View source for Selegiline

{{Short description|Irreversible Type-B selective Monoamine Oxidase Inhibitor}}
{{Use mdy dates|date=March 2014}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| verifiedrevid = 464388442
| image = Selegiline.svg
| image_class = skin-invert-image
| width = 225px
| image2 = SelegilineMV.png
| image_class2 = bg-transparent
| width2 = 225px

<!-- Clinical data -->| pronounce = {{IPAc-en|s|ə|ˈ|l|ɛ|dʒ|ᵻ|l|iː|n}} {{respell|sə|LEJ|i-leen}} ("seh-LEH-ji-leen")<ref name="Parkinsons.org2018" /><ref name="Acosta2020" />
| tradename = Eldepryl, Emsam, others<ref name="Drugs.com-Names" />
| Drugs.com = {{drugs.com|monograph|selegiline-hydrochloride}}
| MedlinePlus = a697046
| pregnancy_AU = B2
| pregnancy_US = C
| legal_AU = S4
| legal_BR = C1
| legal_BR_comment = <ref name="Anivsa2023">{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only
| licence_US = Selegiline
| routes_of_administration = [[Oral administration|Oral]],<ref name="PillLabel" /><ref name="Mahmood1997">{{cite journal | vauthors = Mahmood I | title = Clinical pharmacokinetics and pharmacodynamics of selegiline. An update | journal = Clin Pharmacokinet | volume = 33 | issue = 2 | pages = 91–102 | date = August 1997 | pmid = 9260033 | doi = 10.2165/00003088-199733020-00002 | url = }}</ref> [[Buccal administration|buccal]],<ref name="ODTLabel" /><ref name="PostonWaters2007">{{cite journal | vauthors = Poston KL, Waters C | title = Zydis selegiline in the management of Parkinson's disease | journal = Expert Opin Pharmacother | volume = 8 | issue = 15 | pages = 2615–2624 | date = October 2007 | pmid = 17931095 | doi = 10.1517/14656566.8.15.2615 | url = }}</ref> [[Transdermal administration|transdermal]]<ref name="PatchLabel" /><ref name="LeeChen2007" />
| class = [[Monoamine oxidase inhibitor]]; [[Catecholaminergic activity enhancer]]; [[Norepinephrine releasing agent]]; [[Antiparkinsonian agent|Antiparkinsonian]]; [[Antidepressant]]

<!-- Pharmacokinetic data -->| bioavailability = Oral: 4–10%<ref name="Mahmood1997" /><ref name="Magyar2011">{{cite book | vauthors = Magyar K | title = Monoamine Oxidases and Their Inhibitors | chapter = The Pharmacology of Selegiline | series = International Review of Neurobiology | veditors = Youdim M, Riederer P | volume = 100 | pages = 65–84 | date = 2011 | publisher = Academic Press | pmid = 21971003 | doi = 10.1016/B978-0-12-386467-3.00004-2 | isbn = 978-0-12-386467-3 | url = https://books.google.com/books?id=236nMbuZt2EC | chapter-url = https://www.poison.org/-/media/files/pdf-for-article-dowloads-and-refs/magyar-the-pharmacology-of-selegiline.pdf.}}</ref><ref name="PaeLimHan2007">{{cite journal | vauthors = Pae CU, Lim HK, Han C, Neena A, Lee C, Patkar AA | title = Selegiline transdermal system: current awareness and promise | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 31 | issue = 6 | pages = 1153–1163 | date = August 2007 | pmid = 17614182 | doi = 10.1016/j.pnpbp.2007.04.020 | url = }}</ref><br />{{Abbr|ODT|Orally disintegrating tablet}}: ~5–8× oral<ref name="LöhleStorch2008">{{cite journal | vauthors = Löhle M, Storch A | title = Orally disintegrating selegiline for the treatment of Parkinson's disease | journal = Expert Opin Pharmacother | volume = 9 | issue = 16 | pages = 2881–2891 | date = November 2008 | pmid = 18937619 | doi = 10.1517/14656566.9.16.2881 | url =}}</ref><ref name="PostonWaters2007" /><ref name="ClarkeBrewerJohnson2003">{{cite journal | vauthors = Clarke A, Brewer F, Johnson ES, Mallard N, Hartig F, Taylor S, Corn TH | title = A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition | journal = Journal of Neural Transmission | volume = 110 | issue = 11 | pages = 1241–1255 | date = November 2003 | pmid = 14628189 | doi = 10.1007/s00702-003-0036-4 | s2cid = 711419 }}</ref><br />Transdermal: 75%<ref name="LeeChen2007" />
| protein_bound = 85–90%<ref name="LeeChen2007" /><ref name="PatchLabel" /><ref name="ODTLabel" />
| metabolism = [[Liver]], other [[tissue (biology)|tissue]]s ([[CYP2B6]], [[CYP2C19]], others)<ref name="Mahmood1997" /><ref name="Rodrigues2022">{{cite journal | vauthors = Rodrigues AD | title = Drug Interactions Involving 17α-Ethinylestradiol: Considerations Beyond Cytochrome P450 3A Induction and Inhibition | journal = Clin Pharmacol Ther | volume = 111 | issue = 6 | pages = 1212–1221 | date = June 2022 | pmid = 34342002 | doi = 10.1002/cpt.2383 | url =}}</ref><ref name="LeeChen2007" /><ref name="HidestrandOscarsonSalonen2001">{{cite journal | vauthors = Hidestrand M, Oscarson M, Salonen JS, Nyman L, Pelkonen O, Turpeinen M, Ingelman-Sundberg M | title = CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's disease, as revealed from experiments with recombinant enzymes | journal = Drug Metab Dispos | volume = 29 | issue = 11 | pages = 1480–1484 | date = November 2001 | pmid = 11602525 | doi = | url = https://dmd.aspetjournals.org/content/29/11/1480}}</ref>
| metabolites = {{Nowrap|• [[Desmethylselegiline]] (DMS)}}<br />{{Nowrap|• [[Levomethamphetamine]] (L-MA)}}<br />{{Nowrap|• [[Levoamphetamine]] (L-A)}}
| onset = Oral: ≤1 hour<ref name="Knoll1983" /><ref name="Knoll1986">{{cite book | vauthors = Knoll J | title=Movement Disorders | chapter=Role of B-Type Monoamine Oxidase Inhibition in the Treatment of Parkinson's Disease | publisher=Springer US | publication-place=Boston, MA | year=1986 | isbn=978-1-4684-5040-8 | doi=10.1007/978-1-4684-5038-5_3 | pages=53–81}}</ref>
| elimination_half-life = {{Underline|Oral:}}<br />• {{Abbr|S|Selegiline}} (single): 1.2–3.5{{nbsp}}h<ref name="Mahmood1997" /><br />• {{Abbr|S|Selegiline}} (multi): 7.7–9.7{{nbsp}}h<ref name="Mahmood1997" /><ref name="PaeLimHan2007" /><br />• {{Abbr|DMS|Desmethylselegiline}} (single): 2.2–3.8{{nbsp}}h<ref name="Mahmood1997" /><br />• {{Abbr|DMS|Desmethylselegiline}} (multi): 9.5{{nbsp}}h<ref name="Mahmood1997" /><br />• {{Abbr|L-MA|Levomethamphetamine}}: 14–21{{nbsp}}h<ref name="Mahmood1997" /><ref name="PostonWaters2007" /><br />• {{Abbr|L-A|Levoamphetamine}}: 16–18{{nbsp}}h<ref name="Mahmood1997" /><ref name="PostonWaters2007" /><br />{{Underline|{{Abbr|ODT|Orally disintegrating tablet}}:}}<br />• {{Abbr|S|Selegiline}} (single): 1.3{{nbsp}}h<ref name="ODTLabel" /><br />• {{Abbr|S|Selegiline}} (multi): 10{{nbsp}}h<ref name="ODTLabel" /><br />{{Underline|Patch:}}<br />• {{Abbr|S|Selegiline}}: 20{{nbsp}}h<ref name="PaeLimHan2007" /><ref name="PatchLabel">{{cite web | title=EMSAM® (Selegiline Transdermal System) Label | url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021336s014lbl.pdf | archive-url=https://web.archive.org/web/20201018155328/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021336s014lbl.pdf | archive-date=October 18, 2020 | publisher = Food and Drug Administration | date = July 2017 | access-date=2 July 2024}}</ref>
| duration_of_action = {{plainlist|
* Prolonged use:
* Oral: 2–3{{nbsp}}days (Parkinson's disease relief)<ref name="HeinonenLammintausta1991" /><ref name="Knoll1983" />}}
| excretion = [[Urine]] (87%):<ref name="HeinonenAnttilaLammintausta1994">{{cite journal | vauthors = Heinonen EH, Anttila MI, Lammintausta RA | title = Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites | journal = Clin Pharmacol Ther | volume = 56 | issue = 6 Pt 2 | pages = 742–749 | date = December 1994 | pmid = 7995016 | doi = 10.1038/clpt.1994.204 | url = }}</ref><ref name="HeinonenMyllyläSotaniemi1989">{{cite journal | vauthors = Heinonen EH, Myllylä V, Sotaniemi K, Lamintausta R, Salonen JS, Anttila M, Savijärvi M, Kotila M, Rinne UK | title = Pharmacokinetics and metabolism of selegiline | journal = Acta Neurologica Scandinavica. Supplementum | volume = 126 | pages = 93–99 | date = November 1989 | pmid = 2515726 | doi = 10.1111/j.1600-0404.1989.tb01788.x | s2cid = 221440315 }}</ref><ref name="PostonWaters2007" /><ref name="Mahmood1997" /><ref name="ChrispMammenSorkin1991">{{cite journal | vauthors = Chrisp P, Mammen GJ, Sorkin EM | title = Selegiline: A Review of its Pharmacology, Symptomatic Benefits and Protective Potential in Parkinson's Disease | journal = Drugs Aging | volume = 1 | issue = 3 | pages = 228–248 | date = May 1991 | pmid = 1794016 | doi = 10.2165/00002512-199101030-00006 | url = }}</ref><br />• {{Abbr|L-MA|Levomethamphetamine}}: 20–63%<br />• {{Abbr|L-A|Levoamphetamine}}: 9–26%<br />•  {{Abbr|DMS|Desmethylselegiline}}: 1%<br />• {{Abbr|S|selegiline}}: 0.01–0.03%<br />[[Feces]]: 15%<ref name="HeinonenAnttilaLammintausta1994" /><ref name="PostonWaters2007" />

<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 14611-51-9
| CAS_supplemental = <br />{{CAS|14611-52-0}} <small>([[Hydrochloride|HCl]])</small>
| ATC_prefix = N04
| ATC_suffix = BD01
| ATC_supplemental = {{ATCvet|N06|AX90}}
| PubChem = 26757
| IUPHAR_ligand = 6639
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01037
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 24930
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 2K1V7GP655
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03731
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9086
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 972
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = <small>L</small>-Deprenyl; <small>L</small>-Deprenil; <small>L</small>-Deprenalin; <small>L</small>-Deprenaline; <small>L</small>-E-250; ''l''-E-250; <small>L</small>-Phenylisopropyl<wbr>methylpropinylamine; (''R'')-(–)-''N'',α-Dimethyl-''N''-2-propynylphenethylamine; (''R'')-(–)-''N''-Methyl-''N''-2-propynylamphetamine; (''R'')-(–)-''N''-2-Propynylmethamphetamine; ''N''-Propargyl-<small>L</small>-methamphetamine

<!-- Chemical data -->| IUPAC_name = (''R'')-''N''-methyl-''N''-(1-phenylpropan-2-yl)prop-3-yn-1-amine
| C = 13
| H = 17
| N = 1
| chirality = [[Levorotatory]] [[enantiomer]]
| SMILES = C#CCN([C@@H](Cc1ccccc1)C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H17N/c1-4-10-14(3)12(2)11-13-8-6-5-7-9-13/h1,5-9,12H,10-11H2,2-3H3/t12-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = MEZLKOACVSPNER-GFCCVEGCSA-N
}}
<!-- Definition and medical uses -->

'''Selegiline''', also known as '''<small>L</small>-deprenyl''' and sold under the brand names '''Eldepryl''', '''Zelapar''', and '''Emsam''' among others, is a [[medication]] which is used in the treatment of [[Parkinson's disease]] and [[major depressive disorder]].<ref name="PillLabel" /><ref name="ODTLabel" /><ref name="PatchLabel" /><ref name="Drugs.com-Names">{{cite web|url=https://www.drugs.com/international/selegiline.html|work=Drugs.com |title=Selegiline|access-date=February 7, 2016 | archive-url = https://web.archive.org/web/20240703064615/https://www.drugs.com/international/selegiline.html | archive-date = 2024-07-03}}</ref> It has also been studied and used [[off-label use|off-label]] for a variety of other indications, but has not been formally approved for any other use.<ref name="Miklya2016" /><ref name="RossanoCaiazzaSobrino2023" /> The medication, in the form licensed for depression, has modest [[effectiveness]] for this condition that is similar to that of other [[antidepressant]]s.<ref name="RossanoCaiazzaSobrino2023" /><ref name="CitromeGoldbergPortland2013" /><ref name="CiprianiFurukawaSalanti2018" /> Selegiline is provided as a [[oral administration|swallowed]] [[tablet (pharmacy)|tablet]] or [[capsule (pharmacy)|capsule]]<ref name="PillLabel" /><ref name="Mahmood1997" /> or an [[orally disintegrating tablet]] (ODT)<ref name="ODTLabel" /><ref name="PostonWaters2007" /> for Parkinson's disease and as a [[transdermal patch|patch applied to skin]] for depression.<ref name="PatchLabel" /><ref name="LeeChen2007" />

<!-- Side effects and interactions -->
[[Side effect]]s of selegiline occurring more often than with [[placebo]] include [[insomnia]], [[dry mouth]], [[dizziness]], [[anxiety]], abnormal [[abnormal dream|dream]]s, and [[application site reaction]]s (with the patch form), among others.<ref name="RossanoCaiazzaSobrino2023" /><ref name="CitromeGoldbergPortland2013" /><ref name="RobinsonAmsterdam2008" /><ref name="PillLabel" /><ref name="PatchLabel" /> At high doses, selegiline has the potential for dangerous [[drug interaction|food and drug interactions]], such as [[tyramine]]-related [[hypertensive crisis]] (the so-called "cheese reaction") and risk of [[serotonin syndrome]].<ref name="LeeChen2007" /><ref name="GerlachYoudimRiederer1996">{{cite journal | vauthors = Gerlach M, Youdim MB, Riederer P | title = Pharmacology of selegiline | journal = Neurology | volume = 47 | issue = 6 Suppl 3 | pages = S137–S145 | date = December 1996 | pmid = 8959982 | doi = 10.1212/wnl.47.6_suppl_3.137s | url = }}</ref><ref name="Mahmood1997" /> However, doses within the approved clinical range appear to have little to no risk of these interactions.<ref name="LeeChen2007" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /> In addition, the ODT and [[transdermal patch]] forms of selegiline have reduced risks of such interactions compared to the conventional oral form.<ref name="PostonWaters2007" /><ref name="LeeChen2007" /> Selegiline has no known [[abuse potential|misuse potential]] or [[drug dependence|dependence liability]] and is not a [[controlled substance]] except in [[Japan]].<ref name="FinbergRabey2016" /><ref name="FabbriniAbbruzzeseMarconi2012" /><ref name="YasarGoldbergGoldberg1996">{{cite book | vauthors = Yasar S, Goldberg JP, Goldberg SR | chapter = Are metabolites of l-deprenyl (Selegiline) useful or harmful? Indications from preclinical research | title = Deprenyl — Past and Future | series = Journal of Neural Transmission. Supplementum | pages = 61–73 | date = January 1, 1996 | volume = 48 | pmid = 8988462 | doi = 10.1007/978-3-7091-7494-4_6 | isbn = 978-3-211-82891-5 }}</ref><ref name="NickelSzelenyiSchulze1994" /><ref name="PatchLabel" /><ref name="KEGG" />

<!-- Mechanism of action and chemistry -->
Selegiline acts as a [[monoamine oxidase inhibitor]] (MAOI) and thereby increases levels of [[monoamine neurotransmitter]]s in the [[brain]].<ref name="HeinonenLammintausta1991">{{cite journal | vauthors = Heinonen EH, Lammintausta R | title = A review of the pharmacology of selegiline | journal = Acta Neurologica Scandinavica. Supplementum | volume = 136 | issue =  | pages = 44–59 | date = 1991 | pmid = 1686954 | doi = 10.1111/j.1600-0404.1991.tb05020.x  }}</ref><ref name="Magyar2011" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /> At typical clinical doses used for Parkinson's disease, selegiline is a [[binding selectivity|selective]] and [[irreversible inhibitor]] of [[monoamine oxidase B]] (MAO-B), increasing brain levels of [[dopamine]].<ref name="HeinonenLammintausta1991" /><ref name="Magyar2011" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /> At higher doses, it loses its specificity for MAO-B and also inhibits [[monoamine oxidase A]] (MAO-A), which increases [[serotonin]] and [[norepinephrine]] levels in the brain as well.<ref name="HeinonenLammintausta1991" /><ref name="Magyar2011" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /> In addition to its MAOI activity, selegiline is a [[catecholaminergic activity enhancer]] (CAE) and enhances the [[action potential|impulse]]-mediated [[neurotransmitter release|release]] of norepinephrine and dopamine in the brain.<ref name="Knoll1997">{{cite journal | vauthors = Knoll J | title = Istoriia deprenil--pervogo selektivnogo ingibitora monoaminoksidazy tipa B | trans-title = History of deprenyl--the first selective inhibitor of monoamine oxidase type B | journal = Voprosy Meditsinskoi Khimii | volume = 43 | issue = 6 | pages = 482–493 | date = 1997 | pmid = 9503565 }}</ref><ref name="Knoll1998">{{cite journal | vauthors = Knoll J | title = (-)Deprenyl (selegiline), a catecholaminergic activity enhancer (CAE) substance acting in the brain | journal = Pharmacol Toxicol | volume = 82 | issue = 2 | pages = 57–66 | date = February 1998 | pmid = 9498233 | doi = 10.1111/j.1600-0773.1998.tb01399.x | url = }}</ref><ref name="Miklya2014a" /><ref name="GasznerMiklya2006" /><ref name="GerlachYoudimRiederer1996" /> This action may be mediated by [[TAAR1]] [[agonist|agonism]].<ref name="HarsingTimarMiklya2023">{{cite journal | vauthors = Harsing LG, Timar J, Miklya I | title = Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline | journal = Int J Mol Sci | volume = 24 | issue = 17 | date = August 2023 | article-number = 13334 | pmid = 37686140 | pmc = 10487936 | doi = 10.3390/ijms241713334 | doi-access = free | url = }}</ref><ref name="ShimazuMiklya2004">{{cite journal | vauthors = Shimazu S, Miklya I | title = Pharmacological studies with endogenous enhancer substances: β-phenylethylamine, tryptamine, and their synthetic derivatives | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 28 | issue = 3 | pages = 421–427 | date = May 2004 | pmid = 15093948 | doi = 10.1016/j.pnpbp.2003.11.016 | url = }}</ref><ref name="Berry2007">{{cite journal | vauthors = Berry MD | title = The potential of trace amines and their receptors for treating neurological and psychiatric diseases | journal = Rev Recent Clin Trials | volume = 2 | issue = 1 | pages = 3–19 | date = January 2007 | pmid = 18473983 | doi = 10.2174/157488707779318107 | url = }}</ref> After administration, selegiline partially [[drug metabolism|metabolizes]] into [[levomethamphetamine]] and [[levoamphetamine]], which act as [[norepinephrine releasing agent]]s (NRAs) and may contribute to its therapeutic and adverse effects as well.<ref name="GerlachReichmannRiederer2012">{{cite journal | vauthors = Gerlach M, Reichmann H, Riederer P | title=A critical review of evidence for preclinical differences between rasagiline and selegiline | journal=Basal Ganglia | volume=2 | issue=4 | date=2012 | doi=10.1016/j.baga.2012.04.032 | pages=S9–S15 }}</ref><ref name="YasarGoldbergGoldberg1996" /><ref name="RothmanBaumann2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = Eur J Pharmacol | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 | url = }}</ref> The levels of these [[metabolite]]s are much lower with the ODT and transdermal patch forms of selegiline.<ref name="PostonWaters2007" /><ref name="LeeChen2007" /> Chemically, selegiline is a [[substituted phenethylamine]] and [[substituted amphetamine|amphetamine]],<ref name="KraemerMaurer2002">{{cite journal | vauthors = Kraemer T, Maurer HH | title = Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives | journal = Ther Drug Monit | volume = 24 | issue = 2 | pages = 277–289 | date = April 2002 | pmid = 11897973 | doi = 10.1097/00007691-200204000-00009 | url = }}</ref> a [[chemical derivative|derivative]] of [[methamphetamine]],<ref name="KraemerMaurer2002" /> and the [[enantiopure drug|purified]] [[levorotatory]] [[enantiomer]] of [[deprenyl]] (the [[racemic mixture]] of selegiline and [[D-deprenyl|<small>D</small>-deprenyl]]).<ref name="Parnham1993">{{cite book | vauthors = Parnham MJ | title=Inhibitors of Monoamine Oxidase B: Pharmacology and Clinical Use in Neurodegenerative Disorders | chapter=The History of l-Deprenyl | series=Milestones in Drug Therapy | publisher=Birkhäuser Basel | publication-place=Basel | date=1993 | isbn=978-3-0348-6349-0 | doi=10.1007/978-3-0348-6348-3_12 | pages=237–251}}</ref><ref name="Miklya2016" />

<!-- History, society, and culture -->
Deprenyl was discovered and studied as an antidepressant in the early 1960s by Zoltan Ecseri, [[József Knoll]], and other colleagues at [[Chinoin|Chinoin Pharmaceutical Company]] in [[Hungary]].<ref name="Parnham1993" /><ref name="Miklya2016" /> Subsequently, selegiline was [[chiral resolution|purified]] from deprenyl and was studied and developed itself.<ref name="Parnham1993" /> Selegiline was first introduced for medical use, to treat Parkinson's disease, in Hungary in 1977.<ref name="TábiVécseiYoudim2020">{{cite journal | vauthors = Tábi T, Vécsei L, Youdim MB, Riederer P, Szökő É | title = Selegiline: a molecule with innovative potential | journal = J Neural Transm (Vienna) | volume = 127 | issue = 5 | pages = 831–842 | date = May 2020 | pmid = 31562557 | pmc = 7242272 | doi = 10.1007/s00702-019-02082-0 | url = }}</ref> It was subsequently approved in the [[United Kingdom]] in 1982 and in the [[United States]] in 1989.<ref name="TábiVécseiYoudim2020" /><ref name="MylanHist2011" /> The ODT was approved for Parkinson's disease in the United States in 2006 and in the [[European Union]] in 2010, while the patch was introduced for depression in the United States in 2006.<ref name="TábiVécseiYoudim2020" /><ref name="Miklya2016" /> Selegiline was the first selective MAO-B inhibitor to be discovered and marketed.<ref name="LöhleStorch2008" /><ref name="HoffmanOlsonSchoffstall2023" /><ref name="Golbe1988" /> In addition to its medical use, there has been interest in selegiline as a potential [[anti-aging movement|anti-aging drug]] and [[nootropic]].<ref name="SchifanoCatalaniSharif2022" /><ref name="Knoll2001">{{cite journal | vauthors = Knoll J | title = Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain | journal = CNS Drug Rev | volume = 7 | issue = 3 | pages = 317–345 | date = 2001 | pmid = 11607046 | pmc = 6494119 | doi = 10.1111/j.1527-3458.2001.tb00202.x | url = }}</ref><ref name="SchneiderTariotGoldstein1994">{{cite journal | vauthors = Schneider LS, Tariot PN, Goldstein B | title = Therapy with l-deprenyl (selegiline) and relation to abuse liability | journal = Clin Pharmacol Ther | volume = 56 | issue = 6 Pt 2 | pages = 750–756 | date = December 1994 | pmid = 7995017 | doi = 10.1038/clpt.1994.205 | url =}}</ref> However, effects of this sort are controversial and uncertain.<ref name="SchifanoCatalaniSharif2022" /><ref name="BlazerYaffeLiverman2015">{{cite book | vauthors =  Blazer DG, Yaffe K, Liverman CT | title=Risk and Protective Factors and Interventions: General Cognitive Aging Interventions and Next Steps | publisher=National Academies Press (US) | date=21 July 2015 | url=https://www.ncbi.nlm.nih.gov/books/NBK316206/ | access-date=5 July 2024 }}</ref><ref name="Muskin2008">{{cite journal | vauthors = Brown RP, Gerbarg PL | title = Integrative Psychopharmacology: A Practical Approach to Herbs and Nutrients in Psychiatry | veditors = Muskin PR | series = Complementary and Alternative Medicine and Psychiatry | publisher=American Psychiatric Publishing | journal = Review of Psychiatry | volume = 19 | issue = 1 | pages = 1–66 (39) | year=2008 | isbn=978-1-58562-827-8 | url=https://books.google.com/books?id=BNeqDOqEX0wC&pg=PA39 | access-date=5 July 2024 }}</ref><ref name="Finberg2019">{{cite journal | vauthors = Finberg JP | title = Inhibitors of MAO-B and COMT: their effects on brain dopamine levels and uses in Parkinson's disease | journal = Journal of Neural Transmission | volume = 126 | issue = 4 | pages = 433–448 | date = April 2019 | pmid = 30386930 | doi = 10.1007/s00702-018-1952-7}}</ref> [[Generic drug|Generic]] versions of selegiline are available in the case of the conventional oral form, but not in the case of the ODT or transdermal patch forms.<ref name="Drugs@FDA" /><ref name="AsnisHenderson2014" />

