://books.google.com/books?id=EdUnAQAAIAAJ&pg=PA176#v=onepage&q&f=false |url-status=live }} {{open access}} {{link note|note=Free eBook}}{{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 |archive-url=https://web.archive.org/web/20140108103026/http://www.who.int/bulletin/volumes/86/10/08-011008/en/ |archive-date=8 January 2014 }}

Khat contains a monoamine alkaloid called cathinone, a "keto-amphetamine". This alkaloid causes excitement, loss of appetite, and euphoria. In 1980, the World Health Organization (WHO) classified it as a drug of abuse that can produce mild to moderate psychological dependence (less than tobacco or alcohol),{{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 }} although the WHO does not consider khat to be seriously addictive. It is banned in some countries, such as the United States, Canada, and Germany, while its production, sale, and consumption are legal in other countries, including Djibouti, Ethiopia, Somalia, Kenya and Yemen.Haight-Ashbury Free Medical Clinic, Journal of psychoactive drugs, Volume 41, (Haight-Ashbury Publications: 2009), p.3.

{{Main|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.{{cite journal|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 }} Despite being a CNS stimulant, the addiction and dependence liabilities of modafinil are considered very low.{{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 }}{{cite web|date=January 2015|title=Provigil: Prescribing information |url= http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|access-date=16 August 2015|website= FDA.gov| publisher= United States Food and Drug Administration |agency=Cephalon, Inc|archive-date=17 February 2017|archive-url= https://web.archive.org/web/20170217165804/https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|url-status=live}}{{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 }} Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have mood-elevating properties. The similarities in effects with caffeine are not clearly established.{{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 }}{{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 }} Unlike other stimulants, modafinil does not induce a subjective feeling of pleasure or reward, which is commonly associated with euphoria, an intense feeling of well-being. Euphoria is a potential indicator of 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.{{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 | page = 1109 | date = June 2006 | pmid = 16741217 | doi = 10.1176/ajp.2006.163.6.1109 }}{{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}}}}

{{Main|Pitolisant}}

Pitolisant is an inverse agonist (antagonist) of the histamine 3 (H₃) autoreceptor. As such, pitolisant is an antihistamine medication that also belongs to the class of CNS stimulants.{{cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK573784/|title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|chapter=Pitolisant|date=24 January 2012|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|via=PubMed|pmid=34516055|access-date=24 January 2024|archive-date=14 November 2023|archive-url=https://web.archive.org/web/20231114161839/https://www.ncbi.nlm.nih.gov/books/NBK573784/|url-status=live}}{{cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK548702/|title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|chapter=Central Nervous System (CNS) Stimulants|date=22 January 2012|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|via=PubMed|pmid=31644012|access-date=22 January 2024|archive-date=29 January 2023|archive-url=https://web.archive.org/web/20230129141034/https://www.ncbi.nlm.nih.gov/books/NBK548702/|url-status=live}}{{cite web|url=https://www.drugs.com/mtm/pitolisant.html|title=Pitolisant Uses, Side Effects & Warnings|website=Drugs.com|access-date=22 January 2024|archive-date=19 January 2024|archive-url=https://web.archive.org/web/20240119024743/https://www.drugs.com/mtm/pitolisant.html|url-status=live}}{{cite web|url=https://www.drugs.com/drug-class/cns-stimulants.html|title=List of CNS stimulants + Uses & Side Effects|website=Drugs.com|access-date=22 January 2024|archive-date=6 January 2024|archive-url=https://web.archive.org/web/20240106222450/https://www.drugs.com/drug-class/cns-stimulants.html|url-status=live}} Pitolisant is also considered a medication of eugeroic class, which means that it promotes wakefulness and alertness. Pitolisant is the first wakefulness-promoting agent that acts by blocking the H₃ autoreceptor.

Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.{{cite journal|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 }}{{cite journal|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}}

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

Blocking the histamine 3 (H₃) autoreceptor increases the activity of histamine neurons in the brain. The H₃ autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine biosynthesis and release upon binding to endogenous histamine.{{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 | doi = 10.1016/S0026-895X(25)09479-9 | pmid = 2172771 | url = https://molpharm.aspetjournals.org/content/38/5/610 | access-date = 22 January 2024 | archive-date = 10 December 2023 | archive-url = https://web.archive.org/web/20231210105713/https://molpharm.aspetjournals.org/content/38/5/610 | url-status = live }} By preventing the binding of endogenous histamine at the H₃, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.{{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 | page = 34222 | date = 30 May 2022 | pmid = 35774905 | pmc = 9239364 | doi = 10.52965/001c.34222 }}

{{Main|Recreational drug use#Stimulants}}

{{See also|Substance abuse}}

Stimulants enhance the activity of the central and peripheral nervous systems. Common effects may include increased alertness, awareness, wakefulness, endurance, productivity, and motivation, arousal, 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 "crash", and may provoke reuse of the stimulant.

Abuse of central nervous system (CNS) stimulants is common. Addiction to some CNS stimulants can quickly lead to medical, psychiatric, and psychosocial deterioration. Drug tolerance, dependence, and sensitization as well as a withdrawal syndrome can occur.{{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}} Stimulants may be screened for in animal discrimination and self-administration models which have high sensitivity albeit low specificity.{{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}} 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.{{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}} A progressive ratio self-administration protocol is a way of testing how much an animal or a human wants a drug by making them do a certain action (like pressing a lever or poking a nose device) to get the drug. The number of actions needed to get the drug increases every time, so it becomes harder and harder to get the drug. The highest number of actions that the animal or human is willing to do to get the drug is called the break point. The higher the break point, the more the animal or human wants the drug. In contrast to the classical stimulants such as amphetamine, the effects of modafinil depend on what the animals or humans have to do after getting the drug. If they have to do a performance task, like solving a puzzle or remembering something, modafinil makes them work harder for it than placebo, and the subjects wanted to self-administer modafinil. But if they had to do a relaxation task, like listening to music or watching a video, the subjects did not want to self-administer modafinil. This suggests that modafinil is more rewarding when it helps the animals or humans do something better or faster, especially considering that modafinil is not commonly abused or depended on by people, unlike other stimulants.

Psychosocial treatments, such as contingency management, have demonstrated improved effectiveness when added to treatment as usual consisting of counseling and/or case-management. This is demonstrated with a decrease in dropout rates and a lengthening of periods of abstinence.{{cite journal|last1=Minozzi|first1=Silvia|last2=Saulle|first2=Rosella|last3=De Crescenzo|first3=Franco|last4=Amato|first4=Laura|date=29 September 2016|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}}

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.AJ Giannini. Drug Abuse. Los Angeles, Health Information Press, 1999, pp.203–208

• Antidepressants
• Depressants
• Hallucinogens
• Nootropics
• Psychoanaleptics

{{Reflist|group=note}}

{{Reflist|30em}}

{{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}}

{{Chemical classes of psychoactive drugs}}

{{Drug use}}

{{Authority control}}

Category:Drug classes defined by psychological effects

Category:Psychopharmacology