{{TOC limit|3}}

==Medical uses==

===Parkinson's disease===
In its oral and ODT forms, selegiline is used to treat [[symptom]]s of [[Parkinson's disease]] (PD).<ref name="PillLabel">{{cite web | title=ELDEPRYL® (Selegiline Hydrochloride) Tablets, USP Label | url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020647s006s007lbl.pdf | archive-url=https://web.archive.org/web/20170228152012/http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020647s006s007lbl.pdf | archive-date=February 28, 2017 | publisher = Food and Drug Administration | date = January 2008 | access-date=3 July 2024}}</ref><ref name="ODTLabel">{{cite web | title=ZELAPAR® (Selegiline Hydrochloride) Orally Disintegrating Tablets | url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021479s010lbl.pdf | publisher = Food and Drug Administration | date = July 2021 | access-date=3 July 2024}}</ref> It is most often used as an [[adjunct therapy|adjunct]] to medications such as [[levodopa]] (<small>L</small>-DOPA), although it has been used [[off-label use|off-label]] as a [[monotherapy]].<ref name="RiedererLachenmayerLaux2004">{{cite journal | vauthors = Riederer P, Lachenmayer L, Laux G | title = Clinical applications of MAO-inhibitors | journal = Current Medicinal Chemistry | volume = 11 | issue = 15 | pages = 2033–2043 | date = August 2004 | pmid = 15279566 | doi = 10.2174/0929867043364775 | doi-broken-date = July 11, 2025 |url=https://www.eurekaselect.com/article/7070 | url-access = subscription }}</ref><ref name="Drugs.com-Mono">{{cite web|url=https://www.drugs.com/monograph/selegiline-hydrochloride.html|title=Selegiline Hydrochloride Monograph for Professionals|work=Drugs.com|access-date=February 23, 2018}}</ref> The rationale for adding selegiline to levodopa is to decrease the required dose of levodopa and thus reduce the [[levodopa-induced dyskinesia|motor complications of levodopa therapy]].<ref name="IvesStoweMarro2004">{{cite journal | vauthors = Ives NJ, Stowe RL, Marro J, Counsell C, Macleod A, Clarke CE, Gray R, Wheatley K | title = Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients | journal = BMJ | volume = 329 | issue = 7466 | page = 593 | date = September 2004 | pmid = 15310558 | pmc = 516655 | doi = 10.1136/bmj.38184.606169.AE }}</ref> Selegiline delays the point when levodopa treatment becomes necessary from about 11{{nbsp}}months to about 18{{nbsp}}months after [[diagnosis]].<ref name="RiedererLachenmayer2003">{{cite journal | vauthors = Riederer P, Lachenmayer L | title = Selegiline's neuroprotective capacity revisited | journal = Journal of Neural Transmission | volume = 110 | issue = 11 | pages = 1273–1278 | date = November 2003 | pmid = 14628191 | doi = 10.1007/s00702-003-0083-x | s2cid = 20232921 }}</ref> There is some evidence that selegiline acts as a [[neuroprotective]] and [[disease-modifying treatment|reduces the rate of disease progression]], though this is disputed.<ref name="Drugs.com-Mono" /><ref name="IvesStoweMarro2004" /> In addition to [[parkinsonism]], selegiline can improve symptoms of [[depression (mood)|depression]] in people with Parkinson's disease.<ref name="FrisinaTenenbaumBorod2008">{{cite journal | vauthors = Frisina PG, Tenenbaum HR, Borod JC, Foldi NS | title = The effects of antidepressants in Parkinson's disease: a meta-analysis | journal = Int J Neurosci | volume = 118 | issue = 5 | pages = 667–682 | date = May 2008 | pmid = 18446583 | doi = 10.1080/00207450701239418 | url = }}</ref><ref name="TsuboiSatakeHiraga2022">{{cite journal | vauthors = Tsuboi T, Satake Y, Hiraga K, Yokoi K, Hattori M, Suzuki M, Hara K, Ramirez-Zamora A, Okun MS, Katsuno M | title = Effects of MAO-B inhibitors on non-motor symptoms and quality of life in Parkinson's disease: A systematic review | journal = npj Parkinsons Dis | volume = 8 | issue = 1 | article-number = 75 | date = June 2022 | pmid = 35697709 | pmc = 9192747 | doi = 10.1038/s41531-022-00339-2 | url = }}</ref> There is evidence that selegiline may be more effective than [[rasagiline]] in the treatment of Parkinson's disease.<ref name="Miklya2016" /><ref name="HarsingTimarMiklya2023" /><ref name="BindeTveteGåsemyr2018">{{cite journal | vauthors = Binde CD, Tvete IF, Gåsemyr J, Natvig B, Klemp M | title = A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson's disease | journal = Br J Clin Pharmacol | volume = 84 | issue = 9 | pages = 1917–1927 | date = September 2018 | pmid = 29847694 | pmc = 6089809 | doi = 10.1111/bcp.13651 | url = }}</ref> This may be due to [[pharmacology|pharmacological]] differences between the drugs, such as the [[catecholaminergic activity enhancer]] (CAE) actions of selegiline which rasagiline lacks.<ref name="Miklya2016" /><ref name="HarsingTimarMiklya2023" /><ref name="BindeTveteGåsemyr2018" /><ref name="Knoll1998" />

===Depression===
Selegiline is used as an [[antidepressant]] in the treatment of [[major depressive disorder]] (MDD).<ref name="PatchLabel" /><ref name="RossanoCaiazzaSobrino2023" /> Both the oral selegiline and transdermal selegiline patch formulations are used in the treatment of depression.<ref name="RossanoCaiazzaSobrino2023" /> However, oral selegiline is not approved for depression and is used [[off-label use|off-label]] for this indication, while the transdermal patch is specifically licensed for treatment of depression.<ref name="PillLabel" /><ref name="PatchLabel" /> Both standard clinical doses of oral selegiline (up to 10{{nbsp}}mg/day) and higher doses of oral selegiline (e.g., 30 to 60{{nbsp}}mg/day) have been used to treat depression, with the lower doses selectively inhibiting MAO-B and the higher doses producing dual inhibition of both MAO-A and MAO-B.<ref name="LeeChen2007" /><ref name="RossanoCaiazzaSobrino2023" /> Unlike oral selegiline, transdermal selegiline bypasses [[first-pass metabolism]], thereby avoiding inhibition of [[gastrointestinal]] and [[liver|hepatic]] MAO-A and minimizing the risk of [[drug interaction|food and drug interaction]]s, whilst still allowing for selegiline to reach the brain and inhibit MAO-B.<ref name="LeeChen2007">{{cite journal | vauthors = Lee KC, Chen JJ | title = Transdermal selegiline for the treatment of major depressive disorder | journal = Neuropsychiatric Disease and Treatment | volume = 3 | issue = 5 | pages = 527–537 | date = November 2007 | pmid = 19300583 | pmc = 2656289 | doi = 10.2147/ndt.s12160200 | doi-broken-date = July 11, 2025 | doi-access = free }}</ref>

A 2023 [[systematic review]] and [[meta-analysis]] evaluated the effectiveness and safety of selegiline in the treatment of [[psychiatric disorder]]s including depression.<ref name="RossanoCaiazzaSobrino2023">{{cite journal | vauthors = Rossano F, Caiazza C, Sobrino A, Solini N, Vellucci A, Zotti N, Fornaro M, Gillman K, Cattaneo CI, Van den Eynde V, Birkenhager TK, Ruhé HG, Stahl S, Iasevoli F, de Bartolomeis A | title = Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations | journal = Eur Neuropsychopharmacol | volume = 72 | issue = | pages = 60–78 | date = July 2023 | pmid = 37087864 | doi = 10.1016/j.euroneuro.2023.03.012 | url = | hdl = 2066/293870 | hdl-access = free }}</ref> It included both randomized and non-randomized published clinical studies.<ref name="RossanoCaiazzaSobrino2023" /> The meta-analysis found that selegiline was more effective than [[placebo]] in terms of reduction in depressive symptoms ({{Abbrlink|SMD|standardized mean difference}} = −0.96, k = 10, n = 1,308), [[Response rate (medicine)|response rate]]s for depression improvement ({{Abbrlink|RR|risk ratio}} = 1.61, k = 9, n = 1,238), and response rates for improvement of depression with atypical features ({{Abbr|RR|risk ratio}} = 2.23, k = 3, n = 136).<ref name="RossanoCaiazzaSobrino2023" /> Oral selegiline was significantly more effective than the selegiline patch in terms of depressive symptom improvement ({{Abbr|SMD|standardized mean difference}} = −1.49, k = 6, n = 282 vs. {{Abbr|SMD|standardized mean difference}} = −0.27, k = 4, n = 1,026, respectively; p = 0.03).<ref name="RossanoCaiazzaSobrino2023" /> However, this was largely due to older and less [[methodology|methodologically]] rigorous trials that were at high risk for [[bias]].<ref name="RossanoCaiazzaSobrino2023" /> Oral selegiline studies also often employed much higher doses than usual, for instance 20 to 60{{nbsp}}mg/day.<ref name="RossanoCaiazzaSobrino2023" /> The [[quality of evidence]] of selegiline for depression was rated as very low overall, very low for oral selegiline, and low to moderate for transdermal selegiline.<ref name="RossanoCaiazzaSobrino2023" /> For comparison, meta-analyses of other antidepressants for depression have found a mean [[effect size]] of about 0.3 (a small effect),<ref name="CiprianiFurukawaSalanti2018">{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | title = Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis | journal = Lancet | volume = 391 | issue = 10128 | pages = 1357–1366 | date = April 2018 | pmid = 29477251 | pmc = 5889788 | doi = 10.1016/S0140-6736(17)32802-7 | url = }}</ref><ref name="HengartnerJakobsenSørensen2020">{{cite journal | vauthors = Hengartner MP, Jakobsen JC, Sørensen A, Plöderl M | title = Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials | journal = PLOS ONE | volume = 15 | issue = 2 | article-number = e0229381 | date = 2020 | pmid = 32101579 | pmc = 7043778 | doi = 10.1371/journal.pone.0229381 | doi-access = free | bibcode = 2020PLoSO..1529381H | url = }}</ref> which is similar to that with transdermal selegiline.<ref name="RossanoCaiazzaSobrino2023" />

In two [[Phases of clinical research#Phase III|pivotal regulatory clinical trials]] of 6 to 8{{nbsp}}weeks duration, the selegiline transdermal patch decreased scores on [[rating scales for depression|depression rating scales]] (specifically the 17- and 28-item {{Abbrlink|HDRS|Hamilton Depression Rating Scale}}) by 9.0 to 10.9{{nbsp}}points, whereas placebo decreased scores by 6.5 to 8.6{{nbsp}}points, giving placebo-subtracted differences attributable to selegiline of 2.4 to 2.5{{nbsp}}points.<ref name="PatchLabel" /> A 2013 [[quantitative research|quantitative]] [[literature review|review]] of the transdermal selegiline patch for depression, which pooled the results of these two trials, found that the placebo-subtracted [[number needed to treat]] (NNT) was 11 in terms of depression response (>50% reduction in symptoms) and 9 in terms of remission of depression (score of ≤10 on the {{Abbrlink|MADRS|Montgomery–Åsberg Depression Rating Scale}}).<ref name="CitromeGoldbergPortland2013">{{cite journal | vauthors = Citrome L, Goldberg JF, Portland KB | title = Placing transdermal selegiline for major depressive disorder into clinical context: number needed to treat, number needed to harm, and likelihood to be helped or harmed | journal = Journal of Affective Disorders | volume = 151 | issue = 2 | pages = 409–417 | date = November 2013 | pmid = 23890583 | doi = 10.1016/j.jad.2013.06.027 }}</ref> For comparison, other antidepressants, including [[fluoxetine]], [[paroxetine]], [[duloxetine]], [[vilazodone]], [[adjunct therapy|adjunctive]] [[aripiprazole]], [[olanzapine/fluoxetine]], and [[extended-release]] [[quetiapine]], have NNTs ranging from 6 to 8 in terms of depression response and 7 to 14 in terms of depression remission.<ref name="CitromeGoldbergPortland2013" /> On the basis of these results, it was concluded that transdermal selegiline has similar effectiveness to other antidepressants.<ref name="CitromeGoldbergPortland2013" /><ref name="CristanchoThase2016" /> NNTs are measures of effect size and indicate how many individuals would need to be treated in order to encounter one additional outcome of interest.<ref name="CitromeGoldbergPortland2013" /> Lower NNTs are better, and NNTs corresponding to [[Cohen's d]] effect sizes have been defined as 2.3 for a large effect (d = 0.8), 3.6 for a medium effect (d = 0.5), and 8.9 for a small effect (d = 0.2).<ref name="CitromeGoldbergPortland2013" /> The effectiveness of transdermal selegiline for depression relative to [[side effect]]s and [[drug discontinuation|discontinuation]] was considered to be favorable.<ref name="CitromeGoldbergPortland2013" />

While several large regulatory clinical trials of transdermal selegiline versus placebo for depression have been conducted, there is a lack of trials comparing selegiline to other antidepressants.<ref name="AsnisHenderson2014" /><ref name="CristanchoThase2016" /> Although multiple doses of transdermal selegiline were assessed, a [[dose–response relationship]] for depression was never established.<ref name="AsnisHenderson2014" /><ref name="CristanchoThase2016" /> Transdermal selegiline has shown similar clinical effectiveness in the treatment of [[atypical depression]] relative to typical depression and in the treatment of [[mixed anxiety–depressive disorder|anxious depression]] relative to non-anxious depression.<ref name="AsnisHenderson2014" /><ref name="PaePaktarJang2014">{{cite journal | vauthors = Pae CU, Patkar AA, Jang S, Portland KB, Jung S, Nelson JC | title = Efficacy and safety of selegiline transdermal system (STS) for the atypical subtype of major depressive disorder: pooled analysis of 5 short-term, placebo-controlled trials | journal = CNS Spectr | volume = 19 | issue = 4 | pages = 324–329 | date = August 2014 | pmid = 24168807 | doi = 10.1017/S1092852913000655 | url = }}</ref><ref name="CristanchoThase2016" />

Transdermal selegiline does not cause [[sexual dysfunction]] and may improve certain domains of [[sexual function]], for instance [[sexual desire|sexual interest]], maintaining interest during sex, and [[sexual satisfaction]].<ref name="ClaytonCampbellFavit2007">{{cite journal | vauthors = Clayton AH, Campbell BJ, Favit A, Yang Y, Moonsammy G, Piontek CM, Amsterdam JD | title = Symptoms of sexual dysfunction in patients treated for major depressive disorder: a meta-analysis comparing selegiline transdermal system and placebo using a patient-rated scale | journal = J Clin Psychiatry | volume = 68 | issue = 12 | pages = 1860–1866 | date = December 2007 | pmid = 18162016 | doi = 10.4088/jcp.v68n1205 | url = }}</ref> These benefits were apparent in women but not in men.<ref name="ClaytonCampbellFavit2007" /> The lack of sexual dysfunction with transdermal selegiline is in contrast to many other antidepressants, such as the [[selective serotonin reuptake inhibitor]]s (SSRIs) and [[serotonin–norepinephrine reuptake inhibitor]]s (SNRIs), which are associated with high rates of sexual dysfunction.<ref name="WinterCurtisHu2022">{{cite journal | vauthors = Winter J, Curtis K, Hu B, Clayton AH | title = Sexual dysfunction with major depressive disorder and antidepressant treatments: impact, assessment, and management | journal = Expert Opin Drug Saf | volume = 21 | issue = 7 | pages = 913–930 | date = July 2022 | pmid = 35255754 | doi = 10.1080/14740338.2022.2049753 | url =}}</ref>

Transdermal selegiline patches have been underutilized in the treatment of depression compared to other antidepressants.<ref name="AsnisHenderson2014">{{cite journal | vauthors = Asnis GM, Henderson MA | title = EMSAM (deprenyl patch): how a promising antidepressant was underutilized | journal = Neuropsychiatr Dis Treat | volume = 10 | issue = | pages = 1911–1923 | date = 2014 | pmid = 25336957 | pmc = 4200016 | doi = 10.2147/NDT.S59107 | doi-access = free | url = }}</ref><ref name="CristanchoThase2016" /> A variety of factors contributing to this underutilization have been identified.<ref name="AsnisHenderson2014" /> One major factor is the very high cost of transdermal selegiline, which is often not covered by [[medical insurance|insurance]] and frequently proves to be prohibitive.<ref name="AsnisHenderson2014" /><ref name="CristanchoThase2016" /> Conversely, other widely available antidepressants are much cheaper in comparison.<ref name="AsnisHenderson2014" /><ref name="CristanchoThase2016" />

===Available forms===
Selegiline is available in the following three [[pharmaceutical form]]s:<ref name="Drugs@FDA">{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=accessdata.fda.gov | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | archive-url=https://web.archive.org/web/20161104020633/http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | archive-date=November 4, 2016 | access-date=1 July 2024}}</ref>
* [[Oral administration|Oral]] [[tablet (pharmacy)|tablet]]s and [[capsule (pharmacy)|capsule]]s 5{{nbsp}}mg (brand names Eldepryl, Jumex, and generics) – indicated for Parkinson's disease<ref name="PillLabel" /><ref name="Mahmood1997" /><ref name="TábiVécseiYoudim2020" />
* [[Orally disintegrating tablet]]s (ODTs) 1.25{{nbsp}}mg (brand name Zelapar) – indicated for Parkinson's disease<ref name="ODTLabel" /><ref name="PostonWaters2007" />
* [[Transdermal patch]]es 6, 9, and 12{{nbsp}}mg/24{{nbsp}}hours (brand name Emsam) – indicated for major depressive disorder<ref name="PatchLabel" /><ref name="LeeChen2007" /><ref name="PaeLimHan2007" /><ref name="RobinsonAmsterdam2008" /><ref name="CristanchoThase2016" />

[[Image:Emsamred.jpg|thumb|right|200px|Selegiline transdermal patch (Emsam), 6{{nbsp}}mg/24{{nbsp}}hours form.]]

The transdermal patch form is also known as the "selegiline transdermal system" or "STS" and is applied once daily.<ref name="LeeChen2007" /><ref name="PaeLimHan2007" /><ref name="RobinsonAmsterdam2008" /><ref name="CristanchoThase2016" /><ref name="PatchLabel" /> They are 20, 30, or 40{{nbsp}}cm<sup>2</sup> in size and contain a total of 20, 30, or 40{{nbsp}}mg selegiline per patch (so 20{{nbsp}}mg/20{{nbsp}}cm<sup>2</sup>, 30{{nbsp}}mg/30{{nbsp}}cm<sup>2</sup>, and 40{{nbsp}}mg/40{{nbsp}}cm<sup>2</sup>), respectively.<ref name="PatchLabel" /><ref name="CristanchoThase2016" /> The selegiline transdermal patch is a [[Transdermal patch#Matrix|matrix-type]] adhesive patch with a three-layer structure.<ref name="PatchLabel" /><ref name="CristanchoThase2016" /> It is the only approved non-oral MAOI, having reduced [[dietary restriction]]s and [[side effect]]s in comparison to oral MAOIs, and is also the only approved non-oral [[Therapy#Lines of therapy|first-line]] antidepressant.<ref name="CristanchoThase2016" /> The selegiline patch can be useful for those who have difficulty tolerating oral medications.<ref name="CristanchoThase2016" />

==Contraindications==
Selegiline is [[contraindication|contraindicated]] with [[serotonin|serotonergic]] [[antidepressant]]s including [[selective serotonin reuptake inhibitor]]s (SSRIs), [[serotonin–norepinephrine reuptake inhibitor]]s (SNRIs), and [[tricyclic antidepressant]]s (TCAs), with serotonergic [[opioid]]s like [[meperidine]], [[tramadol]], and [[methadone]], with other [[monoamine oxidase inhibitor]]s (MAOIs) such as [[linezolid]], [[phenelzine]], and [[tranylcypromine]], and with [[dextromethorphan]], [[St. John's wort]], [[cyclobenzaprine]], [[pentazocine]], [[propoxyphene]], and [[carbamazepine]].<ref name="ODTLabel" /><ref name="PatchLabel" /><ref name="PillLabel" /> Combination of selegiline with serotonergic agents may cause [[serotonin syndrome]], while combination of selegiline with [[adrenergic]] or [[sympathomimetic agent|sympathomimetic]] agents like [[ephedrine]] or [[amphetamine-type stimulant|amphetamine]]s may cause [[hypertensive crisis]].<ref name="ODTLabel" /><ref name="PatchLabel" /> Long washout periods are required before starting and stopping these medications with discontinuation or initiation of selegiline.<ref name="ODTLabel" /><ref name="PatchLabel" /><ref name="PillLabel" /><ref name="CristanchoThase2016" />

Consumption of [[tyramine]]-rich foods can result in hypertensive crisis with selegiline, also known as the "cheese effect" or "cheese reaction" due to the high amounts of tyramine present in some cheeses.<ref name="ODTLabel" /><ref name="Magyar2011" /><ref name="HoffmanOlsonSchoffstall2023">{{cite journal | vauthors = Hoffman GR, Olson MG, Schoffstall AM, Estévez RF, Van den Eynde V, Gillman PK, Stabio ME | title = Classics in Chemical Neuroscience: Selegiline, Isocarboxazid, Phenelzine, and Tranylcypromine | journal = ACS Chem Neurosci | volume = 14 | issue = 23 | pages = 4064–4075 | date = December 2023 | pmid = 37966854 | doi = 10.1021/acschemneuro.3c00591 | url = }}</ref><ref name="Knoll1983">{{cite journal | vauthors = Knoll J | title = Deprenyl (selegiline): the history of its development and pharmacological action | journal = Acta Neurol Scand Suppl | volume = 95 | issue = | pages = 57–80 | date = 1983 | pmid = 6428148 | doi = 10.1111/j.1600-0404.1983.tb01517.x | url = | doi-access = free }}</ref> Examples of other foods that may have high amounts of tyramine and similar substances include yeast products, chicken liver, snails, pickled herring, red wines, some beers, canned figs, broad beans, chocolate, and cream products.<ref name="Knoll1983" />

The preceding drug and food contraindications are dependent on selegiline dose and route, and hence are not necessarily absolute contraindications.<ref name="PillLabel" /><ref name="ODTLabel" /><ref name="Mahmood1997" /><ref name="PostonWaters2007" /><ref name="LeeChen2007" /> While high oral doses of selegiline (≥20{{nbsp}}mg/day) can cause such interactions, oral doses within the approved clinical range (≤10{{nbsp}}mg/day) appear to have little to no risk of these interactions.<ref name="LeeChen2007" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /> In addition, the ODT and transdermal forms of selegiline have reduced risks of such interactions compared to the conventional oral form.<ref name="PostonWaters2007" /><ref name="LeeChen2007" />

Selegiline is also contraindicated in children less than 12{{nbsp}}years of age and in people with [[pheochromocytoma]], both due to heightened risk of hypertensive crisis.<ref name="PatchLabel" /> For all human uses and all forms, selegiline is [[pregnancy category]] C, meaning that studies in [[pregnancy|pregnant]] animals have shown adverse effects on the [[fetus]] but there are no adequate studies in humans.<ref name="PillLabel" /><ref name="PatchLabel" />

==Side effects==
[[Side effect]]s of the tablet form in conjunction with [[levodopa]] include, in decreasing order of frequency, [[nausea]], [[hallucination]]s, [[confusion]], [[depression (mood)|depression]], [[loss of balance]], [[insomnia]], increased [[dyskinesia|involuntary movements]], [[agitation (dementia)|agitation]], [[bradycardia|slow]] or [[irregular heart rate]], [[delusion]]s, [[hypertension]], new or increased [[angina pectoris]], and [[syncope (medicine)|syncope]].<ref name="PillLabel" /> Most of the side effects are due to a high dopamine levels, and can be alleviated by reducing the dose of levodopa.<ref name="Drugs.com-Names" /> Selegiline can also cause [[cardiovascular]] side effects such as [[orthostatic hypotension]], [[hypertension]], [[atrial fibrillation]], and other types of [[cardiac arrhythmia]]s.<ref name="AlborghettiNicoletti2019">{{cite journal | vauthors = Alborghetti M, Nicoletti F | title = Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson's Disease: From Bench to Bedside | journal = Curr Neuropharmacol | volume = 17 | issue = 9 | pages = 861–873 | date = 2019 | pmid = 30160213 | pmc = 7052841 | doi = 10.2174/1570159X16666180830100754 | url = }}</ref>

The main side effects of the patch form for depression include [[application site reaction|application-site reaction]]s, [[insomnia]], [[dry mouth]], [[dizziness]], [[nervousness]], and [[abnormal dreams]].<ref name="PatchLabel" /><ref name="RobinsonAmsterdam2008">{{cite journal | vauthors = Robinson DS, Amsterdam JD | title = The selegiline transdermal system in major depressive disorder: a systematic review of safety and tolerability | journal = J Affect Disord | volume = 105 | issue = 1–3 | pages = 15–23 | date = January 2008 | pmid = 17568687 | doi = 10.1016/j.jad.2007.04.024 | url = }}</ref> The selegiline patch carries a [[boxed warning|black box warning]] about a possible increased risk of [[suicide]], especially for young people,<ref name="PatchLabel" /> as do all [[antidepressant]]s since 2007.<ref name="FriedmanLeon2007">{{cite journal | vauthors = Friedman RA, Leon AC | title = Expanding the black box - depression, antidepressants, and the risk of suicide | journal = The New England Journal of Medicine | volume = 356 | issue = 23 | pages = 2343–2346 | date = June 2007 | pmid = 17485726 | doi = 10.1056/NEJMp078015 | doi-access = free }}</ref>

Side effects of selegiline that have been identified as occurring significantly more often than with [[placebo group|placebo]] in [[meta-analysis|meta-analyses]] for psychiatric disorders have included [[xerostomia|dry mouth]] ({{Abbrlink|RR|Risk ratio}} = 1.58), [[insomnia]] ({{Abbr|RR|Risk ratio}} = 1.61, {{Abbrlink|NNH|Number needed to harm}} = 19), and [[application site reaction]]s with the transdermal form ({{Abbr|RR|Risk ratio}} = 1.81, {{Abbr|NNH|Number needed to harm}} = 7).<ref name="RossanoCaiazzaSobrino2023" /><ref name="CitromeGoldbergPortland2013" /> No significant [[diarrhea]], [[headache]], [[dizziness]], [[nausea]], [[sexual dysfunction]], or [[weight gain]] were apparent in these meta-analyses.<ref name="RossanoCaiazzaSobrino2023" /><ref name="CitromeGoldbergPortland2013" />

Selegiline, including in its oral, ODT, and patch forms, has been found to cause [[hypotension]] or [[orthostatic hypotension]] in some individuals.<ref name="PillLabel" /><ref name="ODTLabel" /><ref name="PatchLabel" /> In a clinical trial, the rate of systolic orthostatic hypotension was 21% versus 9% with placebo and the rate of diastolic orthostatic hypotension was 12% versus 4% with placebo in people with Parkinson's disease taking the ODT form of selegiline.<ref name="ODTLabel" /> The risk of hypotension is greater at the start of treatment and in the elderly (3% vs. 0% with placebo).<ref name="ODTLabel" /> The rate of hypotension or orthostatic hypotension with the selegiline patch was 2.2% versus 0.5% with placebo in clinical trials of people with depression.<ref name="RobinsonAmsterdam2008" /> Significant orthostatic blood pressure changes (≥10{{nbsp}}mm{{nbsp}}Hg decrease) occurred in 9.8% versus 6.7% with placebo, but most of these cases were asymptomatic and [[heart rate]] was unchanged.<ref name="RobinsonAmsterdam2008" /><ref name="PatkarPaeMasand2006">{{cite journal | vauthors = Patkar AA, Pae CU, Masand PS | title = Transdermal selegiline: the new generation of monoamine oxidase inhibitors | journal = CNS Spectr | volume = 11 | issue = 5 | pages = 363–375 | date = May 2006 | pmid = 16641841 | doi = 10.1017/s1092852900014498 | url = }}</ref> The rates of other orthostatic hypotension-related side effects in this population were [[dizziness]] or [[vertigo]] 4.9% versus 3.1% with placebo and [[Syncope (medicine)|fainting]] 0.5% versus 0.0% with placebo.<ref name="RobinsonAmsterdam2008" /> It is said that orthostatic hypotension is rarely seen with the selegiline transdermal patch compared to oral MAOIs.<ref name="AsnisHenderson2014" /> Caution is advised against rapidly rising after sitting or lying, especially after prolonged periods or at the start of treatment, as this can result in fainting.<ref name="ODTLabel" /><ref name="FabbriniAbbruzzeseMarconi2012" /><ref name="PatkarPaeMasand2006" /> [[Falling (accident)|Falls]] are of particular concern in the elderly.<ref name="PatkarPaeMasand2006" /> MAOIs like selegiline may lower [[blood pressure]] by increasing dopamine levels and activating [[dopamine receptor]]s, by increasing levels of the [[false neurotransmitter]] [[octopamine]], and/or by other mechanisms.<ref name="FinbergGillman2011">{{cite book | vauthors = Finberg JP, Gillman K | title = Selective inhibitors of monoamine oxidase type B and the "cheese effect" | series = International Review of Neurobiology | volume = 100 | pages = 169–190 | date = 2011 | pmid = 21971008 | doi = 10.1016/B978-0-12-386467-3.00009-1 | isbn = 978-0-12-386467-3 | url =}}</ref>

Meta-analyses published in the 1990s found that the addition of selegiline to [[levodopa]] increased [[mortality rate|mortality]] in people with Parkinson's disease.<ref name="FabbriniAbbruzzeseMarconi2012" /> However, several subsequent meta-analyses with more trials and patients found no increase in mortality with selegiline added to levodopa.<ref name="FabbriniAbbruzzeseMarconi2012" /><ref name="OlanowMyllyläSotaniemi1998">{{cite journal | vauthors = Olanow CW, Myllylä VV, Sotaniemi KA, Larsen JP, Pålhagen S, Przuntek H, Heinonen EH, Kilkku O, Lammintausta R, Mäki-Ikola O, Rinne UK | title = Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis | journal = Neurology | volume = 51 | issue = 3 | pages = 825–830 | date = September 1998 | pmid = 9748034 | doi = 10.1212/wnl.51.3.825 | url = }}</ref><ref name="AaltonenKilkkuHeinonen1998">{{cite journal | vauthors = Aaltonen H, Kilkku O, Heinonen E, Mäki-Ikola O | title = Effect of adding selegiline to levodopa in early, mild Parkinson's disease. Evidence is insufficient to show that combined treatment increases mortality | journal = BMJ | volume = 317 | issue = 7172 | pages = 1586–1587 | date = December 1998 | pmid = 9890764 | doi = 10.1136/bmj.317.7172.1586| pmc = 1114394 | url = }}</ref> If selegiline does increase mortality, it has been theorized that this may be due to cardiovascular side effects, such as its amphetamine-related sympathomimetic effects and its MAO inhibition-related hypotension.<ref name="AbassiBinahYoudim2004">{{cite journal | vauthors = Abassi ZA, Binah O, Youdim MB | title = Cardiovascular activity of rasagiline, a selective and potent inhibitor of mitochondrial monoamine oxidase B: comparison with selegiline | journal = Br J Pharmacol | volume = 143 | issue = 3 | pages = 371–378 | date = October 2004 | pmid = 15339864 | pmc = 1575354 | doi = 10.1038/sj.bjp.0705962 | url = }}</ref> Although selegiline does not seem to increase mortality, it appears to worsen [[cognition]] in people with Parkinson's disease over time.<ref name="RoyDoironTalon-Croteau2018">{{cite journal | vauthors = Roy MA, Doiron M, Talon-Croteau J, Dupré N, Simard M | title = Effects of Antiparkinson Medication on Cognition in Parkinson's Disease: A Systematic Review | journal = Can J Neurol Sci | volume = 45 | issue = 4 | pages = 375–404 | date = July 2018 | pmid = 29747716 | doi = 10.1017/cjn.2018.21 | url = }}</ref> Conversely, rasagiline does not seem to do so and can enhance cognition.<ref name="RoyDoironTalon-Croteau2018" />

Rarely, selegiline has been reported to induce or exacerbate [[impulse control disorder]]s, [[problem gambling|pathological gambling]], [[hypersexuality]], and [[paraphilia]]s in people with Parkinson's disease.<ref name="VitaleAmboniErro2019">{{cite journal | vauthors = Vitale C, Amboni M, Erro R, Picillo M, Pellecchia MT, Barone P, Trojano L, Santangelo G | title = Parkinson's disease management and impulse control disorders: current state and future perspectives | journal = Expert Rev Neurother | volume = 19 | issue = 6 | pages = 495–508 | date = June 2019 | pmid = 31148487 | doi = 10.1080/14737175.2019.1620603 | url =}}</ref><ref name="DjamshidianCardosoGrosset2011">{{cite journal | vauthors = Djamshidian A, Cardoso F, Grosset D, Bowden-Jones H, Lees AJ | title = Pathological gambling in Parkinson's disease--a review of the literature | journal = Mov Disord | volume = 26 | issue = 11 | pages = 1976–1984 | date = September 2011 | pmid = 21661054 | doi = 10.1002/mds.23821 | url = }}</ref><ref name="DrapierDrapierSauleau2006">{{cite journal | vauthors = Drapier D, Drapier S, Sauleau P, Derkinderen P, Damier P, Allain H, Vérin M, Millet B | title = Pathological gambling secondary to dopaminergic therapy in Parkinson's disease | journal = Psychiatry Res | volume = 144 | issue = 2–3 | pages = 241–244 | date = November 2006 | pmid = 17011634 | doi = 10.1016/j.psychres.2006.04.017 | url = }}</ref><ref name="SollaBortolatoCannas2015">{{cite journal | vauthors = Solla P, Bortolato M, Cannas A, Mulas CS, Marrosu F | title = Paraphilias and paraphilic disorders in Parkinson's disease: A systematic review of the literature | journal = Mov Disord | volume = 30 | issue = 5 | pages = 604–613 | date = April 2015 | pmid = 25759330 | pmc = 4428164 | doi = 10.1002/mds.26157 | url = }}</ref><ref name="HiraoKanekoHirose2019">{{cite journal | vauthors = Hirao K, Kaneko Y, Hirose D, Fukasawa R, Shimizu S, Kanetaka H, Umahara T, Sakurai H, Hanyu H | title = Patient with Parkinson's disease presenting with impulse control disorders following treatment with selegiline | journal = Int Psychogeriatr | volume = 31 | issue = 9 | pages = 1375–1376 | date = September 2019 | pmid = 30520410 | doi = 10.1017/S1041610218001862 | url = | doi-access = free }}</ref><ref name="UittiTannerRajput1989">{{cite journal | vauthors = Uitti RJ, Tanner CM, Rajput AH, Goetz CG, Klawans HL, Thiessen B | title = Hypersexuality with antiparkinsonian therapy | journal = Clin Neuropharmacol | volume = 12 | issue = 5 | pages = 375–383 | date = October 1989 | pmid = 2575449 | doi = 10.1097/00002826-198910000-00002 | url = }}</ref><ref name="Riley2002">{{cite journal | vauthors = Riley DE | title = Reversible transvestic fetishism in a man with Parkinson's disease treated with selegiline | journal = Clin Neuropharmacol | volume = 25 | issue = 4 | pages = 234–237 | date = 2002 | pmid = 12151912 | doi = 10.1097/00002826-200207000-00008 | url = }}</ref><ref name="ShapiroChangMunson2006">{{cite journal | vauthors = Shapiro MA, Chang YL, Munson SK, Okun MS, Fernandez HH | title = Hypersexuality and paraphilia induced by selegiline in Parkinson's disease: report of 2 cases | journal = Parkinsonism Relat Disord | volume = 12 | issue = 6 | pages = 392–395 | date = September 2006 | pmid = 16730214 | doi = 10.1016/j.parkreldis.2006.01.010 | url = }}</ref> However, MAO-B inhibitors like selegiline causing impulse control disorders is uncommon, controversial, and less frequent than with [[dopamine receptor agonist]]s like [[pramipexole]].<ref name="VitaleAmboniErro2019" /><ref name="DjamshidianCardosoGrosset2011" /> Impulse control disorders with [[dopaminergic agent]]s have been linked specifically to activation of dopamine [[D3 receptor|D<sub>3</sub> receptor]]s in the [[globus pallidus]].<ref name="Seeman2015">{{cite journal | vauthors = Seeman P | title = Parkinson's disease treatment may cause impulse-control disorder via dopamine D3 receptors | journal = Synapse | volume = 69 | issue = 4 | pages = 183–189 | date = April 2015 | pmid = 25645960 | doi = 10.1002/syn.21805 | url = }}</ref><ref name="Garcia-Ruiz2018">{{cite journal | vauthors = Garcia-Ruiz PJ | title = Impulse Control Disorders and Dopamine-Related Creativity: Pathogenesis and Mechanism, Short Review, and Hypothesis | journal = Front Neurol | volume = 9 | issue = | article-number = 1041 | date = 2018 | pmid = 30574117 | pmc = 6291460 | doi = 10.3389/fneur.2018.01041 | doi-access = free | url = }}</ref><ref name="WilliamsLeeEwah2024">{{cite journal | vauthors = Williams BD, Lee K, Ewah SO, Neelam K | title = Aripiprazole and Other Third-Generation Antipsychotics as a Risk Factor for Impulse Control Disorders: A Systematic Review and Meta-Analysis | journal = J Clin Psychopharmacol | volume = 44 | issue = 1 | pages = 39–48 | date = 2024 | pmid = 38011021 | doi = 10.1097/JCP.0000000000001773 | url = }}</ref><ref name="KubotaZhouZhang2024">{{cite journal | vauthors = Kubota H, Zhou X, Zhang X, Watanabe H, Nagai T | title = Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson's Disease | journal = Int J Mol Sci | volume = 25 | issue = 16 | date = August 2024 | page = 8849 | pmid = 39201535 | pmc = 11354263 | doi = 10.3390/ijms25168849 | doi-access = free | url = }}</ref> Selegiline has also been reported to activate or worsen [[rapid eye movement sleep behavior disorder|rapid eye movement (REM) sleep behavior disorder]] (RBD) in some people with Parkinson's disease.<ref name="HowellAvidanFoldvary-Schaefer2023">{{cite journal | vauthors = Howell M, Avidan AY, Foldvary-Schaefer N, Malkani RG, During EH, Roland JP, McCarter SJ, Zak RS, Carandang G, Kazmi U, Ramar K | title = Management of REM sleep behavior disorder: an American Academy of Sleep Medicine clinical practice guideline | journal = J Clin Sleep Med | volume = 19 | issue = 4 | pages = 759–768 | date = April 2023 | pmid = 36515157 | pmc = 10071384 | doi = 10.5664/jcsm.10424 | url = }}</ref><ref name="HoqueChesson2010">{{cite journal | vauthors = Hoque R, Chesson AL | title = Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis | journal = J Clin Sleep Med | volume = 6 | issue = 1 | pages = 79–83 | date = February 2010 | pmid = 20191944 | pmc = 2823282 | doi = 10.5664/jcsm.27716| url = }}</ref><ref name="LoudenMoreheadSchmidt1995">{{cite journal | vauthors = Louden MB, Morehead MA, Schmidt HS | title = Activation by selegiline (Eldepryle) of REM sleep behavior disorder in parkinsonism | journal = W V Med J | volume = 91 | issue = 3 | page = 101 | date = 1995 | pmid = 7747490 | doi = | url = }}</ref>

Selegiline has shown little or no [[abuse potential|misuse potential]] in humans or monkeys.<ref name="FinbergRabey2016">{{cite journal | vauthors = Finberg JP, Rabey JM | title = Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology | journal = Front Pharmacol | volume = 7 | issue = | page = 340 | date = 2016 | pmid = 27803666 | pmc = 5067815 | doi = 10.3389/fphar.2016.00340 | doi-access = free | url = }}</ref><ref name="FabbriniAbbruzzeseMarconi2012">{{cite journal | vauthors = Fabbrini G, Abbruzzese G, Marconi S, Zappia M | title = Selegiline: a reappraisal of its role in Parkinson disease | journal = Clin Neuropharmacol | volume = 35 | issue = 3 | pages = 134–140 | date = 2012 | pmid = 22592509 | doi = 10.1097/WNF.0b013e318255838b | url =}}</ref><ref name="YasarGoldbergGoldberg1996" /><ref name="GoldbergYasarBergman1994" /><ref name="WingerYasarNegus1994">{{cite journal | vauthors = Winger GD, Yasar S, Negus SS, Goldberg SR | title = Intravenous self-administration studies with l-deprenyl (selegiline) in monkeys | journal = Clin Pharmacol Ther | volume = 56 | issue = 6 Pt 2 | pages = 774–780 | date = December 1994 | pmid = 7995020 | doi = 10.1038/clpt.1994.208 | hdl = 2027.42/110034 | url =  | hdl-access = free }}</ref><ref name="YasarGaálPanlilio2006">{{cite journal | vauthors = Yasar S, Gaál J, Panlilio LV, Justinova Z, Molnár SV, Redhi GH, Schindler CW | title = A comparison of drug-seeking behavior maintained by D-amphetamine, L-deprenyl (selegiline), and D-deprenyl under a second-order schedule in squirrel monkeys | journal = Psychopharmacology (Berl) | volume = 183 | issue = 4 | pages = 413–421 | date = January 2006 | pmid = 16292593 | pmc = 1360227 | doi = 10.1007/s00213-005-0200-7 | url = }}</ref> Likewise, it has no [[drug dependence|dependence]] potential in rodents.<ref name="NickelSzelenyiSchulze1994">{{cite journal | vauthors = Nickel B, Szelenyi I, Schulze G | title = Evaluation of physical dependence liability of l-deprenyl (selegiline) in animals | journal = Clin Pharmacol Ther | volume = 56 | issue = 6 Pt 2 | pages = 757–767 | date = December 1994 | pmid = 7995018 | doi = 10.1038/clpt.1994.206 | url = }}</ref> This is in spite of its amphetamine [[active metabolite]]s, [[levomethamphetamine]] and [[levoamphetamine]], and is in contrast to agents like [[dextroamphetamine]] and [[dextromethamphetamine]].<ref name="FabbriniAbbruzzeseMarconi2012" /><ref name="YasarGoldbergGoldberg1996" /><ref name="NickelSzelenyiSchulze1994" /><ref name="WingerYasarNegus1994" /><ref name="YasarGaálPanlilio2006" /> However, selegiline can strongly potentiate the [[positive reinforcement|reinforcing]] effects of [[exogenous]] [[β-phenethylamine]] by inhibiting its [[MAO-B]]-mediated [[metabolism]].<ref name="YasarGoldbergGoldberg1996" /> Misuse of the [[combination drug|combination]] of selegiline and β-phenethylamine has been reported.<ref name="McKeanLeungDare2015">{{cite journal | vauthors = McKean AJ, Leung JG, Dare FY, Sola CL, Schak KM | title = The Perils of Illegitimate Online Pharmacies: Substance-Induced Panic Attacks and Mood Instability Associated With Selegiline and Phenylethylamine | journal = Psychosomatics | volume = 56 | issue = 5 | pages = 583–587 | date = 2015 | pmid = 26198572 | doi = 10.1016/j.psym.2015.05.003 | url = }}</ref><ref name="MonteithGlennBauer2016">{{cite journal | vauthors = Monteith S, Glenn T, Bauer R, Conell J, Bauer M | title = Availability of prescription drugs for bipolar disorder at online pharmacies | journal = J Affect Disord | volume = 193 | issue = | pages = 59–65 | date = March 2016 | pmid = 26766033 | doi = 10.1016/j.jad.2015.12.043 | url = }}</ref>

==Overdose==
Little information is available about clinically significant selegiline [[overdose]].<ref name="PillLabel" /> The drug has been studied clinically at doses as high as 60{{nbsp}}mg/day orally,<ref name="KuhnMüller1996">{{cite book | vauthors = Kuhn W, Müller T | title = Deprenyl — Past and Future | chapter = The clinical potential of Deprenyl in neurologic and psychiatric disorders | journal = Journal of Neural Transmission. Supplementum | volume = 48  | pages = 85–93 | date = 1996 | pmid = 8988464 | doi = 10.1007/978-3-7091-7494-4_8 | isbn = 978-3-211-82891-5 }}</ref><ref name="RossanoCaiazzaSobrino2023" /> 10{{nbsp}}mg/day as an ODT,<ref name="PostonWaters2007" /> and 12{{nbsp}}mg/24{{nbsp}}hours as a transdermal patch.<ref name="LeeChen2007" /> In addition, [[deprenyl]] (the [[racemic mixture|racemic]] form) has been clinically studied orally at doses as large as 100{{nbsp}}mg/day.<ref name="HeinonenLammintausta1991" /> During clinical development of oral selegiline, some individuals who were exposed to doses of 600{{nbsp}}mg developed severe [[hypotension]] and [[psychomotor agitation]].<ref name="PillLabel" /><ref name="ODTLabel" /> Overdose may result in non-selective inhibition of both [[MAO-A]] and [[MAO-B]] and may be similar to overdose of other non-selective [[monoamine oxidase inhibitor]]s (MAOIs) like [[phenelzine]], [[isocarboxazid]], and [[tranylcypromine]].<ref name="PillLabel" /><ref name="ODTLabel" /> [[Serotonin syndrome]], [[hypertensive crisis]], and/or death may occur with overdose.<ref name="PillLabel" /><ref name="ODTLabel" /><ref name="PatchLabel" /> No specific [[antidote]] to selegiline overdose is available.<ref name="PatchLabel" />

==Interactions==
===Serotonin syndrome and hypertensive crisis===
Both the oral and patch forms of selegiline come with strong warnings against combining it with drugs that could produce [[serotonin syndrome]], such as [[selective serotonin reuptake inhibitor]]s (SSRIs) and the [[cough medicine]] [[dextromethorphan]].<ref name="PillLabel" /><ref name="PatchLabel" /><ref name="HeinonenMyllylä1998">{{cite journal | vauthors = Heinonen EH, Myllylä V | title = Safety of selegiline (deprenyl) in the treatment of Parkinson's disease | journal = Drug Safety | volume = 19 | issue = 1 | pages = 11–22 | date = July 1998 | pmid = 9673855 | doi = 10.2165/00002018-199819010-00002 | s2cid = 9632549 }}</ref> Selegiline in combination with the [[opioid analgesic]] [[pethidine]] is not recommended, as it can lead to severe [[adverse effect]]s.<ref name="HeinonenMyllylä1998" /> Several other [[synthetic compound|synthetic]] [[opioid]]s such as [[tramadol]] and [[methadone]], as well as various [[triptan]]s, are also [[contraindication|contraindicated]] due to potential for serotonin syndrome.<ref name="CsotiStorchMüller2012">{{cite journal | vauthors = Csoti I, Storch A, Müller W, Jost WH | title=Drug interactions with selegiline versus rasagiline | journal=Basal Ganglia | series=Monoamine oxidase B Inhibitors | date=December 1, 2012 | pages=S27–S31 | doi=10.1016/j.baga.2012.06.003 | issn=2210-5336 | volume=2 | issue=4, Supplement }}</ref><ref name="Gillman2005">{{cite journal | vauthors = Gillman PK | title = Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity | journal = British Journal of Anaesthesia | volume = 95 | issue = 4 | pages = 434–441 | date = October 2005 | pmid = 16051647 | doi = 10.1093/bja/aei210 | doi-access = free }}</ref>

All three forms of selegiline carry warnings about [[Monoamine oxidase inhibitor#Hypertensive Crisis & Tyramine|food restrictions]] to avoid hypertensive crisis that are associated with MAOIs.<ref name="PillLabel" /><ref name="ODTLabel" /><ref name="PatchLabel" /> The patch form was created in part to overcome food restrictions; clinical trials showed that it was successful.<ref name="CitromeGoldbergPortland2013" /><ref name="PatchLabel" /> Additionally, in [[post-marketing surveillance]] from April 2006 to October 2010, only 13{{nbsp}}self-reports of possible [[hypertension|hypertensive]] events or hypertension were made out of 29,141{{nbsp}}exposures to the drug, and none were accompanied by objective clinical data.<ref name="CitromeGoldbergPortland2013" /> The lowest dose of the patch method of delivery, 6{{nbsp}}mg/24{{nbsp}}hours, does not require any [[dietary restriction]]s.<ref name="JessenKovalickAzzaro2008">{{cite journal | vauthors = Jessen L, Kovalick LJ, Azzaro AJ | title = The selegiline transdermal system (emsam): a therapeutic option for the treatment of major depressive disorder | journal = P & T | volume = 33 | issue = 4 | pages = 212–246 | date = April 2008 | pmid = 19750165 | pmc = 2730099 }}</ref> Higher doses of the patch and oral formulations, whether in combination with the older non-selective MAOIs or in combination with the [[Reversible inhibitor of monoamine oxidase A|reversible MAO-A inhibitor]] (RIMA) [[moclobemide]], require a low-tyramine diet.<ref name="HeinonenMyllylä1998"/>

A study found that selegiline in transdermal patch form did not importantly modify the [[pharmacodynamic]] effects or [[pharmacokinetics]] of the [[sympathomimetic agent]]s [[pseudoephedrine]] and [[phenylpropanolamine]].<ref name="LeeChen2007" /><ref name="AzzaroVanDenBergZiemniak2007">{{cite journal | vauthors = Azzaro AJ, VanDenBerg CM, Ziemniak J, Kemper EM, Blob LF, Campbell BJ | title = Evaluation of the potential for pharmacodynamic and pharmacokinetic drug interactions between selegiline transdermal system and two sympathomimetic agents (pseudoephedrine and phenylpropanolamine) in healthy volunteers | journal = J Clin Pharmacol | volume = 47 | issue = 8 | pages = 978–90 | date = August 2007 | pmid = 17554106 | doi = 10.1177/0091270007302950 | url = }}</ref> Likewise, oral selegiline at an MAO-B-selective dosage did not appear to modify the pharmacodynamic effects or pharmacokinetics of [[intravenous administration|intravenous]] [[methamphetamine]] in another study.<ref name="ElkashefVocciHanson2008">{{cite journal | vauthors = Elkashef A, Vocci F, Hanson G, White J, Wickes W, Tiihonen J | title = Pharmacotherapy of methamphetamine addiction: an update | journal = Subst Abus | volume = 29 | issue = 3 | pages = 31–49 | date = 2008 | pmid = 19042205 | pmc = 2597382 | doi = 10.1080/08897070802218554 | bibcode = 2008JPkR...29...31E | url = }}</ref><ref name="NewtonDeLaGarzaFong2005">{{cite journal | vauthors = Newton TF, De La Garza R, Fong T, Chiang N, Holmes TH, Bloch DA, Anderson A, Elkashef A | title = A comprehensive assessment of the safety of intravenous methamphetamine administration during treatment with selegiline | journal = Pharmacol Biochem Behav | volume = 82 | issue = 4 | pages = 704–711 | date = December 2005 | pmid = 16413604 | doi = 10.1016/j.pbb.2005.11.012 | url = }}</ref> Conversely, selegiline, also at MAO-B-selective doses, has been found to reduce the physiological and euphoric subjective effects of [[cocaine]] whilst not affecting its pharmacokinetics in some studies but not in others.<ref name="Finberg2014">{{cite journal | vauthors = Finberg JP | title = Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: focus on modulation of CNS monoamine neurotransmitter release | journal = Pharmacol Ther | volume = 143 | issue = 2 | pages = 133–152 | date = August 2014 | pmid = 24607445 | doi = 10.1016/j.pharmthera.2014.02.010 | url = }}</ref><ref name="HoutsmullerNotesNewton2004">{{cite journal | vauthors = Houtsmuller EJ, Notes LD, Newton T, van Sluis N, Chiang N, Elkashef A, Bigelow GE | title = Transdermal selegiline and intravenous cocaine: safety and interactions | journal = Psychopharmacology (Berl) | volume = 172 | issue = 1 | pages = 31–40 | date = February 2004 | pmid = 14605792 | doi = 10.1007/s00213-003-1616-6 | url = }}</ref><ref name="BartzokisBecksonNewton1999">{{cite journal | vauthors = Bartzokis G, Beckson M, Newton T, Mandelkern M, Mintz J, Foster JA, Ling W, Bridge TP | title = Selegiline effects on cocaine-induced changes in medial temporal lobe metabolism and subjective ratings of euphoria | journal = Neuropsychopharmacology | volume = 20 | issue = 6 | pages = 582–590 | date = June 1999 | pmid = 10327427 | doi = 10.1016/S0893-133X(98)00092-X | url = }}</ref><ref name="HabernyWalshGinn1995">{{cite journal | vauthors = Haberny KA, Walsh SL, Ginn DH, Wilkins JN, Garner JE, Setoda D, Bigelow GE | title = Absence of acute cocaine interactions with the MAO-B inhibitor selegiline | journal = Drug Alcohol Depend | volume = 39 | issue = 1 | pages = 55–62 | date = July 1995 | pmid = 7587975 | doi = 10.1016/0376-8716(95)01137-n | url = | doi-access = free }}</ref><ref name="HarrisEverhartJacob2009">{{cite journal | vauthors = Harris DS, Everhart T, Jacob P, Lin E, Mendelson JE, Jones RT | title = A phase 1 trial of pharmacologic interactions between transdermal selegiline and a 4-hour cocaine infusion | journal = BMC Clin Pharmacol | volume = 9 | issue = | article-number = 13 | date = August 2009 | pmid = 19646280 | pmc = 2731040 | doi = 10.1186/1472-6904-9-13 | doi-access = free | url = }}</ref><ref name="NewtonKalechsteinBeckson1999">{{cite journal | vauthors = Newton TF, Kalechstein A, Beckson M, Bartzokis G, Bridge TP, Ling W | title = Effects of selegiline pretreatment on response to experimental cocaine administration | journal = Psychiatry Res | volume = 87 | issue = 2–3 | pages = 101–106 | date = October 1999 | pmid = 10579543 | doi = 10.1016/s0165-1781(99)00058-x | url = }}</ref> Cautious safe combination of MAOIs like selegiline with [[psychostimulant|stimulant]]s like [[lisdexamfetamine]] has been reported.<ref name="Feinberg2004">{{cite journal | vauthors = Feinberg SS | title = Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication | journal = J Clin Psychiatry | volume = 65 | issue = 11 | pages = 1520–1524 | date = November 2004 | pmid = 15554766 | doi = 10.4088/jcp.v65n1113 | url = }}</ref><ref name="ThomasShinMcInnis2015">{{cite journal | vauthors = Thomas SJ, Shin M, McInnis MG, Bostwick JR | title = Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression | journal = Pharmacotherapy | volume = 35 | issue = 4 | pages = 433–449 | date = April 2015 | pmid = 25884531 | doi = 10.1002/phar.1576 | url = | hdl = 2027.42/111275 | hdl-access = free }}</ref><ref name="Israel2015">{{cite journal | vauthors = Israel JA | title = Combining Stimulants and Monoamine Oxidase Inhibitors: A Reexamination of the Literature and a Report of a New Treatment Combination | journal = Prim Care Companion CNS Disord | volume = 17 | issue = 6 | pages = | date = 2015 | pmid = 27057401 | pmc = 4805402 | doi = 10.4088/PCC.15br01836 | url = }}</ref> However, a hypertensive crisis with selegiline and [[ephedrine]] has also been reported.<ref name="PillLabel" /> The selegiline drug labels warn about combination of selegiline with indirectly acting sympathomimetic agents, like amphetamines, ephedrine, pseudoephedrine, and phenylpropanolamine, due to the potential risk of hypertensive crisis, and recommend monitoring [[blood pressure]] with such combinations.<ref name="ODTLabel" /><ref name="PatchLabel" /> The combination of selegiline with certain other medications, like [[phenylephrine]] and [[buspirone]], is also warned against for similar reasons.<ref name="PatchLabel" /><ref name="PaeLimHan2007" /><ref name="CulpepperKovalick2008">{{cite journal | vauthors = Culpepper L, Kovalick LJ | title = A review of the literature on the selegiline transdermal system: an effective and well-tolerated monoamine oxidase inhibitor for the treatment of depression | journal = Prim Care Companion J Clin Psychiatry | volume = 10 | issue = 1 | pages = 25–30 | date = 2008 | pmid = 18311418 | pmc = 2249821 | doi = 10.4088/pcc.v10n0105 | url = }}</ref><ref name="PatkarPaeMasand2006" /> In the case of phenylephrine, this drug is substantially metabolized by monoamine oxidase, including by both [[MAO-A]] and [[MAO-B]].<ref name="Eccles2007">{{cite journal | vauthors = Eccles R | title = Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse | journal = Br J Clin Pharmacol | volume = 63 | issue = 1 | pages = 10–14 | date = January 2007 | pmid = 17116124 | pmc = 2000711 | doi = 10.1111/j.1365-2125.2006.02833.x | url = }}</ref><ref name="RichardsLopezMaani2023">{{cite book | vauthors = Richards E, Lopez MJ, Maani CV |chapter = Phenylephrine |date=2023 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK534801/ | title = StatPearls |access-date=2023-04-27 |place=Treasure Island, Florida |publisher=StatPearls Publishing |pmid=30521222 }}</ref> Selegiline can interact with [[exogenous]] [[dopamine (medication)|dopamine]], which is metabolized by MAO-A and MAO-B, and result in hypertensive crisis as well.<ref name="Schachter2002">{{cite book | vauthors=Schachter M | title=Side Effects of Drugs Annual | chapter=Drugs affecting autonomic functions or the extrapyramidal system | publisher=Elsevier | volume=25 | date=2002 | isbn=978-0-444-50674-0 | doi=10.1016/s0378-6080(02)80020-4 | pages=166–174}}</ref><ref name="RoseOhlingerMauro2000">{{cite journal | vauthors = Rose LM, Ohlinger MJ, Mauro VF | title = A hypertensive reaction induced by concurrent use of selegiline and dopamine | journal = Ann Pharmacother | volume = 34 | issue = 9 | pages = 1020–1024 | date = September 2000 | pmid = 10981248 | doi = 10.1345/aph.19221 | url = }}</ref>

Besides [[norepinephrine releasing agent]]s, selective [[norepinephrine reuptake inhibitor]]s (NRIs) may be safe in combination with MAOIs like selegiline.<ref name="Gillman2011">{{cite journal | vauthors = Gillman PK | title = Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors | journal = J Clin Psychopharmacol | volume = 31 | issue = 1 | pages = 66–74 | date = February 2011 | pmid = 21192146 | doi = 10.1097/JCP.0b013e31820469ea | url = }}</ref><ref name="Gillman2018">{{cite journal | vauthors = Gillman PK | title = A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired old tyramine myths | journal = J Neural Transm (Vienna) | volume = 125 | issue = 11 | pages = 1707–1717 | date = November 2018 | pmid = 30255284 | doi = 10.1007/s00702-018-1932-y | url = }}</ref><ref name="GillmanVandenEyndeGodet2023">{{cite journal | vauthors = Van den Eynde V, Godet L, Redhead C, Horwitz A, Barnett B | title=Monoamine Oxidase Inhibitors and Clinically Relevant Drug Interactions: A Guide for Preventing Serotonin Toxicity and Hypertensive Reactions | journal=Psychiatric Annals | volume=53 | issue=8 | date=2023 | issn=0048-5713 | doi=10.3928/00485713-20230713-02 | pages=353–358}}</ref> Potent NRIs, such as [[reboxetine]], [[desipramine]], [[protriptyline]], and [[nortriptyline]], can reduce or block the [[pressor]] effects of [[tyramine]], including in those taking MAOIs.<ref name="Gillman2011" /><ref name="Gillman2018" /><ref name="GillmanVandenEyndeGodet2023" /> This is by inhibiting the [[norepinephrine transporter]] (NET) and preventing entry of tyramine into [[presynaptic neuron|presynaptic]] [[noradrenergic]] [[neuron]]s where tyramine induces the release of norepinephrine.<ref name="Gillman2011" /><ref name="Gillman2018" /><ref name="GillmanVandenEyndeGodet2023" /> As a result, NRIs may reduce the risk of tyramine-related hypertensive crisis in people taking MAOIs.<ref name="Gillman2011" /><ref name="Gillman2018" /><ref name="GillmanVandenEyndeGodet2023" /> [[Norepinephrine–dopamine reuptake inhibitor]]s (NDRIs), like [[methylphenidate]] and [[bupropion]], are also considered to be safe in combination with MAOIs.<ref name="VandenEyndeAbdelmoeminAbraham2022">{{cite journal | vauthors = Van den Eynde V, Abdelmoemin WR, Abraham MM, Amsterdam JD, Anderson IM, Andrade C, Baker GB, Beekman AT, Berk M, Birkenhäger TK, Blackwell BB, Blier P, Blom MB, Bodkin AJ, Cattaneo CI, Dantz B, Davidson J, Dunlop BW, Estévez RF, Feinberg SS, Finberg JP, Fochtmann LJ, Gotlib D, Holt A, Insel TR, Larsen JK, Mago R, Menkes DB, Meyer JM, Nutt DJ, Parker G, Rego MD, Richelson E, Ruhé HG, Sáiz-Ruiz J, Stahl SM, Steele T, Thase ME, Ulrich S, van Balkom AJ, Vieta E, Whyte I, Young AH, Gillman PK | title = The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression | journal = CNS Spectr | volume = 28| issue = 4| pages = 427–440 | date = July 2022 | pmid = 35837681 | doi = 10.1017/S1092852922000906 | url = | hdl = 2292/61637 | hdl-access = free }}</ref> However, initiation at low doses and slow upward dose titration is advisable in the case of both NRIs and NDRIs due to possible potentiation of their effects and side effects by MAOIs.<ref name="VandenEyndeAbdelmoeminAbraham2022" />

Selegiline may potentiate the effects of [[serotonergic psychedelic]]s that are MAO-B substrates, such as [[2C drug]]s like [[2C-B]], [[2C-I]], and [[2C-E]].<ref name="HalmanKongSarris2024">{{Cite journal |vauthors=Halman A, Kong G, Sarris J, Perkins D |date=January 2024 |title=Drug-drug interactions involving classic psychedelics: A systematic review |journal=J Psychopharmacol |volume=38 |issue=1 |pages=3–18 |doi=10.1177/02698811231211219 |pmc=10851641 |pmid=37982394}}</ref><ref name="DeanStellpflugBurnett2013">{{cite journal | vauthors = Dean BV, Stellpflug SJ, Burnett AM, Engebretsen KM | title = 2C or not 2C: phenethylamine designer drug review | journal = J Med Toxicol | volume = 9 | issue = 2 | pages = 172–178 | date = June 2013 | pmid = 23494844 | pmc = 3657019 | doi = 10.1007/s13181-013-0295-x | url = }}</ref><ref name="TheobaldMaurer2007">{{cite journal | vauthors = Theobald DS, Maurer HH | title = Identification of monoamine oxidase and cytochrome P450 isoenzymes involved in the deamination of phenethylamine-derived designer drugs (2C-series) | journal = Biochem Pharmacol | volume = 73 | issue = 2 | pages = 287–297 | date = January 2007 | pmid = 17067556 | doi = 10.1016/j.bcp.2006.09.022 | url = }}</ref>

===Cytochrome P450 inhibitors and inducers===
The [[cytochrome P450]] [[enzyme]]s involved in the metabolism of selegiline have not been fully elucidated.<ref name="Mahmood1997" /><ref name="Rodrigues2022" /> [[CYP2D6]] and [[CYP2C19]] [[metabolism|metabolizer]] [[phenotype]]s did not significantly affect the [[pharmacokinetics]] of selegiline, suggesting that these enzymes are minimally involved in its metabolism and that [[enzyme inhibitor|inhibitors]] and [[enzyme inducer|inducer]]s of these enzymes would not importantly affect its pharmacokinetics.<ref name="Rodrigues2022" /><ref name="KraemerMaurer2002" /><ref name="ScheininAnttilaDahl1998">{{cite journal | vauthors = Scheinin H, Anttila M, Dahl ML, Karnani H, Nyman L, Taavitsainen P, Pelkonen O, Bertilsson L | title = CYP2D6 polymorphism is not crucial for the disposition of selegiline | journal = Clin Pharmacol Ther | volume = 64 | issue = 4 | pages = 402–411 | date = October 1998 | pmid = 9797797 | doi = 10.1016/S0009-9236(98)90071-6 | url = }}</ref><ref name="LaineAnttilaNyman2001">{{cite journal | vauthors = Laine K, Anttila M, Nyman L, Wahlberg A, Bertilsson L | title = CYP2C19 polymorphism is not important for the in vivo metabolism of selegiline | journal = Eur J Clin Pharmacol | volume = 57 | issue = 2 | pages = 137–142 | date = May 2001 | pmid = 11417445 | doi = 10.1007/s002280100289 | url = }}</ref> However, although most pharmacokinetic variables were unaffected, [[area under the curve (pharmacokinetics)|overall exposure]] to selegiline's metabolite [[levomethamphetamine]] was 46% higher in CYP2D6 [[poor metabolizer]]s compared to [[extensive metabolizer]]s and exposure to its metabolite [[desmethylselegiline]] was 68% higher in CYP2C19 poor metabolizers compared to extensive metabolizers.<ref name="KraemerMaurer2002" /><ref name="ScheininAnttilaDahl1998" /><ref name="LaineAnttilaNyman2001" /> As with the cases of CYP2D6 and CYP2C19, the strong [[CYP3A4]] and [[CYP3A5]] inhibitor [[itraconazole]] has minimal impact on the pharmacokinetics of selegiline, suggesting lack of major involvement of this enzyme as well.<ref name="Rodrigues2022" /><ref name="KivistöWangBackman2001">{{cite journal | vauthors = Kivistö KT, Wang JS, Backman JT, Nyman L, Taavitsainen P, Anttila M, Neuvonen PJ | title = Selegiline pharmacokinetics are unaffected by the CYP3A4 inhibitor itraconazole | journal = Eur J Clin Pharmacol | volume = 57 | issue = 1 | pages = 37–42 | date = April 2001 | pmid = 11372588 | doi = 10.1007/s002280100278 | url = }}</ref><ref name="ODTLabel" /> On the other hand, the [[anticonvulsant]] [[carbamazepine]], which is known to act as a strong inducer of CYP3A enzymes,<ref name="FDA2023" /> has paradoxically been found to increase exposure to selegiline and its metabolites levomethamphetamine and [[levoamphetamine]] by approximately 2-fold (with selegiline used as the transdermal patch form).<ref name="PatchLabel" /><ref name="LeeChen2007" /> One enzyme thought to be majorly involved in the metabolism of selegiline based on ''[[in vitro|in-vitro]]'' studies is [[CYP2B6]].<ref name="Mahmood1997" /><ref name="Rodrigues2022" /><ref name="LeeChen2007" /><ref name="HidestrandOscarsonSalonen2001" /> However, there are no clinical studies of different CYP2B6 metabolizer phenotypes or of CYP2B6 inhibitors or inducers on the pharmacokinetics of selegiline.<ref name="HoffmanOlsonSchoffstall2023" /> In addition to CYP2B6, [[CYP2A6]] may be involved in the metabolism of selegiline to a lesser extent.<ref name="HoffmanOlsonSchoffstall2023" /><ref name="NaoiMaruyamaShamoto-Nagai2022">{{cite journal | vauthors = Naoi M, Maruyama W, Shamoto-Nagai M | title = Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies | journal = Int J Mol Sci | volume = 23 | issue = 19 | date = September 2022 | article-number = 11059 | pmid = 36232361 | pmc = 9570229 | doi = 10.3390/ijms231911059 | doi-access = free}}</ref>

[[Birth control pill]]s containing the [[synthetic compound|synthetic]] [[estrogen (medication)|estrogen]] [[ethinylestradiol]] and a [[progestin]] like [[gestodene]] or [[levonorgestrel]] have been found to increase [[Cmax (pharmacology)|peak]] levels and overall exposure to oral selegiline by 10- to 20-fold.<ref name="Rodrigues2022" /><ref name="KlietzGretenWegner2019">{{cite journal | vauthors = Klietz M, Greten S, Wegner F, Höglinger GU | title = Safety and Tolerability of Pharmacotherapies for Parkinson's Disease in Geriatric Patients | journal = Drugs & Aging | volume = 36 | issue = 6 | pages = 511–530 | date = June 2019 | pmid = 30937878 | doi = 10.1007/s40266-019-00654-z | url =}}</ref><ref name="LaineAnttilaHelminen1999">{{cite journal | vauthors = Laine K, Anttila M, Helminen A, Karnani H, Huupponen R | title = Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids | journal = Br J Clin Pharmacol | volume = 47 | issue = 3 | pages = 249–254 | date = March 1999 | pmid = 10215747 | pmc = 2014223 | doi = 10.1046/j.1365-2125.1999.00891.x | url = }}</ref> High levels of selegiline can lead to loss of MAO-B selectivity and inhibition of MAO-A as well.<ref name="Rodrigues2022" /><ref name="LaineAnttilaHelminen1999" /> This increases susceptibility to side effects and interactions of non-selective [[monoamine oxidase inhibitor]]s (MAOIs), such as [[tyramine]]-induced [[hypertensive crisis]] and serotonin toxicity when combined with [[serotonin|serotonergic]] medications.<ref name="Rodrigues2022" /><ref name="LaineAnttilaHelminen1999" /> However, this study had a small [[sample size]] of four individuals as well as other [[methodology|methodological]] limitations.<ref name="Rodrigues2022" /><ref name="LaineAnttilaHelminen1999" /> The precise mechanism underlying the interaction is unknown, but is likely related to cytochrome P450 inhibition and consequent inhibition of selegiline [[first-pass metabolism]] by ethinylestradiol.<ref name="Rodrigues2022" /> In contrast to birth control pills containing ethinylestradiol, [[menopausal hormone therapy]] with [[estradiol (medication)|estradiol]] and levonorgestrel did not modify peak levels of selegiline and only modestly increased overall exposure (+59%).<ref name="Rodrigues2022" /><ref name="KlietzGretenWegner2019" /><ref name="PalovaaraAnttilaNyman2002">{{cite journal | vauthors = Palovaara S, Anttila M, Nyman L, Laine K | title = Effect of concomitant hormone replacement therapy containing estradiol and levonorgestrel on the pharmacokinetics of selegiline | journal = European Journal of Clinical Pharmacology | volume = 58 | issue = 4 | pages = 259–263 | date = July 2002 | pmid = 12136372 | doi = 10.1007/s00228-002-0469-y | url = }}</ref> Hence, menopausal hormone therapy does not pose the same risk of interaction as ethinylestradiol-containing birth control pills when taken together with selegiline.<ref name="KlietzGretenWegner2019" /><ref name="PalovaaraAnttilaNyman2002" />

Overall exposure to selegiline with oral selegiline has been found to be 23-fold lower in people taking [[anticonvulsant]]s known to strongly activate [[xenobiotic metabolism|drug-metabolizing enzymes]].<ref name="AnttilaSotaniemiPelkonen2005">{{cite journal | vauthors = Anttila M, Sotaniemi EA, Pelkonen O, Rautio A | title = Marked effect of liver and kidney function on the pharmacokinetics of selegiline | journal = Clin Pharmacol Ther | volume = 77 | issue = 1 | pages = 54–62 | date = January 2005 | pmid = 15637531 | doi = 10.1016/j.clpt.2004.09.004 | url = }}</ref> The anticonvulsants included [[phenobarbital]], [[phenytoin]], [[carbamazepine]], and [[amobarbital]].<ref name="AnttilaSotaniemiPelkonen2005" /> In a previous study however, carbamazepine specifically did not reduce selegiline exposure.<ref name="PatchLabel" /><ref name="LeeChen2007" /> Phenobarbital and certain other anticonvulsants are known to strongly induce CYP2B6, one of the major enzymes believed to be involved in selegiline metabolism.<ref name="AnttilaSotaniemiPelkonen2005" /> As such, it was concluded that strong CYP2B6 induction was most likely responsible for the dramatically reduced exposure to selegiline observed in the study.<ref name="AnttilaSotaniemiPelkonen2005" />

===Selegiline inhibition of cytochrome P450 enzymes===
Selegiline has been reported to inhibit several cytochrome P450 enzymes, including CYP2D6, CYP3A4/5, CYP2C19, CYP2B6, and CYP2A6.<ref name="PatchLabel" /><ref name="ZangerKlein2013" /> It is a [[suicide inhibitor|mechanism-based inhibitor]] (suicide inhibitor) of CYP2B6 and has been said to "potently" or "strongly" inhibit this enzyme ''in vitro''.<ref name="HedrichHassanWang2016">{{cite journal | vauthors = Hedrich WD, Hassan HE, Wang H | title = Insights into CYP2B6-mediated drug-drug interactions | journal = Acta Pharm Sin B | volume = 6 | issue = 5 | pages = 413–425 | date = September 2016 | pmid = 27709010 | pmc = 5045548 | doi = 10.1016/j.apsb.2016.07.016 | url =}}</ref><ref name="ZangerKlein2013">{{cite journal | vauthors = Zanger UM, Klein K | title = Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance | journal = Front Genet | volume = 4 | issue = | page = 24 | date = 2013 | pmid = 23467454 | pmc = 3588594 | doi = 10.3389/fgene.2013.00024 | doi-access = free | url = }}</ref><ref name="SridarKenaanHollenberg2012">{{cite journal | vauthors = Sridar C, Kenaan C, Hollenberg PF | title = Inhibition of bupropion metabolism by selegiline: mechanism-based inactivation of human CYP2B6 and characterization of glutathione and peptide adducts | journal = Drug Metab Dispos | volume = 40 | issue = 12 | pages = 2256–2266 | date = December 2012 | pmid = 22936314 | pmc = 3500550 | doi = 10.1124/dmd.112.046979 | url = }}</ref><ref name="NirogiPalacharlaMohammed2015">{{cite journal | vauthors = Nirogi R, Palacharla RC, Mohammed AR, Manoharan A, Ponnamaneni RK, Bhyrapuneni G | title = Evaluation of metabolism dependent inhibition of CYP2B6 mediated bupropion hydroxylation in human liver microsomes by monoamine oxidase inhibitors and prediction of potential as perpetrators of drug interaction | journal = Chem Biol Interact | volume = 230 | issue = | pages = 9–20 | date = March 2015 | pmid = 25656918 | doi = 10.1016/j.cbi.2015.01.028 | bibcode = 2015CBI...230....9N | url = }}</ref> It may inhibit the metabolism of [[bupropion]], a major CYP2B6 [[substrate (biochemistry)|substrate]], into its [[active metabolite]] [[hydroxybupropion]].<ref name="HedrichHassanWang2016" /><ref name="ZangerKlein2013" /><ref name="SridarKenaanHollenberg2012" /> However, a study predicted that inhibition of CYP2B6 by selegiline would non-significantly affect exposure to bupropion.<ref name="NirogiPalacharlaMohammed2015" /> Selegiline has not been listed or described as a clinically significant CYP2B6 inhibitor by the [[Food and Drug Administration]] (FDA) as of 2023.<ref name="FDA2023">{{cite web | title=Table of Substrates, Inhibitors and Inducers | website=U.S. Food and Drug Administration | date=5 June 2023 | url=https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers | archive-url=https://web.archive.org/web/20190503132546/https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers | archive-date=May 3, 2019 | access-date=5 July 2024}}</ref><ref name="PatchLabel" /> One small study observing three patients found that selegiline was safe and well-tolerated in combination with bupropion.<ref name="SridarKenaanHollenberg2012" /><ref name="RitterAlexander1997">{{cite journal | vauthors = Ritter JL, Alexander B | title = Retrospective study of selegiline-antidepressant drug interactions and a review of the literature | journal = Ann Clin Psychiatry | volume = 9 | issue = 1 | pages = 7–13 | date = March 1997 | pmid = 9167831 | doi = 10.1023/a:1026222106851 | url = }}</ref> In addition to CYP2B6 and other cytochrome P450 enzymes, selegiline is a potent mechanism-based inhibitor of CYP2A6 and may increase exposure to [[nicotine]] (a major CYP2A6 substrate).<ref name="TannerTyndale2017">{{cite journal | vauthors = Tanner JA, Tyndale RF | title = Variation in CYP2A6 Activity and Personalized Medicine | journal = J Pers Med | volume = 7 | issue = 4 | date = December 2017 | page = 18 | pmid = 29194389 | pmc = 5748630 | doi = 10.3390/jpm7040018 | doi-access = free | url =  }}</ref><ref name="SiuTyndale2008">{{cite journal | vauthors = Siu EC, Tyndale RF | title = Selegiline is a mechanism-based inactivator of CYP2A6 inhibiting nicotine metabolism in humans and mice | journal = J Pharmacol Exp Ther | volume = 324 | issue = 3 | pages = 992–9 | date = March 2008 | pmid = 18065502 | doi = 10.1124/jpet.107.133900 | url = }}</ref> By inhibiting cytochrome P450 enzymes like CYP2B6 and CYP1A2, selegiline may inhibit its own metabolism and thereby interact with itself.<ref name="SiuTyndale2008" /><ref name="LaineAnttilaHuupponen2000">{{cite journal | vauthors = Laine K, Anttila M, Huupponen R, Mäki-Ikola O, Heinonen E | title = Multiple-dose pharmacokinetics of selegiline and desmethylselegiline suggest saturable tissue binding | journal = Clin Neuropharmacol | volume = 23 | issue = 1 | pages = 22–27 | date = 2000 | pmid = 10682227 | doi = 10.1097/00002826-200001000-00005 | url = }}</ref>

===Other interactions===
[[Dopamine antagonist]]s like [[antipsychotic]]s or [[metoclopramide]], which block [[dopamine receptor]]s and thereby antagonize the dopaminergic effects of selegiline, could potentially reduce the effectiveness of the medication.<ref name="ODTLabel" /> [[Monoamine-depleting agent|Dopamine-depleting agent]]s like [[reserpine]] and [[tetrabenazine]], by reducing dopamine levels, can also oppose the effectiveness of dopaminergic medications like selegiline.<ref name="Pfeiffer1996">{{cite journal | vauthors = Pfeiffer RF | title = Antiparkinsonian agents. Drug interactions of clinical significance | journal = Drug Saf | volume = 14 | issue = 5 | pages = 343–354 | date = May 1996 | pmid = 8800629 | doi = 10.2165/00002018-199614050-00006 | url = }}</ref>

==Pharmacology==
{{Main|Pharmacology of selegiline}}

===Pharmacodynamics===
{{Main|Pharmacology of selegiline#Pharmacodynamics}}

Selegiline has multiple known [[mechanism of action|mechanisms of action]] in terms of its [[pharmacodynamic]] activity.<ref name="HeinonenLammintausta1991" /><ref name="Magyar2011" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /> It is most notably an [[irreversible inhibitor|irreversible]] [[monoamine oxidase]] (MAO) [[monoamine oxidase inhibitor|inhibitor]] (MAOI).<ref name="HeinonenLammintausta1991" /><ref name="Magyar2011" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /> More specifically, it is a [[binding selectivity|selective]] inhibitor of [[monoamine oxidase B]] (MAO-B) at lower doses (≤10{{nbsp}}mg/day) but additionally inhibits [[monoamine oxidase A]] (MAO-A) at higher doses (≥20{{nbsp}}mg/day).<ref name="HeinonenLammintausta1991" /><ref name="Magyar2011" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /> MAO-B inhibition is thought to result in increased levels of [[dopamine]] and [[β-phenethylamine]], whereas MAO-A inhibition results in increased levels of [[serotonin]], [[norepinephrine]], and dopamine.<ref name="HeinonenLammintausta1991" /><ref name="Magyar2011" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /> Selegiline is also a [[catecholaminergic activity enhancer]] (CAE) and enhances the [[action potential]]-evoked release of norepinephrine and dopamine.<ref name="Knoll1997" /><ref name="Knoll1998" /><ref name="Miklya2014a" /><ref name="GasznerMiklya2006" /><ref name="GerlachYoudimRiederer1996" /> The CAE activity of selegiline may be mediated by [[TAAR1]] [[agonist|agonism]].<ref name="HarsingTimarMiklya2023" /><ref name="ShimazuMiklya2004" /><ref name="Berry2007" /> Both the MAOI activity and CAE activity of selegiline may be involved in its therapeutic effects in the treatment of [[Parkinson's disease]] and [[depression (mood)|depression]].<ref name="Knoll1998" /><ref name="Miklya2016" /><ref name="HarsingTimarMiklya2023" /><ref name="BindeTveteGåsemyr2018" /><ref name="GasznerMiklya2004" /><ref name="GasznerMiklya2006" /> According to [[József Knoll]] and other researchers, selegiline might have [[dopaminergic]] [[neuroprotective]] effects, might be able to modestly slow the rate of [[aging]]-related dopaminergic [[neurodegeneration]], and might thereby have a [[disease-modifying treatment|disease-modifying effect]] in Parkinson's disease and [[antiaging]] effects generally.<ref name="Miklya2016" /><ref name="Knoll2003" /><ref name="Knoll1998" /><ref name="Knoll1995">{{cite journal | vauthors = Knoll J | title = Rationale for (-)deprenyl (selegiline) medication in Parkinson's disease and in prevention of age-related nigral changes | journal = Biomed Pharmacother | volume = 49 | issue = 4 | pages = 187–195 | date = 1995 | pmid = 7669938 | doi = 10.1016/0753-3322(96)82619-9 | url = }}</ref><ref name="Knoll2012" /><ref name="Knoll1994">{{cite journal | vauthors = Knoll J | title = Memories of my 45 years in research | journal = Pharmacol Toxicol | volume = 75 | issue = 2 | pages = 65–72 | date = August 1994 | pmid = 7971740 | doi = 10.1111/j.1600-0773.1994.tb00326.x | url = }}</ref> However, these theoretical effects of selegiline have not been clearly demonstrated in humans as of present and remain to be substantiated.<ref name="Finberg2019" /><ref name="Miklya2016" /><ref name="GoldsteinKopinSharabi2014">{{cite journal | vauthors = Goldstein DS, Kopin IJ, Sharabi Y | title = Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders | journal = Pharmacol Ther | volume = 144 | issue = 3 | pages = 268–82 | date = December 2014 | pmid = 24945828 | pmc = 4591072 | doi = 10.1016/j.pharmthera.2014.06.006 | url = }}</ref><ref name="Goldstein2021">{{cite journal | vauthors = Goldstein DS | title = The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know | journal = Int J Mol Sci | volume = 22 | issue = 11 | date = June 2021 | page = 5999 | pmid = 34206133 | pmc = 8199574 | doi = 10.3390/ijms22115999 | doi-access = free | url = }}</ref><ref name="Goldstein2020">{{cite journal | vauthors = Goldstein DS | title = The catecholaldehyde hypothesis: where MAO fits in | journal = J Neural Transm (Vienna) | volume = 127 | issue = 2 | pages = 169–177 | date = February 2020 | pmid = 31807952 | pmc = 10680281 | doi = 10.1007/s00702-019-02106-9 | url = }}</ref> Through its [[active metabolite]]s [[levomethamphetamine]] (<small>L</small>-MA) and [[levoamphetamine]] (<small>L</small>-A), selegiline acts as a weak [[norepinephrine–dopamine releasing agent|norepinephrine and/or dopamine releasing agent]] (NDRA).<ref name="GerlachReichmannRiederer2012" /><ref name="YasarGoldbergGoldberg1996" /><ref name="RothmanBaumann2003" /> The clinical significance of this action is unclear, but it may be relevant to the effects and [[side effect]]s of selegiline, especially at higher doses.<ref name="GerlachReichmannRiederer2012" /><ref name="YasarGoldbergGoldberg1996" /><ref name="RothmanBaumann2003" /> Its active metabolite [[desmethylselegiline]] (DMS) also has MAOI and CAE activity and likely contributes to its effects as well.<ref name="GerlachReichmannRiederer2012" /><ref name="HeinonenLammintausta1991" /><ref name="HeinonenAnttilaKarnani1997">{{cite journal | vauthors = Heinonen EH, Anttila MI, Karnani HL, Nyman LM, Vuorinen JA, Pyykkö KA, Lammintausta RA | title = Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of monoamine oxidase type B in humans | journal = J Clin Pharmacol | volume = 37 | issue = 7 | pages = 602–609 | date = July 1997 | pmid = 9243353 | doi = 10.1002/j.1552-4604.1997.tb04342.x | url = }}</ref><ref name="Miklya2014b" /><ref name="Miklya2008">{{cite journal | vauthors = Miklya I | title = (-)-deprenil, az N-metilprogargilamin-1-aminoindan (J-508) és a J-508 dezmetil analógjának (rasagilin) összehasonlító farmakológiai analízise | trans-title = A comparison of the pharmacology of (-)-deprenyl to N-methylpropargylamine-1-aminoindane (J-508) and rasagiline, the desmethyl-analogue of J-508 | language = Hungarian | journal = Neuropsychopharmacol Hung | volume = 10 | issue = 1 | pages = 15–22 | date = March 2008 | pmid = 18771016 | doi = | url = https://mppt.hu/magazin/pdf/x-evfevfolyam-1-szam/a---deprenil-az-n.pdf}}</ref> Levels of selegiline's metabolites are much lower with the ODT and transdermal patch forms of selegiline than with the oral form and this may result in differences in its effects and side effects.<ref name="PostonWaters2007" /><ref name="LeeChen2007" />

===Pharmacokinetics===
{{Main|Pharmacology of selegiline#Pharmacokinetics}}
[[File:SelegilineMetabolism.png|class=skin-invert-image|thumb|right|300px|Metabolism of selegiline. [[Levomethamphetamine|(''R'')-Methamphetamine]] (levomethamphetamine) and [[levoamphetamine|(''R'')-amphetamine]] (levoamphetamine) are not extensively metabolized and are excreted substantially unchanged so their metabolic profiles are omitted.]]

Selegiline is available in forms for use by multiple different [[route of administration|routes of administration]] and its [[pharmacokinetics]] vary by route.<ref name="Drugs@FDA" /><ref name="PostonWaters2007" /><ref name="LeeChen2007" /><ref name="PaeLimHan2007" /> The [[bioavailability]] of the [[oral administration|oral]] form of selegiline is 4 to 10%,<ref name="Mahmood1997" /><ref name="Magyar2011" /><ref name="PaeLimHan2007" /> of the ODT is 5 to 8{{nbsp}}times that of the oral form,<ref name="LöhleStorch2008" /><ref name="PostonWaters2007" /><ref name="ClarkeBrewerJohnson2003" /> and of the transdermal patch is 75%.<ref name="LeeChen2007" /> The [[Tmax (pharmacology)|time to peak]] levels of selegiline with oral administration is about 0.5 to 1.5{{nbsp}}hours.<ref name="Mahmood1997" /> The [[plasma protein binding]] of selegiline is 85 to 90%.<ref name="LeeChen2007" /><ref name="PatchLabel" /><ref name="ODTLabel" /> It is [[metabolism|metabolized]] extensively in the [[liver]] by the [[cytochrome P450]] [[enzyme]] [[CYP2B6]] among other [[enzyme]]s.<ref name="Mahmood1997" /><ref name="Rodrigues2022" /><ref name="LeeChen2007" /><ref name="HidestrandOscarsonSalonen2001" /> [[Metabolite]]s of selegiline include [[desmethylselegiline]] (DMS), [[levomethamphetamine]] (<small>L</small>-MA), and [[levoamphetamine]] (<small>L</small>-A).<ref name="HeinonenLammintausta1991" /><ref name="GerlachYoudimRiederer1996" /><ref name="Mahmood1997" /><ref name="KalászMagyarSzőke2014" /> The oral form of selegiline is subject to strong [[first-pass metabolism]] and levels of the metabolites of selegiline are much lower with the ODT and transdermal patch forms than with the oral form.<ref name="PostonWaters2007" /><ref name="LeeChen2007" /> The [[elimination half-life|elimination half-lives]] of selegiline and its metabolites range from 1.2 to 10{{nbsp}}hours for selegiline, 2.2 to 9.5{{nbsp}}hours for DMS, 14 to 21{{nbsp}}hours for levomethamphetamine, and 16 to 18{{nbsp}}hours for levoamphetamine.<ref name="Mahmood1997" /><ref name="PaeLimHan2007" /><ref name="PostonWaters2007" /><ref name="ODTLabel" /><ref name="PatchLabel" /> Selegiline and its metabolites are [[elimination (pharmacology)|eliminated]] mainly in [[urine]] (87% in urine and 15% in [[feces]] via oral administration), with its metabolites accounting for virtually all of the eliminated material in the case of the oral form.<ref name="HeinonenAnttilaLammintausta1994" /><ref name="HeinonenMyllyläSotaniemi1989" /><ref name="PostonWaters2007" /><ref name="Mahmood1997" /><ref name="ChrispMammenSorkin1991" /> [[Hepatic impairment]] and [[renal impairment]] have been found to dramatically increase exposure to selegiline.<ref name="VelenosiUrquhart2014">{{cite journal | vauthors = Velenosi TJ, Urquhart BL | title = Pharmacokinetic considerations in chronic kidney disease and patients requiring dialysis | journal = Expert Opin Drug Metab Toxicol | volume = 10 | issue = 8 | pages = 1131–1143 | date = August 2014 | pmid = 24961255 | doi = 10.1517/17425255.2014.931371 | url = }}</ref><ref name="BaghdadyBanikSwartz2009">{{cite journal | vauthors = Baghdady NT, Banik S, Swartz SA, McIntyre RS | title = Psychotropic drugs and renal failure: translating the evidence for clinical practice | journal = Adv Ther | volume = 26 | issue = 4 | pages = 404–424 | date = April 2009 | pmid = 19444657 | doi = 10.1007/s12325-009-0021-x | url = }}</ref><ref name="AnttilaSotaniemiPelkonen2005" /><ref name="PillLabel" /><ref name="ODTLabel" />

==Chemistry==
Selegiline is a [[substituted phenethylamine]] and [[substituted amphetamine|amphetamine]] [[chemical derivative|derivative]].<ref name="KraemerMaurer2002" /> It is also known as (''R'')-(–)-''N'',α-dimethyl-''N''-(2-propynyl)phenethylamine, (''R'')-(–)-''N''-methyl-''N''-2-propynylamphetamine, or ''N''-propargyl-<small>L</small>-methamphetamine.<ref name="PubChem-Selegiline">{{cite web | title=Selegiline | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/26757 | access-date=18 July 2024}}</ref><ref name="DrugBank">{{cite web | title=Selegiline: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=5 June 1989 | url=https://go.drugbank.com/drugs/DB01037 | access-date=18 July 2024}}</ref><ref name="ChemSpider">{{cite web | title=Selegiline | website=ChemSpider | date=21 July 2022 | url=https://www.chemspider.com/Chemical-Structure.24930.html | access-date=18 July 2024}}</ref><ref name="PostonWaters2007" /> Selegiline (<small>L</small>-deprenyl) is the [[enantiopure]] [[levorotatory]] [[enantiomer]] of the [[racemic mixture]] [[deprenyl]], whereas [[D-Deprenyl|<small>D</small>-deprenyl]] is the [[dextrorotatory]] enantiomer.<ref name="Parnham1993" /><ref name="Miklya2016" /> Selegiline is a derivative of [[levomethamphetamine]] (<small>L</small>-methamphetamine), the levorotatory enantiomer of the [[psychostimulant]] and [[sympathomimetic agent]] [[methamphetamine]] (''N''-methylamphetamine), with a [[propargyl]] [[functional group|group]] attached to the [[nitrogen]] [[atom]] of the [[molecule]].<ref name="CristanchoThase2016">{{cite journal | vauthors = Cristancho MA, Thase ME | title = Critical appraisal of selegiline transdermal system for major depressive disorder | journal = Expert Opinion on Drug Delivery | volume = 13 | issue = 5 | pages = 659–665 | date = 2016 | pmid = 26837935 | doi = 10.1517/17425247.2016.1140145 | url = }}</ref>

Selegiline is a [[small-molecule]] [[chemical compound|compound]], with the [[molecular formula]] C<sub>13</sub>H<sub>17</sub>N and a low [[molecular weight]] of 187.281{{nbsp}}g/mol.<ref name="PubChem-Selegiline" /><ref name="DrugBank" /><ref name="ChemSpider" /><ref name="PillLabel" /><ref name="CristanchoThase2016" /> It has high [[lipophilicity]], with an experimental [[partition coefficient|log P]] of 2.7 and predicted log P values of 2.9 to 3.1.<ref name="PubChem-Selegiline" /><ref name="DrugBank" /><ref name="ChemSpider" /><ref name="CristanchoThase2016" /> Pharmaceutically, selegiline is used almost always as the [[hydrochloride]] [[salt (chemistry)|salt]], though the [[free base]] form has also been used.<ref name="PillLabel" /><ref name="IndexNominum2000" /> At room temperature, selegiline hydrochloride is a white to near white [[crystalline]] [[powder]].<ref name="PillLabel" /> Selegiline hydrochloride is freely [[solubility|soluble]] in [[water]], [[chloroform]], and [[methanol]].<ref name="PillLabel" />

===Analogues===
Selegiline is a close [[structural analog|analogue]] of methamphetamine and [[amphetamine]], and in fact produces their levorotatory forms, levomethamphetamine and [[levoamphetamine]], as [[metabolite]]s.<ref name="GerlachReichmannRiederer2012" /><ref name="YasarGoldbergGoldberg1996" /> Selegiline is [[structural analog|structurally similar]] to the [[antihypertensive agent]] [[pargyline]] (''N''-methyl-''N''-propargylbenzylamine), an earlier non-selective MAOI of the [[phenylalkylamine]] group.<ref name="FowlerOrelandCallingham1981">{{cite journal | vauthors = Fowler CJ, Oreland L, Callingham BA | title = The acetylenic monoamine oxidase inhibitors clorgyline, deprenyl, pargyline and J-508: their properties and applications | journal = J Pharm Pharmacol | volume = 33 | issue = 6 | pages = 341–347 | date = June 1981 | pmid = 6115003 | doi = 10.1111/j.2042-7158.1981.tb13800.x | url = }}</ref><ref name="Miklya2014a">{{cite web|title = The History of Selegiline/(-)-Deprenyl the First Selective Inhibitor of B-Type Monoamine Oxidase and The First Synthetic Catecholaminergic Activity Enhancer Substance|url = http://inhn.org/archives/miklya-collection/the-history-of-selegiline-deprenyl-the-first-selective-inhibitor-of-b-type-monoamine-oxidase-and-the-first-synthetic-catecholaminergic-activity-enhancer-substance.html|website = International Network for the History of Neuropsychopharmacology|access-date = January 7, 2016|vauthors = Miklya I|date = March 13, 2014|archive-date = February 7, 2016|archive-url = https://web.archive.org/web/20160207154819/http://inhn.org/archives/miklya-collection/the-history-of-selegiline-deprenyl-the-first-selective-inhibitor-of-b-type-monoamine-oxidase-and-the-first-synthetic-catecholaminergic-activity-enhancer-substance.html}}</ref> Besides selegiline and pargyline, another clinically used MAOI of the phenylalkylamine and amphetamine families is the [[antidepressant]] [[tranylcypromine]] (''trans''-2-phenylcyclopropylamine).<ref name="HoffmanOlsonSchoffstall2023" /> Tranylcypromine can be conceptualized as a [[cyclic compound|cyclized]] amphetamine and has amphetamine-like actions at high doses similarly to selegiline.<ref name="HoffmanOlsonSchoffstall2023" /><ref name="UlrichRickenAdli2017">{{cite journal | vauthors = Ulrich S, Ricken R, Adli M | title = Tranylcypromine in mind (Part I): Review of pharmacology | journal = Eur Neuropsychopharmacol | volume = 27 | issue = 8 | pages = 697–713 | date = August 2017 | pmid = 28655495 | doi = 10.1016/j.euroneuro.2017.05.007 | url = | doi-access = free }}</ref><ref name="RickenUlrichSchlattman2017">{{cite journal | vauthors = Ricken R, Ulrich S, Schlattmann P, Adli M | title = Tranylcypromine in mind (Part II): Review of clinical pharmacology and meta-analysis of controlled studies in depression | journal = Eur Neuropsychopharmacol | volume = 27 | issue = 8 | pages = 714–731 | date = August 2017 | pmid = 28579071 | doi = 10.1016/j.euroneuro.2017.04.003 | url = | doi-access = free }}</ref> Another notable analogue of selegiline is [[4-fluoroselegiline]], a variation of selegiline in which one of the [[hydrogen]] atoms of the [[phenyl ring]] has been replaced with a [[fluorine]] atom.<ref name="Magyar1994">{{cite book | vauthors = Magyar K | title = Amine Oxidases: Function and Dysfunction | chapter = Behaviour of (-)-deprenyl and its analogues | journal = Journal of Neural Transmission. Supplementum | pages = 167–175 | date = 1994 | volume = 41 | pmid = 7931223 | doi = 10.1007/978-3-7091-9324-2_23 | isbn = 978-3-211-82521-1 }}</ref> A large number of other analogues of selegiline derived via [[structural modification]] have been [[chemical synthesis|synthesized]] and characterized.<ref name="KnollEcseryMagyar1978">{{cite journal | vauthors = Knoll J, Ecsery Z, Magyar K, Sátory E | title = Novel (-)deprenyl-derived selective inhibitors of B-type monoamine oxidase. The relation of structure to their action | journal = Biochem Pharmacol | volume = 27 | issue = 13 | pages = 1739–1747 | date = 1978 | pmid = 708454 | doi = 10.1016/0006-2952(78)90550-6 | url = }}</ref><ref name="Magyar1994"/><ref name="MagyarEcseriBernáth1980">{{cite book | vauthors = Magyar K, Ecseri Z, Bernáth G, Satory E, Knoll J | chapter = Structure-activity relationship of selective inhibitors of MAO-B | title = Monoamine Oxidases and Their Selective Inhibition | date = 1980 | pages = 11–21 | publisher = Pergamon | url = https://scholar.google.com/scholar?cluster=9614587838869916607}}</ref><ref name="Knoll1980">{{cite book | vauthors = Knoll J | chapter = Selective inhibitors of MAO-B with different pharmacological profiles | title = Monoamine Oxidases and Their Selective Inhibition | date = 1980 | pages = 23–36 | publisher = Pergamon | url = https://scholar.google.com/scholar?cluster=3040048394270379323}}</ref>

[[Rasagiline]] ((''R'')-''N''-propargyl-1-aminoindan) is an analogue of selegiline in which the amphetamine base structure has been replaced with a [[1-aminoindan]] structure and the ''N''-methyl group has been removed.<ref name="GerlachReichmannRiederer2012" /> Like selegiline, it is also a selective MAO-B inhibitor and used to treat Parkinson's disease.<ref name="GerlachReichmannRiederer2012" /> In contrast to selegiline however, rasagiline lacks the amphetamine metabolites and activity of selegiline.<ref name="GerlachReichmannRiederer2012" /> A further derivative of rasagiline, [[ladostigil]] ([''N''-propargyl-(3''R'')-aminoindan-5-yl]-''N''-propylcarbamate), a dual MAO-B inhibitor and [[acetylcholinesterase inhibitor]], was developed for treatment of [[Alzheimer's disease]] and other conditions but was ultimately never introduced for medical use.<ref name="WeinrebAmitBarAm2012">{{cite journal | vauthors = Weinreb O, Amit T, Bar-Am O, Youdim MB | title = Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer's disease treatment | journal = Curr Drug Targets | volume = 13 | issue = 4 | pages = 483–494 | date = April 2012 | pmid = 22280345 | doi = 10.2174/138945012799499794 | url = }}</ref>

===Synthesis===
Selegiline can be [[chemical synthesis|synthesized]] by the [[alkylation]] of [[levomethamphetamine]] using [[propargyl bromide]].<ref name="HoffmanOlsonSchoffstall2023" /><ref name="DE1568277">{{cite patent|country=DE|number=1568277|title=Verfahren zur Herstellung von neuen,optisch aktiven Phenylisopylamin-Derivaten [Process for the preparation of new, optically active phenylisopylamine derivatives]|pubdate=1970-04-30|inventor = Ecsery Z, Kosa I, Knoll J, Somfai E |assign1=Chinoin Gyógyszer-és Vegyészeti Termékek Gyára RT}}</ref><ref name="US4564706">J. Hermann Nee Voeroes, Z. Ecsery, G. Sabo, L. Arvai, L. Nagi, O. Orban, E. Sanfai, {{US patent| 4564706}} (1986)</ref><ref name="EP344675">{{cite patent|country=EP|number=344675|title=Method for the production of selegiline hydrochloride|pubdate=989-12-06|assign1=SPOFA Spojené Podniky Pro Zdravotnickou Vyrobu|inventor = Hájicek J, Hrbata J, Pihera P, Brunová B, Ferenc M, Krepelka J, Kvapil L, Pospisil J }}</ref><ref name="Fowler1977">{{cite journal | vauthors = Fowler JS | title = 2-Methyl-3-butyn-2-ol as an acetylene precursor in the Mannich reaction. A new synthesis of suicide inactivators of monoamine oxidase | journal = The Journal of Organic Chemistry | volume = 42 | issue = 15 | pages = 2637–2639 | date = July 1977 | pmid = 874623 | doi = 10.1021/jo00435a026 }}</ref>

[[File:Selegiline synthesis.svg|class=skin-invert-image|500px|center]]

==History==
Following the discovery in 1952 that the [[tuberculosis]] drug [[iproniazid]] elevated the [[mood (psychology)|mood]] of people taking it, and the subsequent discovery that the effect was likely due to inhibition of [[monoamine oxidase]] (MAO) and elevation of [[monoamine neurotransmitter]]s in the [[brain]], many people and companies started trying to discover [[monoamine oxidase inhibitor]]s (MAOIs) to use as [[antidepressant]]s.<ref name="Magyar2011" /><ref name="ZellerBarsky1952">{{cite journal | vauthors = Zeller EA, Barsky J | title = In vivo inhibition of liver and brain monoamine oxidase by 1-Isonicotinyl-2-isopropyl hydrazine | journal = Proc Soc Exp Biol Med | volume = 81 | issue = 2 | pages = 459–461 | date = November 1952 | pmid = 13027339 | doi = 10.3181/00379727-81-19910 | url = }}</ref> [[Deprenyl]], the [[racemic mixture|racemic form]] of selegiline, was synthesized and discovered by Zoltan Ecseri at the [[Chinoin|Chinoin Pharmaceutical Company]] (part of [[Sanofi]] since 1993) in [[Budapest, Hungary]].<ref name="Magyar2011" /><ref name="PL1993">{{cite web|url=https://www.thepharmaletter.com/article/sanofi-extends-holding-in-chinoin|title=Sanofi Extends Holding in Chinoin |date=September 19, 1993|work=The Pharma Letter|url-access=subscription }}</ref> Chinoin received a patent on the drug in 1962 and the compound was first published in the scientific literature in English in 1965.<ref name="Magyar2011" /><ref name="KnollEcseriKelemen1965">{{cite journal | vauthors = Knoll J, Ecseri Z, Kelemen K, Nievel J, Knoll B | title = Phenylisopropylmethylpropinylamine (E-250), a new spectrum psychic energizer | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 155 | issue = 1 | pages = 154–164 | date = May 1965 | pmid = 4378644 }}</ref> Chinoin researchers had been studying [[substituted amphetamine]]s since 1960, and decided to try synthesizing amphetamines that acted as MAOIs.<ref name="Knoll1983" /> It had been known that [[methamphetamine]] was a [[reversible inhibitor]] of MAO.<ref name="Knoll1983" /> Deprenyl, also known as ''N''-propargyl-''N''-methylamphetamine,<ref name="Miklya2014a" /> is closely related to and inspired by [[pargyline]] (''N''-propargyl-''N''-methylbenzylamine), another MAOI that had been synthesized earlier.<ref name="Magyar2011" /><ref name="Knoll1983" /><ref name="BryantTorosdagSchvartz1961">{{cite journal | vauthors = Bryant JM, Torosdag S, Schvartz N, Fletcher L, Fertig H, Schwartz MS, Quan RB | title = Antihypertensive properties of pargyline hydrochloride. New non-hydrazine monoamine oxidase inhibitor compared with sulphonamide diuretics | journal = JAMA | volume = 178 | issue = | pages = 406–409 | date = October 1961 | pmid = 13874134 | doi = 10.1001/jama.1961.73040430005010 | url = }}</ref> Deprenyl was initially referred to by the chemical name ''phenylisopropylmethylpropinylamine'' and the developmental code name ''E-250''.<ref name="Magyar2011" /><ref name="Knoll1983" /><ref name="KnollEcseriKelemen1965" /> Work on the biology and effects of E-250 in animals and humans was conducted by a group led by [[József Knoll]] at [[Semmelweis University]], which was also in Budapest.<ref name="Magyar2011" />

Deprenyl is a [[racemic mixture|racemic]] compound (a mixture of two [[isomer]]s called [[enantiomer]]s).<ref name="Magyar2011" /><ref name="Knoll1983" /> The racemic form has mild amphetamine-like [[psychostimulant]] effects that are diminished compared to those of amphetamine but are still present.<ref name="Knoll1983" /> The [[levorotatory]] enantiomer has further reduced stimulant effects, and further work, published in 1967, determined that the levorotatory enantiomer was a more potent MAOI than the [[dextrorotatory]] enantiomer.<ref name="Magyar2011" /><ref name="Knoll1983" /><ref name="Healy2000" /><ref name="MagyarViziEcseri1967" /> As a result, subsequent work was done with the single enantiomer <small>L</small>-deprenyl.<ref name="Magyar2011" /><ref name="Knoll1983" /><ref name="Healy2000">{{cite book | vauthors = Healy D |author-link1=David Healy (psychiatrist)| title=The Psychopharmacologists, Vol. III: Interviews |publisher=Arnold |location=London |year=2000 |pages=81–110 |doi=10.4324/9781003058892-3|isbn=978-0-340-76110-6 |chapter=The Psychopharmacology of Life and Death. Interview with Joseph Knoll. | chapter-url=https://books.google.com/books?id=NJEBEAAAQBAJ&pg=PT109}}</ref><ref name="MagyarViziEcseri1967">{{cite journal | vauthors = Magyar K, Vizi ES, Ecseri Z, Knoll J | title = Comparative pharmacological analysis of the optical isomers of phenyl-isopropyl-methyl-propinylamine (E-250) | journal = Acta Physiologica Academiae Scientiarum Hungaricae | volume = 32 | issue = 4 | pages = 377–387 | year = 1967 | pmid = 5595908 }}</ref> In 1968, it was discovered by J. P. Johnston that monoamine oxidase exists in multiple forms.<ref name="Magyar2011" /><ref name="Knoll1983" /><ref name="Johnston1968">{{cite journal | vauthors = Johnston JP | title = Some observations upon a new inhibitor of monoamine oxidase in brain tissue | journal = Biochem Pharmacol | volume = 17 | issue = 7 | pages = 1285–1297 | date = July 1968 | pmid = 5659776 | doi = 10.1016/0006-2952(68)90066-x | url = }}</ref> In 1971, Knoll showed that selegiline highly selectively inhibits the B-isoform of monoamine oxidase (MAO-B) and proposed that it is unlikely to cause the infamous "cheese effect" ([[hypertensive emergency|hypertensive crisis]] resulting from consuming [[foods containing tyramine]]) that occurs with non-selective MAOIs.<ref name="Magyar2011" /><ref name="Knoll1983" /><ref name="KnollMagyar1972">{{cite journal | vauthors = Knoll J, Magyar K | title = Some puzzling pharmacological effects of monoamine oxidase inhibitors | journal = Adv Biochem Psychopharmacol | volume = 5 | issue = | pages = 393–408 | date = 1972 | pmid = 5066229 | doi = | url = }}</ref> The lack of potentiation of tyramine effect by deprenyl had previously been reported in 1966 and 1968 studies, but could not be mechanistically explained until after the existence of multiple forms of MAO was discovered.<ref name="Magyar2011" /><ref name="Knoll1983" /><ref name="KnollViziSomogyi1968">{{cite journal | vauthors = Knoll J, Vizi ES, Somogyi G | date = 1968 | title = Phenylisopropylmethylpropynylamine (E-250), a Monoaminooxidase Inhibitor Antagonising Effects of Tyramine | journal = Arzneimittel-Forschung | volume = 18 | issue = 1 | pages = 109–112 | url = https://scholar.google.com/scholar?cluster=5232790289020141390 }}</ref> Selegiline was the first selective MAO-B inhibitor to be discovered<ref name="LöhleStorch2008" /> and hence is described as prototypical of these agents.<ref name="HoffmanOlsonSchoffstall2023" /><ref name="Golbe1988">{{cite journal | vauthors = Golbe LI | title = Deprenyl as symptomatic therapy in Parkinson's disease | journal = Clin Neuropharmacol | volume = 11 | issue = 5 | pages = 387–400 | date = October 1988 | pmid = 3146432 | doi = 10.1097/00002826-198810000-00001 | url = }}</ref>

Deprenyl and selegiline were initially studied as [[antidepressant]]s for treatment of [[depression (mood)|depression]].<ref name="Knoll2001" /><ref name="KnollEcseriKelemen1965" /> Deprenyl was first found to be effective for depression from 1965 to 1967,<ref name="Knoll2001" /><ref name="Varga1965">{{cite book | vauthors = Varga E | date = 1965 | chapter = Vorläufiger Bericht über die Wirkung des Präparates E-250 (phenyl-isopropyl-methyl-propinylamine-chlorhydrat) | title = III Conferentia Hungarica pro Therapia et Investigatione in Pharmacologia | location = Budapest | publisher = Publishing House of the Hungarian Academy of Sciences | pages = 197–201 | url = https://scholar.google.com/scholar?cluster=18272383476858777801}}</ref><ref name="VargaTringer1967">{{cite journal | vauthors = Varga E, Tringer L | title = Clinical trial of a new type promptly acting psychoenergetic agent (phenyl-isopropyl-methylpropinyl-HCl, "E-250") | journal = Acta Med Acad Sci Hung | volume = 23 | issue = 3 | pages = 289–295 | date = 1967 | pmid = 6056555 | doi = | url = }}</ref> while selegiline was first found to be effective for depression in 1971 and this was further corroborated in 1980.<ref name="Knoll2001" /><ref name="TringerHaitsVarga1971">{{cite book | vauthors = Tringer L, Haits G, Varga E | date = 1971 | chapter = The effect of (-) E-250,(-) L-phenyl-isopropylmethylpropinyl-amine HCl, in depression | title = V. Conferentia Hungarica pro Therapia et Investigatione in Pharmacologia | pages = 111–114 | url = https://scholar.google.com/scholar?cluster=3488257935143350565}}</ref><ref name="MannGershon1980">{{cite journal | vauthors = Mann J, Gershon S | title = L-deprenyl, a selective monoamine oxidase type-B inhibitor in endogenous depression | journal = Life Sci | volume = 26 | issue = 11 | pages = 877–882 | date = March 1980 | pmid = 6768943 | doi = 10.1016/0024-3205(80)90350-1 }}</ref> A 1984 study that combined selegiline with [[phenylalanine]] reported remarkably high effectiveness in the treatment of depression similar to that with [[electroconvulsive therapy]] (ECT).<ref name="Knoll2001" /><ref name="BirkmayerRiedererLinauer1984" /> However, selegiline in its original oral form was never further developed or approved for the treatment of depression.<ref name="Knoll2001" />

A few years after the discovery that selegiline was a selective MAO-B inhibitor, two Parkinson's disease researchers based in Vienna, Peter Riederer and Walther Birkmayer, realized that selegiline could be useful in Parkinson's disease. One of their colleagues, [[Moussa B. H. Youdim]], visited Knoll in Budapest and took selegiline from him to Vienna. In 1975, Birkmayer's group published the first paper on the effect of selegiline in Parkinson's disease.<ref name="Healy2000" /><ref name="BirkmayerRiedererYoudim1975">{{cite journal | vauthors = Birkmayer W, Riederer P, Youdim MB, Linauer W | title = The potentiation of the anti akinetic effect after L-dopa treatment by an inhibitor of MAO-B, Deprenil | journal = Journal of Neural Transmission | volume = 36 | issue = 3–4 | pages = 303–326 | year = 1975 | pmid = 1172524 | doi = 10.1007/BF01253131 | url = http://link.springer.de/link/service/journals/00702/bibs/5036003/50360303.htm | s2cid = 38179089 | archive-url = https://archive.today/20130212002238/http://link.springer.de/link/service/journals/00702/bibs/5036003/50360303.htm | archive-date = 2013-02-12 | url-access = subscription }}</ref>

Speculation, by József Knoll, that selegiline could be useful as an [[anti-aging]] and [[aphrodisiac|pro-sexual agent]], began in the 1980s.<ref name="Knoll1983" /><ref name="Knoll1985">{{cite journal | vauthors = Knoll J | title = The facilitation of dopaminergic activity in the aged brain by (-)deprenyl. A proposal for a strategy to improve the quality of life in senescence | journal = Mech Ageing Dev | volume = 30 | issue = 2 | pages = 109–122 | date = May 1985 | pmid = 3927074 | doi = 10.1016/0047-6374(85)90001-6 | url = }}</ref><ref name="BirkmayerKnollRiederer1985">{{cite journal | vauthors = Birkmayer W, Knoll J, Riederer P, Youdim MB, Hars V, Marton J | title = Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease: a longterm study | journal = J Neural Transm | volume = 64 | issue = 2 | pages = 113–127 | date = 1985 | pmid = 3935752 | doi = 10.1007/BF01245973 | url = }}</ref><ref name="Knoll1988">{{cite journal | vauthors = Knoll J | title = The striatal dopamine dependency of life span in male rats. Longevity study with (-)deprenyl | journal = Mech Ageing Dev | volume = 46 | issue = 1–3 | pages = 237–262 | date = December 1988 | pmid = 3147347 | doi = 10.1016/0047-6374(88)90128-5 | url = }}</ref><ref name="HG2002" /> ''[[The New York Times]]'' reported that selegiline was being used non-medically as a [[nootropic|"smart drug"]] by 1992.<ref name="Bishop1992">{{cite web | vauthors = Bishop K | title='Smart Drugs': Elixir or Snake Oil? | website=The New York Times | date=10 June 1992 | url=https://www.nytimes.com/1992/06/10/style/smart-drugs-elixir-or-snake-oil.html | access-date=16 August 2024 | quote = And in the case of selegiline (also known as Deprenyl or l-deprenyl), which is prescribed for the treatment of Parkinson's disease and which smart-drug users have ordered by mail from Switzerland, the drug itself produces amphetamine as a byproduct in the brain. [...]}}</ref>

Selegiline was first introduced for clinical use in [[Hungary]] in 1977.<ref name="TábiVécseiYoudim2020" /> It was approved in the oral pill form under the brand name Jumex to treat Parkinson's disease.<ref name="TábiVécseiYoudim2020" /> The drug was then introduced in the [[United Kingdom]] in 1982.<ref name="TábiVécseiYoudim2020" /> In 1987, Somerset Pharmaceuticals in New Jersey, which had acquired the rights to develop selegiline in the [[United States]], filed a [[New Drug Application]] (NDA) with the [[Food and Drug Administration]] (FDA) to market the drug for Parkinson's disease in this country.<ref name="MylanHist2011">{{cite book|title=Mylan: 50 Years of Unconventional Success: Making Quality Medicine Affordable and Accessible| vauthors = Seaman J, Landry JT |publisher=University Press of New England|year=2011|isbn=978-1-61168-269-4|page=50}}</ref> While the NDA was under review, Somerset was acquired in a joint venture by two [[generic drug]] companies, [[Mylan]] and Bolan Pharmaceuticals.<ref name="MylanHist2011" /> Selegiline was approved for Parkinson's disease by the FDA in 1989.<ref name="MylanHist2011" />

It had been known since the mid-1960s that high doses of deprenyl had [[psychostimulant]] effects.<ref name="HeinonenLammintausta1991" /><ref name="Magyar2011" /><ref name="KnollEcseriKelemen1965" /><ref name="VargaTringer1967" /> Selegiline was first shown to [[metabolism|metabolize]] into [[levomethamphetamine]] and [[levoamphetamine]] in humans in 1978.<ref name="YasarGoldbergGoldberg1996" /><ref name="ReynoldsElsworthBlau1978">{{cite journal | vauthors = Reynolds GP, Elsworth JD, Blau K, Sandler M, Lees AJ, Stern GM | title = Deprenyl is metabolized to methamphetamine and amphetamine in man | journal = Br J Clin Pharmacol | volume = 6 | issue = 6 | pages = 542–544 | date = December 1978 | pmid = 728327 | pmc = 1429688 | doi = 10.1111/j.1365-2125.1978.tb00883.x | url = }}</ref> The involvement of these metabolites in the effects and side effects of selegiline has remained controversial and unresolved in the decades afterwards.<ref name="YasarGoldbergGoldberg1996" /><ref name="GerlachReichmannRiederer2012" /> In any case, concerns about these metabolites have contributed to the development of newer MAO-B inhibitors like [[rasagiline]] and [[safinamide]] that lack such metabolites.<ref name="GerlachReichmannRiederer2012" /><ref name="DezsiVecsei2017">{{cite journal | vauthors = Dezsi L, Vecsei L | title = Monoamine Oxidase B Inhibitors in Parkinson's Disease | journal = CNS Neurol Disord Drug Targets | volume = 16 | issue = 4 | pages = 425–439 | date = 2017 | pmid = 28124620 | doi = 10.2174/1871527316666170124165222 | url = }}</ref>

The [[catecholaminergic activity enhancer]] (CAE) effects of selegiline became well-characterized and distinctly named in 1994.<ref name="Knoll2005" /><ref name="Knoll1998" /><ref name="GerlachYoudimRiederer1996" /><ref name="Miklya2014b">{{cite journal | vauthors = Miklya I | title = Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline | journal = Pharmacol Rep | volume = 66 | issue = 3 | pages = 453–458 | date = June 2014 | pmid = 24905523 | doi = 10.1016/j.pharep.2013.11.003 | url = }}</ref><ref name="Miklya2016" /><ref name="GasznerMiklya2006" /><ref name="KnollMiklya1994">{{cite journal | vauthors = Knoll J, Miklya I | title = Multiple, small dose administration of (-)deprenyl enhances catecholaminergic activity and diminishes serotoninergic activity in the brain and these effects are unrelated to MAO-B inhibition | journal = Arch Int Pharmacodyn Ther | volume = 328 | issue = 1 | pages = 1–15 | date = 1994 | pmid = 7893186 | doi = | url = }}</ref><ref name="KnollMiklyaKnoll1996">{{cite journal | vauthors = Knoll J, Miklya I, Knoll B, Markó R, Kelemen K | title = (-)Deprenyl and (-)1-phenyl-2-propylaminopentane, [(-)PPAP], act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons | journal = Life Sci | volume = 58 | issue = 10 | pages = 817–827 | date = 1996 | pmid = 8602114 | doi = 10.1016/0024-3205(96)00014-8 | url = }}</ref><ref name="KnollKnollTörök1992">{{cite journal | vauthors = Knoll J, Knoll B, Török Z, Timár J, Yasar S | title = The pharmacology of 1-phenyl-2-propylamino-pentane (PPAP), a deprenyl-derived new spectrum psychostimulant | journal = Arch Int Pharmacodyn Ther | volume = 316 | issue = | pages = 5–29 | date = 1992 | pmid = 1356324 | doi = | url = }}</ref> These effects had been observed much earlier, dating back to the 1960s and 1970s, but were not properly distinguished from the other actions of selegiline, like MAO-B inhibition, until the 1990s.<ref name="Knoll1998" /><ref name="GerlachYoudimRiederer1996" /><ref name="GasznerMiklya2006" /><ref name="Knoll2005">{{cite book | vauthors = Knoll J | title=The Brain and Its Self: A Neurochemical Concept of the Innate and Acquired Drives | chapter=Enhancer Regulation: A Neurochemical Approach to the Innate and Acquired Drives | publisher=Springer-Verlag | publication-place=Berlin/Heidelberg | date=2005 | isbn=978-3-540-23969-7 | doi=10.1007/3-540-27434-0_4 | pages=25–94}}</ref> More potent, selective, and/or expansive [[monoaminergic activity enhancer]]s (MAEs), like [[phenylpropylaminopentane]] (PPAP) and [[benzofuranylpropylaminopentane]] (BPAP), were derived from selegiline and other compounds and were first described in 1988 and 1999, respectively.<ref name="Miklya2014a" /><ref name="ShimazuMiklya2004" /><ref name="KnollYonedaKnoll1999">{{cite journal | vauthors = Knoll J, Yoneda F, Knoll B, Ohde H, Miklya I | title = (-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain | journal = Br J Pharmacol | volume = 128 | issue = 8 | pages = 1723–1732 | date = December 1999 | pmid = 10588928 | pmc = 1571822 | doi = 10.1038/sj.bjp.0702995 | url = }}</ref><ref name="Knoll2001" /><ref name="KnollTimarKnoll1988">{{cite journal | vauthors = Knoll B, Timar J, Knoll J | title=Amphetamine-derived potent psychostimulants devoid of biogenic amine releasing properties | journal=Pharmacological Research Communications | volume=20 | date=1988 | doi=10.1016/S0031-6989(88)80670-2 | pages=119–120}}</ref> These drugs had been proposed for potential treatment of psychiatric disorders like depression as well as for Parkinson's disease and [[Alzheimer's disease]], but were never developed or marketed.<ref name="GasznerMiklya2004">{{cite journal | vauthors = Gaszner P, Miklya I | title = The use of the synthetic enhancer substances (-)-deprenyl and (-)-BPAP in major depression | journal = Neuropsychopharmacol Hung | volume = 6 | issue = 4 | pages = 210–220 | date = December 2004 | pmid = 15825677 | doi = | url = }}</ref><ref name="GasznerMiklya2006">{{cite journal | vauthors = Gaszner P, Miklya I | title = Major depression and the synthetic enhancer substances, (-)-deprenyl and R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 30 | issue = 1 | pages = 5–14 | date = January 2006 | pmid = 16023777 | doi = 10.1016/j.pnpbp.2005.06.004 | url = }}</ref><ref name="ShimazuMiklya2004" /><ref name="Knoll2003">{{cite journal | vauthors = Knoll J | title = Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives | journal = Neurochem Res | volume = 28 | issue = 8 | pages = 1275–1297 | date = August 2003 | pmid = 12834268 | doi = 10.1023/a:1024224311289 | url = }}</ref><ref name="Knoll2001" />

In the 1990s, [[J. Alexander Bodkin]] at [[McLean Hospital]], an affiliate of [[Harvard Medical School]], began a collaboration with Somerset to develop delivery of selegiline via a [[transdermal patch]] in order to avoid the well known [[Monoamine oxidase inhibitor#Hypertensive Crisis & Tyramine|dietary restrictions of MAOIs]].<ref name="HG2002">{{cite web|url=https://news.harvard.edu/gazette/story/2002/11/bodkin-is-patching-up-depression/|title=Bodkin is Patching up Depression| vauthors = Cromie WJ |date=November 7, 2002|work=Harvard University Gazette|access-date=September 8, 2007}}</ref><ref name="FramptonPlosker2007">{{cite journal | vauthors = Frampton JE, Plosker GL | title = Selegiline transdermal system: in the treatment of major depressive disorder | journal = Drugs | volume = 67 | issue = 2 | pages = 257–265; discussion 266–267 | year = 2007 | pmid = 17284087 | doi = 10.2165/00003495-200767020-00006 | s2cid = 42425086 }}</ref><ref name="Duffy2002">{{cite news|url=https://www.nytimes.com/2002/12/03/health/patch-raises-new-hope-for-beating-depression.html|title=Patch Raises New Hope For Beating Depression| vauthors = Duffy M |date=3 December 2002|work=The New York Times|issn=0362-4331}}</ref> Somerset obtained FDA approval to market the patch for depression in 2006.<ref name="Cascade2007">{{cite journal | vauthors = Cascade EF, Kalali AH, Preskorn SH | title = Emsam: the first year | journal = Psychiatry | volume = 4 | issue = 6 | pages = 19–21 | date = June 2007 | pmid = 20711332 | pmc = 2921248 }}</ref> Similarly, the [[orally disintegrating tablet]] (ODT) form of selegiline, marketed under the brand name Zelapar, was approved for Parkinson's disease in the United States in 2006 and in the [[European Union]] in 2010.<ref name="TábiVécseiYoudim2020" />

Binding to and agonism of the [[trace amine-associated receptor]]s (TAARs) as the [[mechanism of action|mechanism]] responsible for the MAE effects of selegiline and related MAEs like PPAP and BPAP was first suggested in the early 2000s following the discovery of the TAARs.<ref name="ShimazuMiklya2004" /><ref name="Knoll2003" /><ref name="Berry2007" /> Activation of the [[TAAR1]] as the mechanism of the MAE effects was first clearly substantiated in 2022.<ref name="HarsingKnollMiklya2022">{{cite journal | vauthors = Harsing LG, Knoll J, Miklya I | title = Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum | journal = Int J Mol Sci | volume = 23 | issue = 15 | date = August 2022 | page = 8543 | pmid = 35955676 | pmc = 9369307 | doi = 10.3390/ijms23158543 | doi-access = free | url = }}</ref><ref name="HarsingTimarMiklya2023" />

==Society and culture==
===Names===
''Selegiline'' is the [[generic term|generic name]] of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|BAN|British Approved Name}}, and {{Abbrlink|DCF|Dénomination Commune Française}}, while ''selegiline hydrochloride'' is the {{Abbrlink|USAN|United States Adopted Name}}.<ref name="Elks1990">{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=1990 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA441 | access-date=4 July 2024 | page=441}}</ref><ref name="MortonHall1999">{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=1999 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA254 | access-date=4 July 2024 | page=254 }}</ref><ref name="IndexNominum2000">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum 2000: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2000 | isbn=978-3-88763-075-1 | url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA939 | access-date=4 July 2024 | page=939}}</ref> The word "selegiline" is pronounced {{IPAc-en|s|ə|ˈ|l|ɛ|dʒ|ᵻ|l|iː|n}} ({{respell|sə|LEJ|i-leen}}) or as "seh-LEH-ji-leen".<ref name="Parkinsons.org2018">{{cite web | title=Drug Treatments for Parkinson's | url=https://www.parkinsons.org.uk/sites/default/files/2018-09/Drug%20treatments%20for%20Parkinsons%20WEB.pdf | access-date=5 July 2024 | quote=Selegiline (seh-LEH-ji-leen) | archive-date=July 5, 2024 | archive-url=https://web.archive.org/web/20240705225218/https://www.parkinsons.org.uk/sites/default/files/2018-09/Drug%20treatments%20for%20Parkinsons%20WEB.pdf }}</ref><ref name="Acosta2020">{{cite book | vauthors = Acosta WR | title=Pharmacology for Health Professionals | publisher=Jones & Bartlett Learning | year=2020 | isbn=978-1-284-24083-2 | url=https://books.google.com/books?id=W2rnDwAAQBAJ&pg=PA66 | access-date=5 July 2024 | page=66 | quote = sell-eh'-geh-leen}}</ref> Selegiline is also known as <small>L</small>-deprenyl, <small>L</small>-deprenil, <small>L</small>-deprenalin, <small>L</small>-deprenaline, <small>L</small>-phenylisopropylmethylpropinylamine, and <small>L</small>-E-250.<ref name="Miklya2016" /><ref name="Elks1990" /><ref name="MortonHall1999" /><ref name="IndexNominum2000" /><ref name="KnollEcseriKelemen1965" /> It should not be confused with the [[racemic mixture|racemic]] form, [[deprenyl]] (E-250), or with the [[dextrorotatory]] [[enantiomer]], [[D-deprenyl|<small>D</small>-deprenyl]], which are distinct substances.<ref name="Elks1990" /><ref name="Parnham1993" /><ref name="Miklya2016" />

Major brand names of selegiline include Eldepryl, Jumex, and Movergan (oral tablet and/or capsule), Zelapar (orally disintegrating tablet or ODT), and Emsam (transdermal patch).<ref name="Drugs.com-Names" /><ref name="IndexNominum2000" /><ref name="KalászMagyarSzőke2014">{{cite journal | vauthors = Kalász H, Magyar K, Szőke É, Adeghate E, Adem A, Hasan MY, Nurulain SM, Tekes K | title = Metabolism of selegiline [(-)-deprenyl)] | journal = Curr Med Chem | volume = 21 | issue = 13 | pages = 1522–1530 | date = 2014 | pmid = 24350849 | doi = 10.2174/0929867321666131218094352 | url = }}</ref> Selegiline has been marketed under more than 70{{nbsp}}brand names worldwide.<ref name="KnollZelenaTimar2020">{{cite journal | vauthors = Knoll J, Zelena D, Timar J, Baghy K, Mervai Z, Miklya I | title = Synthetic enhancer compounds, besides acting on biogenic amine system, influence the glutamate transmission and stress response | journal = Behav Brain Res | volume = 378 | issue = | article-number = 112290 | date = January 2020 | pmid = 31610214 | doi = 10.1016/j.bbr.2019.112290 | url = http://repo.lib.semmelweis.hu//handle/123456789/8054}}</ref><ref name="Drugs.com-Names" /> The brand name "Emsam" was derived from the names of two children, Emily and Samuel, of one of the executives at Somerset Pharmaceuticals, the developer of Emsam.<ref name="CristanchoThase2016" /><ref name="Feinberg2006">{{cite web | vauthors = Feinberg S | title=EMSAM: A User-Friendly MAOI? | website=CARLAT PUBLISHING | date=1 November 2006 | url=https://www.thecarlatreport.com/articles/1410-emsam-a-user-friendly-maoi- | access-date=4 July 2024}}</ref>

===Generic forms===
[[Generic drug|Generic]] forms of oral selegiline are available in the [[United States]].<ref name="Drugs@FDA" /> However, generic forms of the orally disintegrating tablet and the transdermal patch are not available in this country.<ref name="Drugs@FDA" /><ref name="AsnisHenderson2014" /> The latter formulations of selegiline are very expensive, and this can be prohibitive to their use.<ref name="AsnisHenderson2014" /><ref name="DorseyThompsonDayoub2009">{{cite journal | vauthors = Dorsey ER, Thompson JP, Dayoub EJ, George B, Saubermann LA, Holloway RG | title = Selegiline shortage: Causes and costs of a generic drug shortage | journal = Neurology | volume = 73 | issue = 3 | pages = 213–217 | date = July 2009 | pmid = 19620609 | pmc = 2715573 | doi = 10.1212/WNL.0b013e3181ae7b04 | url = }}</ref> There has been poor [[medical insurance|insurance]] coverage of the transdermal patch form for depression, with insurance companies often requiring patients to first fail to respond to one or two other antidepressants and to be responsible for larger copayments.<ref name="AsnisHenderson2014" /> It is expected that generics of the transdermal patch will become available at some point in the future.<ref name="AsnisHenderson2014" />

===Availability===
Conventional oral selegiline (brand names Eldepryl, Jumex) is widely marketed throughout the world, including in over 70{{nbsp}}countries.<ref name="Drugs.com-Names" /><ref name="IndexNominum2000" /><ref name="Miklya2016" /><ref name="KnollZelenaTimar2020" /> Conversely, the selegiline transdermal patch (brand name Emsam) is only marketed in the [[United States]], while the selegiline orally disintegrating tablet (brand name Zelapar) is marketed in the United States, the [[United Kingdom]], and the [[European Union]].<ref name="Drugs.com-Names" /><ref name="TábiVécseiYoudim2020" /><ref name="Miklya2016" />

===Notable users===
[[József Knoll]], one of the developers of selegiline, began taking a low 1{{nbsp}}mg daily dose of selegiline on January 1, 1989, at the age of 64.<ref name="Knoll2012" />{{rp|92}}<ref name="Healy2000" /> He reported in 2012 that this had continued for 22{{nbsp}}years uninterrupted.<ref name="Knoll2012" />{{rp|92}} Knoll stated that he had become so fascinated with the possible longevity-promoting effects of selegiline that he had decided to start taking it as a self-experiment.<ref name="Knoll2012" />{{rp|92}}<ref name="Healy2000" /> Knoll later died in 2018 at the age of 93.<ref name="FerdinandyYonedaMuraoka2020" />

[[David Pearce (philosopher)|David Pearce]], a British [[transhumanist]] [[philosopher]], wrote his self-published book-length internet manifesto ''The Hedonistic Imperative''<ref name="Pearce1995">{{Cite book| vauthors = Pearce D |url=https://www.hedweb.com/hedab.htm|title=The Hedonistic Imperative|year=1995|oclc=44325836}}</ref> six weeks after starting to take selegiline.<ref name="FLIPodcast2020">{{cite web|date=2020-06-24|title=Sam Barker and David Pearce on Art, Paradise Engineering, and Existential Hope (With Guest Mix) {{!}} The FLI Podcast|url=https://futureoflife.org/2020/06/24/sam-barker-and-david-pearce-on-art-paradise-engineering-and-existential-hope-featuring-a-guest-mix/|website=Future of Life Institute|type=audio, transcript}}</ref>

[[Sam Bankman-Fried]], the founder and former CEO of the [[FTX]] [[cryptocurrency exchange]], is known to have used selegiline for depression in the form of the Emsam patch for at least 5 to 10{{nbsp}}years.<ref name="Murphy2022">{{cite web | vauthors = Murphy HT | title=Sam Bankman-Fried Confirmed He Wears an Emsam Patch. What's an Emsam Patch? | website=Slate Magazine | date=14 December 2022 | url=https://slate.com/technology/2022/12/sam-bankman-fried-ftx-emsam-patch-testimony-arrested.html | access-date=2 July 2024}}</ref><ref name="Sigalos2023">{{cite web | vauthors = Sigalos M | title=Sam Bankman-Fried wins approval to receive Adderall for ADHD while in jail | website=CNBC | date=14 August 2023 | url=https://www.cnbc.com/2023/08/14/sam-bankman-frieds-lawyer-demands-he-get-adderall-for-adhd-in-jail.html | access-date=2 July 2024}}</ref> He is also known to have simultaneously taken [[Adderall]] for treatment of [[attention deficit hyperactivity disorder]] (ADHD)<ref name="Murphy2022" /><ref name="Sigalos2023" /> and to have possessed non-pharmaceutical [[adrafinil]], a [[prodrug]] of [[modafinil]].<ref name="Alexander2022">{{cite web | vauthors = Alexander S | title=The Psychopharmacology Of The FTX Crash | website=Astral Codex Ten | date=16 November 2022 | url=https://www.astralcodexten.com/p/the-psychopharmacology-of-the-ftx | access-date=4 July 2024 }}</ref>

===Fictional representations===
In [[Gregg Hurwitz]]'s novel ''Out of the Dark'', selegiline (''Emsam'') and [[tyramine]]-containing food were used to assassinate the president of the United States.<ref name="Hurwitz2019">{{cite book | vauthors = Hurwitz G |title=Out of the dark |year=2019 |isbn=978-0-7181-8548-0 |page=431|publisher=Penguin Books}}</ref>

===Internet vendors===
Selegiline in non-pharmaceutical form is sold on the Internet without a prescription by online vendors for uses such as purported cognitive enhancement (i.e., as a so-called "smart drug" or [[nootropic]]) and anti-aging effects.<ref name="LidskySchneider2010">{{cite book | vauthors = Lidsky T, Schneider J | title=Brain Candy: Boost Your Brain Power with Vitamins, Supplements, Drugs, and Other Substance | publisher=Touchstone | year=2010 | isbn=978-0-7432-1843-6 | url=https://books.google.com/books?id=MOYBvKeDbLMC&pg=PA89 | access-date=5 July 2024 | pages=89–93 }}</ref><ref name="Miklya2014b" /><ref name="Miklya2011">{{cite book | vauthors = Miklya I | veditors = Finkelstein D | chapter = The Knoll-Concept to Decrease the Prevalence of Parkinson's Disease | title=Towards New Therapies for Parkinson's Disease | year=2011 | isbn=978-953-307-463-4 | url=https://www.researchgate.net/publication/221918998 | access-date=29 July 2024 | pages=77–100 | publisher = IntechOpen }}</ref> It is widely available for such purposes, for instance under informal brand names like Dep-Pro, Selepryl, and Cyprenil, which are oral liquid [[solution (chemistry)|solution]]s of selegiline at a concentration of 1{{nbsp}}mg per drop.<ref name="Miklya2014b" /><ref name="Miklya2011" /><ref name="Knoll2012" />{{rp|86}}

===Presence in ecstasy===
In his 1993 book ''[[E for Ecstasy]]'' examining the uses of the street drug [[methylenedioxymethamphetamine|ecstasy]] in the [[United Kingdom]], the writer, activist, and ecstasy advocate [[Nicholas Saunders (activist)|Nicholas Saunders]] highlighted test results showing that certain consignments of the drug also contained selegiline.<ref name="Saunders1993">{{cite book|title=E for Ecstasy| vauthors = Saunders N, Heron L |publisher=N. Saunders|year=1993|isbn=978-0-9501628-8-1|location=London|oclc=29388575|url=https://books.google.com/books?id=cDWYAAAACAAJ}}{{Page needed|date=January 2012}}</ref> Consignments of ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of [[ketamine]], [[ephedrine]] and selegiline," as did a consignment of "Sitting Duck" Ecstasy tablets.<ref name="ecstasy.org">{{cite web|url=http://ecstasy.org/testing/pillstilJuly.html|title=Test results of 30 samples of Ecstasy bought in British clubs between 11/94 and 7/95| vauthors = Saunders N}}</ref>

===Doping in sport===
Selegline is on the [[World Anti-Doping Agency]] (WADA)'s [[List of drugs banned by the World Anti-Doping Agency|list of prohibited substances]].<ref name="Docherty2008">{{cite journal | vauthors = Docherty JR | title = Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) | journal = Br J Pharmacol | volume = 154 | issue = 3 | pages = 606–622 | date = June 2008 | pmid = 18500382 | pmc = 2439527 | doi = 10.1038/bjp.2008.124 | url = }}</ref> It is classified as a "[[psychostimulant|stimulant]]" in this list, along with various [[amphetamine-type stimulant|amphetamine]]s, [[methylphenidate]], [[adrenergic]] [[sympathomimetic]]s, [[modafinil]], and other agents.<ref name="Docherty2008" /> A review of the [[pharmacology]] of WADA prohibited substances noted that although selegiline is classified as a stimulant in the WADA prohibited substances list and stimulants can enhance [[physical fitness|physical performance]], selegiline was seemingly included in the list not because of any short-term stimulant effects of its own, but rather because it metabolizes into small amounts of [[levomethamphetamine]] and [[levoamphetamine]] and can produce false positives for amphetamines on [[drug test]]s.<ref name="Docherty2008" /> In any case, levomethamphetamine and levoamphetamine are [[monoamine releasing agent|catecholamine releasing agent]]s and can produce sympathomimetic and psychostimulant effects with sufficiently high exposure.<ref name="HealSmithGosden2013">{{cite journal | vauthors = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present--a pharmacological and clinical perspective | journal = J Psychopharmacol | volume = 27 | issue = 6 | pages = 479–496 | date = June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 | url = }}</ref><ref name="BarkholtzHadzimaMiles2023">{{cite journal | vauthors = Barkholtz HM, Hadzima R, Miles A | title = Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature | journal = ACS Pharmacol Transl Sci | volume = 6 | issue = 7 | pages = 914–924 | date = July 2023 | pmid = 37470013 | pmc = 10353062 | doi = 10.1021/acsptsci.3c00019 }}</ref><ref name="SmithDavis1977">{{cite journal | vauthors = Smith RC, Davis JM | title = Comparative effects of d-amphetamine, l-amphetamine, and methylphenidate on mood in man | journal = Psychopharmacology (Berl) | volume = 53 | issue = 1 | pages = 1–12 | date = June 1977 | pmid = 407607 | doi = 10.1007/BF00426687 | url = }}</ref> Such actions may have [[performance-enhancing drug|performance-enhancing]] effects.<ref name="Docherty2008" />

===Regulatory status===
Selegiline is a [[prescription drug]].<ref name="PillLabel" /><ref name="PatchLabel" /><ref name="ODTLabel" /> It is not specifically a [[controlled substance]] in the [[United States]] and hence is not an [[illegal drug]].<ref name="PatchLabel" /> However, [[deprenyl]] and selegiline are controlled substances in [[Japan]].<ref name="ZhouLiuLai2009">{{cite journal | vauthors = Zhou SF, Liu JP, Lai XS | title = Substrate specificity, inhibitors and regulation of human cytochrome P450 2D6 and implications in drug development | journal = Curr Med Chem | volume = 16 | issue = 21 | pages = 2661–805 | date = 2009 | pmid = 19601803 | doi = 10.2174/092986709788681985 | url = }}</ref><ref name="KEGG">{{cite web | title=KEGG DRUG: Narcotics and Psychotropics in Japan | website=KEGG | date=26 April 2024 | url=https://www.kegg.jp/kegg/drug/br08308.html?id=D03731#7 | access-date=10 July 2024}}</ref> They are classified as "[[psychostimulant|Stimulant]]s", alongside a variety of other [[substituted amphetamine|amphetamine]]s, under Article 2 of Japan's [[Narcotics and Psychotropics Control Law]].<ref name="KEGG" /> Selegiline is known to [[metabolism|metabolize]] into small amounts of [[levoamphetamine]] and [[levomethamphetamine]] but is thought to have little to no [[abuse potential|misuse potential]] or [[drug dependence|dependence liability]].<ref name="FinbergRabey2016" /><ref name="FabbriniAbbruzzeseMarconi2012" /><ref name="YasarGoldbergGoldberg1996" /><ref name="NickelSzelenyiSchulze1994" /><ref name="GoldbergYasarBergman1994">{{cite journal | vauthors = Goldberg SR, Yasar S, Bergman J, Youdim MB | title = Introduction: examination of clinical and preclinical pharmacologic data relating to abuse liability of l-deprenyl (selegiline) | journal = Clin Pharmacol Ther | volume = 56 | issue = 6 Pt 2 | pages = 721–724 | date = December 1994 | pmid = 7995013 | doi = 10.1038/clpt.1994.201 | url = }}</ref><ref name="PatchLabel" />

==Non-medical use==
===Anti-aging and longevity===
[[József Knoll]] and his team are credited with having developed selegiline. Although selegiline's development as a potential treatment for [[Parkinson's disease]], [[Alzheimer's disease]], and depression was headed by other teams, Knoll remained at the forefront of research into the potential longevity enhancing effects of selegiline up until his death in 2018.<ref name="FerdinandyYonedaMuraoka2020">{{cite journal | vauthors = Ferdinandy P, Yoneda F, Muraoka S, Fürst S, Gyires K, Miklya I | title = Geroprotection in the future. In memoriam of Joseph Knoll: The selegiline story continues | journal = European Journal of Pharmacology | volume = 868 | article-number = 172793 | date = February 2020 | pmid = 31743738 | doi = 10.1016/j.ejphar.2019.172793 | s2cid = 208185366 | url = http://repo.lib.semmelweis.hu//handle/123456789/8055 }}</ref><ref name="KnollMiklya2016">{{cite journal | vauthors = Knoll J, Miklya I | title = Longevity study with low doses of selegiline/(-)-deprenyl and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) | journal = Life Sciences | volume = 167 | pages = 32–38 | date = December 2016 | pmid = 27777099 | doi = 10.1016/j.lfs.2016.10.023 }}</ref><ref name="Furst2018">{{cite web | vauthors = Furst S |title=In memoriam Joseph Knoll (1925-2018) {{!}} Hungarian Society for Experimental and Clinical Pharmacology |url=https://huphar.org/en/in-memoriam-joseph-knoll-1925-2018/ |date=2018|access-date=2023-04-10}}</ref> Knoll published his 2012 book ''How Selegiline ((–)-Deprenyl) Slows Brain Aging'' wherein he claims that:<ref name="Knoll2012">{{cite book | vauthors = Knoll J | title=How Selegiline ((-)-Deprenyl) Slows Brain Aging | publisher=Bentham Science Publishers | year=2012 | isbn=978-1-60805-470-1 | url=https://books.google.com/books?id=wV0NAgAAQBAJ&pg=PP1 | access-date=4 July 2024 | pages=16, 43, 70, 86, 90, 92}}</ref>{{rp|90}}

<blockquote>"In humans, maintenance from sexual maturity on (–)-deprenyl (1mg daily) is, for the time being, the most promising prophylactic treatment to fight against the age related decay of behavioral performances, prolonging life, and preventing or delaying the onset of age-related neurodegenerative diseases such as Parkinson's and Alzheimer's".</blockquote>

The mechanism of selegiline's longevity-promoting effect has been researched by several groups, including Knoll and his associates at Semmelweis University, Budapest.<ref name="Miklya2016">{{cite journal | vauthors = Miklya I | title = The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015) | journal = Molecular Psychiatry | volume = 21 | issue = 11 | pages = 1499–1503 | date = November 2016 | pmid = 27480491 | doi = 10.1038/mp.2016.127 | doi-access = free }}</ref> The drug has been determined to be a [[catecholaminergic activity enhancer]] when present in minuscule concentrations far below those at which monoamine oxidase inhibitory activity can be observed, thereby potentiating the release of catecholamine neurotransmitters in response to stimuli. Knoll maintains that micro-doses of selegiline act as a synthetic analogue to a known or unknown [[trace amine]] in order to preserve the brain catecholaminergic system, which he perceives as integral to the organism's ability to function in an adaptive, goal-directed and motivated manner during advancing physical age:<ref name="Knoll2012" />{{rp|70,43}}

<blockquote>"[...] enhancer regulation in the catecholaminergic brain stem neurons play[s] a key role in controlling the uphill period of life and the transition from adolescence to adulthood. The results of our longevity studies support the hypothesis that quality and duration of life rests upon the inborn efficiency of the catecholaminergic brain machinery, i.e. a high performing, long-living individual has a more active, more slowly deteriorating catecholaminergic system than its low performing, shorter living peer. Thus, a better brain engine allows for a better performance and a longer lifespan."</blockquote>

<blockquote>"Since the catecholaminergic and serotonergic neurons in the brain stem are of key importance in ensuring that the mammalian organism works as a purposeful, motivated, goal-directed entity, it is hard to overestimate the significance of finding safe and efficient means to slow the decay of these systems with passing time. The conclusion that the maintenance on (–)-deprenyl that keeps the catecholaminergic neurons on a higher activity level is a safe and efficient anti-aging therapy follows from the discovery of the enhancer regulation in the catecholaminergic neurons of the brain stem. From the finding that this regulation starts working on a high activity level after weaning and the enhanced activity subsists during the uphill period of life, until sexual hormones dampen the enhancer regulation in the catecholaminergic and serotonergic neurons in the brain stem, and this event signifies the transition from developmental longevity into postdevelopmental longevity, the downhill period of life."</blockquote>

Despite findings by Knoll that selegiline can prolong lifespan in rodents by 35% however, other studies have had conflicting findings and have even found increased [[mortality rate|mortality]] with selegiline in rodents.<ref name="Finberg2019" /> In humans with Parkinson's disease, selegiline has been associated with [[cardiovascular]] and [[psychiatric]] complications and has not been found to reduce mortality in long-term studies.<ref name="Finberg2019" /> As such, the claimed anti-aging and longevity benefits of selegiline have yet to be substantiated in humans and are controversial and uncertain.<ref name="Finberg2019" /><ref name="Muskin2008" />

===Nootropic or "smart drug"===
Selegiline is considered by some to be a [[nootropic]], otherwise known as a cognitive enhancer or "smart drug", both at clinical and sub-clinical dosages, and has been used [[off-label use|off-label]] and non-medically to improve [[cognitive skill|cognitive performance]].<ref name="SchifanoCatalaniSharif2022">{{cite journal | vauthors = Schifano F, Catalani V, Sharif S, Napoletano F, Corkery JM, Arillotta D, Fergus S, Vento A, Guirguis A | title = Benefits and Harms of 'Smart Drugs' (Nootropics) in Healthy Individuals | journal = Drugs | volume = 82 | issue = 6 | pages = 633–647 | date = April 2022 | pmid = 35366192 | doi = 10.1007/s40265-022-01701-7 | url = | hdl = 2299/25614 | hdl-access = free }}</ref><ref name="FroestlMuhsPfeifer2014">{{cite journal | vauthors = Froestl W, Muhs A, Pfeifer A | title = Cognitive enhancers (nootropics). Part 2: drugs interacting with enzymes. Update 2014 | journal = J Alzheimers Dis | volume = 42 | issue = 1 | pages = 1–68 | date = 2014 | pmid = 24903780 | doi = 10.3233/JAD-140402 | url = https://infoscience.epfl.ch/handle/20.500.14299/107878}}</ref> It is one of the most popular such agents.<ref name="SchifanoCatalaniSharif2022" /> Selegiline has been found to have [[neuroprotective]] activity against certain [[neurotoxin]]s and to increase the production of several brain [[growth factor]]s, such as [[nerve growth factor]] (NGF), [[brain-derived neurotrophic factor]] (BDNF), and [[glial cell line-derived neurotrophic factor]] (GDNF).<ref name="Miklya2016" /> The drug has also been found in [[animal model]]s to improve [[learning]] ability and to help preserve it during [[ischemia]] and [[aging]].<ref name="CarageorgiouSiderisMessari2008">{{cite journal | vauthors = Carageorgiou H, Sideris AC, Messari I, Liakou CI, Tsakiris S | title = The effects of rivastigmine plus selegiline on brain acetylcholinesterase, (Na, K)-, Mg-ATPase activities, antioxidant status, and learning performance of aged rats | journal = Neuropsychiatric Disease and Treatment | volume = 4 | issue = 4 | pages = 687–699 | date = August 2008 | pmid = 19043511 | pmc = 2536534 | doi = 10.2147/ndt.s3272 | doi-access = free }}</ref><ref name="StollHafnerPhol1994">{{cite journal | vauthors = Stoll S, Hafner U, Pohl O, Müller WE | title = Age-related memory decline and longevity under treatment with selegiline | journal = Life Sciences | volume = 55 | issue = 25–26 | pages = 2155–2163 | date = 1994 | pmid = 7997074 | doi = 10.1016/0024-3205(94)00396-3 }}</ref><ref name="PuurunenJolkkonenSirviö2001">{{cite journal | vauthors = Puurunen K, Jolkkonen J, Sirviö J, Haapalinna A, Sivenius J | title = Selegiline combined with enriched-environment housing attenuates spatial learning deficits following focal cerebral ischemia in rats | journal = Experimental Neurology | volume = 167 | issue = 2 | pages = 348–355 | date = February 2001 | pmid = 11161623 | doi = 10.1006/exnr.2000.7563 | s2cid = 22769187 }}</ref><ref name="Knoll1992b">{{cite journal | vauthors = Knoll J | title = The pharmacological profile of (-)deprenyl (selegiline) and its relevance for humans: a personal view | journal = Pharmacology & Toxicology | volume = 70 | issue = 5 Pt 1 | pages = 317–321 | date = May 1992 | pmid = 1608919 | doi = 10.1111/j.1600-0773.1992.tb00480.x }}</ref> Despite claims that selegiline and other claimed nootropics have cognitive-enhancing effects however, these effects are controversial and their benefits versus risks are uncertain.<ref name="SchifanoCatalaniSharif2022" />

==Research==
===Depression===
Selegiline has been clinically studied in [[combination drug|combination]] with [[oral administration|oral]] [[phenylalanine|<small>L</small>-phenylalanine]] or [[β-phenethylamine]] in the treatment of [[depression (mood)|depression]] and was reported to be effective.<ref name="ShimazuMiklya2004" /><ref name="JanssenLeysenMegens1999">{{cite journal | vauthors = Janssen PA, Leysen JE, Megens AA, Awouters FH | title = Does phenylethylamine act as an endogenous amphetamine in some patients? | journal = Int J Neuropsychopharmacol | volume = 2 | issue = 3 | pages = 229–240 | date = September 1999 | article-number = S1461145799001522 | pmid = 11281991 | doi = 10.1017/S1461145799001522 | url = }}</ref><ref name="BirkmayerRiedererLinauer1984">{{cite journal | vauthors = Birkmayer W, Riederer P, Linauer W, Knoll J | title = L-deprenyl plus L-phenylalanine in the treatment of depression | journal = J Neural Transm | volume = 59 | issue = 1 | pages = 81–87 | date = 1984 | pmid = 6425455 | doi = 10.1007/BF01249880 | url = }}</ref><ref name="Sabelli1991">{{cite journal | vauthors = Sabelli HC | title = Rapid treatment of depression with selegiline-phenylalanine combination | journal = J Clin Psychiatry | volume = 52 | issue = 3 | page = 137 | date = March 1991 | pmid = 1900832 | doi = | url = https://psycnet.apa.org/record/1991-25376-001}}</ref><ref name="SabelliFinkFawcett1996">{{cite journal | vauthors = Sabelli H, Fink P, Fawcett J, Tom C | title = Sustained antidepressant effect of PEA replacement | journal = J Neuropsychiatry Clin Neurosci | volume = 8 | issue = 2 | pages = 168–71 | date = 1996 | pmid = 9081552 | doi = 10.1176/jnp.8.2.168 | url = }}</ref> <small>L</small>-Phenylalanine is known to be [[metabolism|metabolized]] into β-phenethylamine, selegiline is known to strongly [[enzyme inhibitor|inhibit]] the metabolism of β-phenethylamine, and β-phenethylamine has been implicated in having [[psychostimulant]]-like [[mood (psychology)|mood]]-lifting effects.<ref name="ShimazuMiklya2004" /><ref name="HeinonenLammintausta1991" /><ref name="JanssenLeysenMegens1999" />

===Social anxiety===
A small clinical study found that oral selegiline (10{{nbsp}}mg/day) reduced symptoms of [[social anxiety disorder]].<ref name="PaeLimHan2007" /><ref name="RossanoCaiazzaSobrino2023" /><ref name="SimpsonSchneierMarshall1998">{{cite journal | vauthors = Simpson HB, Schneier FR, Marshall RD, Campeas RB, Vermes D, Silvestre J, Davies S, Liebowitz MR | title = Low dose selegiline (L-Deprenyl) in social phobia | journal = Depress Anxiety | volume = 7 | issue = 3 | pages = 126–129 | date = 1998 | pmid = 9656093 | doi = 10.1002/(SICI)1520-6394(1998)7:3<126::AID-DA5>3.0.CO;2-9| url = }}</ref> The effectiveness was modest, with a reduction in social anxiety scores from baseline of 32% over 6{{nbsp}}weeks of treatment.<ref name="PaeLimHan2007" /><ref name="RossanoCaiazzaSobrino2023" /><ref name="SimpsonSchneierMarshall1998" /> It was seemingly less effective than certain other agents used in the treatment of social anxiety, such as the non-selective MAOI [[phenelzine]] (45% symptom reduction) and the [[benzodiazepine]] [[clonazepam]] (51% symptom reduction), though it was similar to the SSRI [[sertraline]] (32% symptom decrease).<ref name="SimpsonSchneierMarshall1998" />

===ADHD===
Selegiline has been limitedly studied in the treatment of [[attention deficit hyperactivity disorder]] (ADHD) in children, adolescents, and adults.<ref name="RossanoCaiazzaSobrino2023" /><ref name="PadilhaVirtuosoTonin2018">{{cite journal | vauthors = Padilha SC, Virtuoso S, Tonin FS, Borba HH, Pontarolo R | title = Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis | journal = European Child & Adolescent Psychiatry | volume = 27 | issue = 10 | pages = 1335–1345 | date = October 2018 | pmid = 29460165 | doi = 10.1007/s00787-018-1125-0 | s2cid = 3402756 }}</ref><ref name="BuoliSeratiCahn2016">{{cite journal | vauthors = Buoli M, Serati M, Cahn W | title = Alternative pharmacological strategies for adult ADHD treatment: a systematic review | journal = Expert Review of Neurotherapeutics | volume = 16 | issue = 2 | pages = 131–144 | date = 2016 | pmid = 26693882 | doi = 10.1586/14737175.2016.1135735 | s2cid = 33004517 }}</ref><ref name="BlochPanza2009">{{cite journal | vauthors = Bloch MH, Panza KE, Landeros-Weisenberger A, Leckman JF | title = Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders | journal = J Am Acad Child Adolesc Psychiatry | volume = 48 | issue = 9 | pages = 884–893 | date = September 2009 | pmid = 19625978 | pmc = 3943246 | doi = 10.1097/CHI.0b013e3181b26e9f | url = }}</ref> In a small randomized trial of selegiline for treatment of ADHD in children, there were improvements in attention, hyperactivity, and learning/memory performance but not in impulsivity.<ref name="RubinsteinMaloneRoberts2006">{{cite journal | vauthors = Rubinstein S, Malone MA, Roberts W, Logan WJ | title = Placebo-controlled study examining effects of selegiline in children with attention-deficit/hyperactivity disorder | journal = Journal of Child and Adolescent Psychopharmacology | volume = 16 | issue = 4 | pages = 404–415 | date = August 2006 | pmid = 16958566 | doi = 10.1089/cap.2006.16.404 }}</ref> A small clinical randomized trial compared selegiline to methylphenidate, a first line treatment for ADHD, and reported equivalent efficacy as assessed by parent and teacher ratings.<ref name="AkhondzadehTavakolianDavari-Ashtiani2003">{{cite journal | vauthors = Akhondzadeh S, Tavakolian R, Davari-Ashtiani R, Arabgol F, Amini H | title = Selegiline in the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 27 | issue = 5 | pages = 841–845 | date = August 2003 | pmid = 12921918 | doi = 10.1016/S0278-5846(03)00117-9 | s2cid = 23234928 }}</ref> In another small randomized controlled trial of selegiline for the treatment of adult ADHD, a high dose of the medication for 6{{nbsp}}weeks was not significantly more effective than placebo in improving symptoms.<ref name="BuoliSeratiCahn2016" /><ref name="WilensSpencerBiederman2002">{{cite journal | vauthors = Wilens TE, Spencer TJ, Biederman J | title = A review of the pharmacotherapy of adults with attention-deficit/hyperactivity disorder | journal = Journal of Attention Disorders | volume = 5 | issue = 4 | pages = 189–202 | date = March 2002 | pmid = 11967475 | doi = 10.1177/108705470100500401 | s2cid = 37417459 }}</ref><ref name="TcheremissineSalazar2008">{{cite journal | vauthors = Tcheremissine OV, Salazar JO | title = Pharmacotherapy of adult attention deficit/hyperactivity disorder: review of evidence-based practices and future directions | journal = Expert Opinion on Pharmacotherapy | volume = 9 | issue = 8 | pages = 1299–1310 | date = June 2008 | pmid = 18473705 | doi = 10.1517/14656566.9.8.1299 | s2cid = 73193888 }}</ref> Selegiline in its transdermal patch form (brand name Emsam) has also been assessed in the treatment of ADHD in children and adolescents in a small [[open-label study|open-label]] [[pilot study]] sponsored by the manufacturer in 2003.<ref name="PaeLimHan2007" /><ref name="Mechcatie2003">{{cite news | vauthors = Mechcatie E | title = Transdermal MAO inhibitor patch effective for ADHD | work = Clinical Psychiatry News | date = July 2003 | volume = | issue = | pages = | url = https://www.thefreelibrary.com/Transdermal+MAO+inhibitor+appears+effective+for+ADHD%3a+the+transdermal...-a0105643839}}</ref> However, there was a high rate of [[drug discontinuation|discontinuation]] and development was not further pursued.<ref name="PaeLimHan2007" /><ref name="Mechcatie2003" />

===Motivational disorders===
Selegiline has been found to produce [[pro-motivational agent|pro-motivational]] effects and to reverse [[motivational disorder|motivational deficits]] in rodents.<ref name="Hailwood2018">{{cite thesis | vauthors = Hailwood JM | title=Novel approaches towards pharmacological enhancement of motivation | publisher = University of Cambridge | date=27 September 2018 | doi=10.17863/CAM.40216 | pages=13–14 | url = https://api.repository.cam.ac.uk/server/api/core/bitstreams/bfa48cf2-6047-4400-b0c0-8801328d2776/content }}</ref><ref name="CallaghanRouineOMara2018">{{cite book | vauthors = Callaghan CK, Rouine J, O'Mara SM | chapter = Potential roles for opioid receptors in motivation and major depressive disorder | title = The Opioid System as the Interface between the Brain's Cognitive and Motivational Systems | series = Progress in Brain Research | volume = 239 | pages = 89–119 | date = 2018 | pmid = 30314570 | doi = 10.1016/bs.pbr.2018.07.009 | isbn = 978-0-444-64167-0 | chapter-url = }}</ref><ref name="YohnReynoldsTripodi2018">{{cite journal | vauthors = Yohn SE, Reynolds S, Tripodi G, Correa M, Salamone JD | title = The monoamine-oxidase B inhibitor deprenyl increases selection of high-effort activity in rats tested on a progressive ratio/chow feeding choice procedure: Implications for treating motivational dysfunctions | journal = Behav Brain Res | volume = 342 | issue = | pages = 27–34 | date = April 2018 | pmid = 29292157 | doi = 10.1016/j.bbr.2017.12.039 | url = }}</ref><ref name="Contreras-MoraRowlandYohn2018">{{cite journal | vauthors = Contreras-Mora H, Rowland MA, Yohn SE, Correa M, Salamone JD | title = Partial reversal of the effort-related motivational effects of tetrabenazine with the MAO-B inhibitor deprenyl (selegiline): Implications for treating motivational dysfunctions | journal = Pharmacol Biochem Behav | volume = 166 | issue = | pages = 13–20 | date = March 2018 | pmid = 29309800 | doi = 10.1016/j.pbb.2018.01.001 | url = }}</ref> In [[case report]]s and small [[clinical study|clinical studies]], selegiline has been reported to improve [[disorders of diminished motivation]] like [[apathy]] and [[abulia]] due to conditions such as [[traumatic brain injury]].<ref name="Hailwood2018" /><ref name="vanDalenMollvanCharanteNederkoorn2013">{{cite journal | vauthors = van Dalen JW, Moll van Charante EP, Nederkoorn PJ, van Gool WA, Richard E | title = Poststroke apathy | journal = Stroke | volume = 44 | issue = 3 | pages = 851–860 | date = March 2013 | pmid = 23362076 | doi = 10.1161/STROKEAHA.112.674614 | url = }}</ref><ref name="Al-Adawi1998">{{cite thesis | vauthors = Al-Adawi SH | title=The neuropsychopharmacology of motivation: an examination of reward and frontal-subcortical mechanisms and functions | date=1998 | url=https://www.researchgate.net/publication/34990547 | access-date=5 July 2024 }}</ref><ref name="MarinFogelHawkins1995">{{cite journal | vauthors = Marin RS, Fogel BS, Hawkins J, Duffy J, Krupp B | title = Apathy: a treatable syndrome | journal = J Neuropsychiatry Clin Neurosci | volume = 7 | issue = 1 | pages = 23–30 | date = 1995 | pmid = 7711487 | doi = 10.1176/jnp.7.1.23 | url = }}</ref><ref name="NewburnNewburn2005">{{cite journal | vauthors = Newburn G, Newburn D | title = Selegiline in the management of apathy following traumatic brain injury | journal = Brain Inj | volume = 19 | issue = 2 | pages = 149–154 | date = February 2005 | pmid = 15841758 | doi = 10.1080/02699050410001719989 | url = }}</ref><ref name="MoutaouakilElOtmaniFadel2009">{{cite journal | vauthors = Moutaouakil F, El Otmani H, Fadel H, Slassi I | title = Apathie sévère après un traumatisme crânien: évolution favorable sous Sélégiline | trans-title = Severe apathy following head injury: improvement with Selegiline treatment | language = French | journal = Neurochirurgie | volume = 55 | issue = 6 | pages = 551–554 | date = December 2009 | pmid = 19084243 | doi = 10.1016/j.neuchi.2008.10.009 | url = }}</ref> In accordance with the preceding findings, selegiline, along with other [[dopaminergic]] and [[stimulant|activating agents]], may be useful in the treatment of disorders of diminished motivation, including apathy, abulia, and [[akinetic mutism]].<ref name="CallaghanRouineOMara2018" /><ref name="MarinWilkosz2005">{{cite journal | vauthors = Marin RS, Wilkosz PA | title = Disorders of diminished motivation | journal = J Head Trauma Rehabil | volume = 20 | issue = 4 | pages = 377–88 | date = 2005 | pmid = 16030444 | doi = 10.1097/00001199-200507000-00009 | url = }}</ref><ref name="Al-Adawi1998" />

===Addiction===
Selegiline has been evaluated for [[smoking cessation]] both as a monotherapy and in combination with [[nicotine replacement therapy]] in five clinical studies.<ref name="DengShangGuo2023">{{cite journal | vauthors = Deng X, Shang X, Guo K, Zhou L, Wang Y, Wu Y, Liang S, E F, Liu W, Wang Z, Li X, Yang K | title = Efficacy and safety of antidepressants for smoking cessation: A systematic review and network meta-analysis | journal = Addict Biol | volume = 28 | issue = 8 | article-number = e13303 | date = August 2023 | pmid = 37500482 | doi = 10.1111/adb.13303 | url = }}</ref><ref name="HajizadehHowesTheodoulou2023">{{cite journal | vauthors = Hajizadeh A, Howes S, Theodoulou A, Klemperer E, Hartmann-Boyce J, Livingstone-Banks J, Lindson N | title = Antidepressants for smoking cessation | journal = Cochrane Database Syst Rev | volume = 2023 | issue = 5 | article-number = CD000031 | date = May 2023 | pmid = 37230961 | pmc = 10207863 | doi = 10.1002/14651858.CD000031.pub6 | url = }}</ref><ref name="RossanoCaiazzaSobrino2023" /> However, it is limitedly or not effective for this use.<ref name="DengShangGuo2023" /><ref name="HajizadehHowesTheodoulou2023" /><ref name="RossanoCaiazzaSobrino2023" /> It was also evaluated for treatment of [[cocaine dependence]] in one study, but was similarly not effective.<ref name="CastellsCasasPérez-Mañá2010">{{cite journal | vauthors = Castells X, Casas M, Pérez-Mañá C, Roncero C, Vidal X, Capellà D | veditors = Castells X | title = Efficacy of psychostimulant drugs for cocaine dependence | journal = Cochrane Database Syst Rev | volume = | issue = 2 | article-number = CD007380 | date = February 2010 | pmid = 20166094 | doi = 10.1002/14651858.CD007380.pub3 | url = }}</ref> Studies are mixed on whether selegiline, at MAO-B-selective doses, reduces the effects of cocaine in humans.<ref name="Finberg2014" /><ref name="HoutsmullerNotesNewton2004" /><ref name="BartzokisBecksonNewton1999" /><ref name="HabernyWalshGinn1995" /><ref name="HarrisEverhartJacob2009" /><ref name="NewtonKalechsteinBeckson1999" /> Selegiline, also at an MAO-B-selective dosage, did not modify or potentiate the pharmacological effects of [[intravenous administration|intravenous]] [[methamphetamine]] in a small clinical study.<ref name="ElkashefVocciHanson2008" /><ref name="NewtonDeLaGarzaFong2005" />

===Sexual dysfunction===
Selegiline has been assessed for treatment of [[sexual dysfunction]] induced by [[antipsychotic]]s in people with [[schizophrenia]], but was not effective in a single small clinical study.<ref name="CostaLimaMariJde2006">{{cite journal | vauthors = Costa AM, Lima MS, Mari Jde J | title = A systematic review on clinical management of antipsychotic-induced sexual dysfunction in schizophrenia | journal = Sao Paulo Med J | volume = 124 | issue = 5 | pages = 291–297 | date = September 2006 | pmid = 17262163 | doi = 10.1590/s1516-31802006000500012 | pmc = 11068300 | url = }}</ref><ref name="SchmidtHagenKriston2012">{{cite journal | vauthors = Schmidt HM, Hagen M, Kriston L, Soares-Weiser K, Maayan N, Berner MM | title = Management of sexual dysfunction due to antipsychotic drug therapy | journal = Cochrane Database Syst Rev | volume = 2012 | issue = 11 | article-number = CD003546 | date = November 2012 | pmid = 23152218 | pmc = 7003677 | doi = 10.1002/14651858.CD003546.pub3 | url = }}</ref> It also did not improve sexual function in men with depression, but did improve several domains of sexual function in women with depression.<ref name="ClaytonCampbellFavit2007" />

===Psychosis===
Selegiline has been studied as an [[adjunct therapy|adjunct]] to [[antipsychotic]]s in the treatment of [[schizophrenia]] in four clinical studies.<ref name="RossanoCaiazzaSobrino2023" /><ref name="MurphyChungPark2006">{{cite journal | vauthors = Murphy BP, Chung YC, Park TW, McGorry PD | title = Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review | journal = Schizophr Res | volume = 88 | issue = 1–3 | pages = 5–25 | date = December 2006 | pmid = 16930948 | doi = 10.1016/j.schres.2006.07.002 | url = }}</ref> However, it failed to significantly reduce [[Schizophrenia#Positive symptoms|positive]] or [[Schizophrenia#Negative symptoms|negative symptoms]] of schizophrenia in [[meta-analysis|meta-analyses]] of these studies.<ref name="RossanoCaiazzaSobrino2023" /><ref name="MurphyChungPark2006" />

===Excessive sleepiness===
Selegiline has been evaluated for the treatment of [[narcolepsy]] in three small clinical studies.<ref name="MaskiTrottiKotagal2021">{{cite journal | vauthors = Maski K, Trotti LM, Kotagal S, Robert Auger R, Swick TJ, Rowley JA, Hashmi SD, Watson NF | title = Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment | journal = J Clin Sleep Med | volume = 17 | issue = 9 | pages = 1895–1945 | date = September 2021 | pmid = 34743790 | pmc = 8636345 | doi = 10.5664/jcsm.9326 | url = }}</ref><ref name="NishinoKotorii2016">{{cite book | vauthors = Nishino S, Kotorii N | title=Narcolepsy: A Clinical Guide | edition=2 | chapter=Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics | publisher=Springer International Publishing | publication-place=Cham | date=2016 | isbn=978-3-319-23738-1 | doi=10.1007/978-3-319-23739-8_22 | pages=307–329 | url = https://www.researchgate.net/publication/314626865 }}</ref><ref name="NishinoArrigoniKanbayashi1996">{{cite journal | vauthors = Nishino S, Arrigoni J, Kanbayashi T, Dement WC, Mignot E | title = Comparative effects of MAO-A and MAO-B selective inhibitors on canine cataplexy | date = 1996 | journal = Sleep Res | volume = 25 | page = 315 | url = https://scholar.google.com/scholar?cluster=5131594531799950229}}</ref> It was found to be effective in these studies.<ref name="MaskiTrottiKotagal2021" /><ref name="NishinoKotorii2016" /> A dosage of 10{{nbsp}}mg/day had no effect on symptoms, but 20 to 30{{nbsp}}mg/day improved [[alertness]], [[mood (psychology)|mood]], and somewhat reduced [[cataplexy]], clinical effects that have been described as comparable to the same dosages of [[amphetamine]].<ref name="NishinoKotorii2016" /> [[Animal research]] indicates that the beneficial effects of high doses of selegiline in narcolepsy are likely due to conversion into its [[active metabolite]]s, [[levoamphetamine]] and [[levomethamphetamine]].<ref name="NishinoKotorii2016" /><ref name="NishinoArrigoniKanbayashi1996" /> Selegiline has also been evaluated for treatment of [[hypersomnia]] (excessive sleeping or sleepiness) in people with [[myotonic dystrophy]], but its effectiveness was very uncertain.<ref>{{cite journal | vauthors = Annane D, Laberge L, Gallais B, Chevret S | title = Psychostimulants for hypersomnia (excessive daytime sleepiness) in myotonic dystrophy | journal = The Cochrane Database of Systematic Reviews | volume = 2024 | issue = 11 | article-number = CD003218 | date = November 2024 | pmid = 39555632 | pmc = 11571272 | doi = 10.1002/14651858.CD003218.pub3 }}</ref><ref name="MaskiTrottiKotagal2021" />

===Periodic limb movement disorder===
Selegiline has been studied in the treatment of [[periodic limb movement disorder]] (PLMD) in a single small [[open-label study|open-label]] clinical study.<ref name="YehSpruytDelRosso2023">{{cite journal | vauthors = Yeh PG, Spruyt K, DelRosso LM, Walters AS | title = A Narrative Review of the Lesser Known Medications for Treatment of Restless Legs Syndrome and Pathogenetic Implications for Their Use | journal = Tremor Other Hyperkinet Mov (N Y) | volume = 13 | issue = | article-number = 7 | date = 2023 | pmid = 36873914 | pmc = 9983500 | doi = 10.5334/tohm.739 | doi-access = free | url = }}</ref><ref name="AuroraKristoBista2012">{{cite journal | vauthors = Aurora RN, Kristo DA, Bista SR, Rowley JA, Zak RS, Casey KR, Lamm CI, Tracy SL, Rosenberg RS | title = The treatment of restless legs syndrome and periodic limb movement disorder in adults--an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline | journal = Sleep | volume = 35 | issue = 8 | pages = 1039–1062 | date = August 2012 | pmid = 22851801 | pmc = 3397811 | doi = 10.5665/sleep.1988 | url = }}</ref><ref name="GrewalHawaShapiro2002">{{cite journal | vauthors = Grewal M, Hawa R, Shapiro C | title = Treatment of periodic limb movements in sleep with selegiline HCl | journal = Mov Disord | volume = 17 | issue = 2 | pages = 398–401 | date = March 2002 | pmid = 11921131 | doi = 10.1002/mds.10082 | url = }}</ref> It was reported to be effective as assessed by [[polysomnography]], reducing periodic limb movements during sleep by about 60%.<ref name="YehSpruytDelRosso2023" /><ref name="GrewalHawaShapiro2002" /> Selegiline has not been studied for the related condition [[restless legs syndrome]] (RLS) as of 2023.<ref name="YehSpruytDelRosso2023" /><ref name="AuroraKristoBista2012" /> The drug has not been studied well enough in PLMD or RLS to be widely used in their treatment.<ref name="YehSpruytDelRosso2023" />

===Tardive dyskinedia===
Selegiline was studied in the treatment of [[antipsychotic]]-induced [[tardive dyskinesia]] in one small clinical study, but was ineffective.<ref name="Soares-WeiserRathboneOgawa2018">{{cite journal | vauthors = Soares-Weiser K, Rathbone J, Ogawa Y, Shinohara K, Bergman H | title = Miscellaneous treatments for antipsychotic-induced tardive dyskinesia | journal = Cochrane Database Syst Rev | volume = 2018 | issue = 3 | article-number = CD000208 | date = March 2018 | pmid = 29552749 | pmc = 6494382 | doi = 10.1002/14651858.CD000208.pub2 | url = }}</ref>

===Dementia and stroke===
Selegiline has also been used [[off-label use|off-label]] as a palliative treatment for [[dementia]] in [[Alzheimer's disease]].<ref name="Drugs.com-Mono" /> However, its clinical effectiveness is limited or lacking for this use.<ref name="WilcockBirksWhitehead2002">{{cite journal | vauthors = Wilcock GK, Birks J, Whitehead A, Evans SJ | title = The effect of selegiline in the treatment of people with Alzheimer's disease: a meta-analysis of published trials | journal = Int J Geriatr Psychiatry | volume = 17 | issue = 2 | pages = 175–183 | date = February 2002 | pmid = 11813282 | doi = 10.1002/gps.545 | url = }}</ref><ref name="BirksFlicker2003">{{cite journal | vauthors = Birks J, Flicker L | title = Selegiline for Alzheimer's disease | journal = Cochrane Database Syst Rev | volume = | issue = 1 | article-number = CD000442 | date = 2003 | pmid = 12535396 | doi = 10.1002/14651858.CD000442 | url = }}</ref><ref name="SandersRajagopal2020">{{cite journal | vauthors = Sanders O, Rajagopal L | title = Phosphodiesterase Inhibitors for Alzheimer's Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale | journal = J Alzheimers Dis Rep | volume = 4 | issue = 1 | pages = 185–215 | date = June 2020 | pmid = 32715279 | pmc = 7369141 | doi = 10.3233/ADR-200191 | url = }}</ref><ref name="LaverDyerWhitehead2016">{{cite journal | vauthors = Laver K, Dyer S, Whitehead C, Clemson L, Crotty M | title = Interventions to delay functional decline in people with dementia: a systematic review of systematic reviews | journal = BMJ Open | volume = 6 | issue = 4 | article-number = e010767 | date = April 2016 | pmid = 27121704 | pmc = 4854009 | doi = 10.1136/bmjopen-2015-010767 | url = }}</ref> It was also ineffective in the treatment of [[Lewy body dementia]].<ref name="StintonMcKeithTaylor2015">{{cite journal | vauthors = Stinton C, McKeith I, Taylor JP, Lafortune L, Mioshi E, Mak E, Cambridge V, Mason J, Thomas A, O'Brien JT | title = Pharmacological Management of Lewy Body Dementia: A Systematic Review and Meta-Analysis | journal = Am J Psychiatry | volume = 172 | issue = 8 | pages = 731–742 | date = August 2015 | pmid = 26085043 | doi = 10.1176/appi.ajp.2015.14121582 | url = https://www.repository.cam.ac.uk/handle/1810/253094}}</ref> Selegiline has been used to support motor rehabilitation in [[stroke recovery]], but evidence for this use is inadequate and no recommendation can be made for or against it.<ref name="BeghiBinderBirle2021">{{cite journal | vauthors = Beghi E, Binder H, Birle C, Bornstein N, Diserens K, Groppa S, Homberg V, Lisnic V, Pugliatti M, Randall G, Saltuari L, Strilciuc S, Vester J, Muresanu D | title = European Academy of Neurology and European Federation of Neurorehabilitation Societies guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke | journal = Eur J Neurol | volume = 28 | issue = 9 | pages = 2831–2845 | date = September 2021 | pmid = 34152062 | doi = 10.1111/ene.14936 }}</ref>

===Disorders of consciousness===
Selegiline has been studied in patients with [[disorders of consciousness]], such as [[minimally conscious state]], [[persistent vegetative state]], and persistent [[coma]], in a small [[open-label trial|open-label]] clinical study.<ref name="SzymkowiczAlnaggerSeyfzadehdarabad2023">{{cite book | vauthors = Szymkowicz E, Alnagger N, Seyfzadehdarabad F, Cardone P, Whyte J, Gosseries O | title=Coma and Disorders of Consciousness | edition=3 | chapter=Pharmacological Treatments | publisher=Springer International Publishing | publication-place=Cham | date=2023 | isbn=978-3-031-50562-1 | doi=10.1007/978-3-031-50563-8_7 | pages=115–146 }}</ref><ref name="MasottaTrojanoLoreto2018">{{cite journal | vauthors = Masotta O, Trojano L, Loreto V, Moretta P, Estraneo A | title = Selegiline in Patients With Disorder of Consciousness: An Open Pilot Study | journal = Can J Neurol Sci | volume = 45 | issue = 6 | pages = 688–691 | date = November 2018 | pmid = 30430963 | doi = 10.1017/cjn.2018.315 | url = }}</ref> It was found to be effective in enhancing [[arousal]] and promoting recovery of [[consciousness]] in some of these individuals.<ref name="SzymkowiczAlnaggerSeyfzadehdarabad2023" /><ref name="MasottaTrojanoLoreto2018" />

===Neurotoxicity===
Selegiline has been reported to protect against the damage caused by the potent [[dopaminergic]] and/or [[noradrenergic]] [[neurotoxin]]s [[6-hydroxydopamine]] (6-OHDA), [[DSP-4|''N''-(2-chloroethyl)-''N''-ethyl-2-bromobenzylamine]] (DSP-4), and [[1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]] (MPTP) in animals.<ref name="Knoll1989">{{cite journal | vauthors = Knoll J | title = The pharmacology of selegiline ((-)deprenyl). New aspects | journal = Acta Neurologica Scandinavica. Supplementum | volume = 126 | issue =  | pages = 83–91 | date = 1989 | pmid = 2515725 | doi = 10.1111/j.1600-0404.1989.tb01787.x | doi-access = free }}</ref><ref name="HeinonenLammintausta1991" /><ref name="EbadiSharmaShavali2002">{{cite journal | vauthors = Ebadi M, Sharma S, Shavali S, El Refaey H | title = Neuroprotective actions of selegiline | journal = Journal of Neuroscience Research | volume = 67 | issue = 3 | pages = 285–289 | date = February 2002 | pmid = 11813232 | doi = 10.1002/jnr.10148 }}</ref><ref name="Bentué-FerrerMénardAllain1996" /><ref name="Knoll1978">{{cite journal | vauthors = Knoll J | title = The possible mechanisms of action of (-)deprenyl in Parkinson's disease | journal = Journal of Neural Transmission | volume = 43 | issue = 3–4 | pages = 177–198 | date = 1978 | pmid = 745011 | doi = 10.1007/BF01246955 }}</ref><ref name="CohenPasikCohen1984">{{cite journal | vauthors = Cohen G, Pasik P, Cohen B, Leist A, Mytilineou C, Yahr MD | title = Pargyline and deprenyl prevent the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys | journal = European Journal of Pharmacology | volume = 106 | issue = 1 | pages = 209–210 | date = October 1984 | pmid = 6442232 | doi = 10.1016/0014-2999(84)90700-3 }}</ref> Conversely, selegiline is ineffective in protecting against the [[serotonin|serotonergic]] and noradrenergic neurotoxin [[5,7-dihydroxytryptamine]] (5,7-DHT).<ref name="HeinonenLammintausta1991" /><ref name="FinneganDeLanneyIrwin1989">{{cite journal | vauthors = Finnegan KT, DeLanney LE, Irwin I, Ricaurte GA, Langston JW | title = The amine-depleting effects of 5,7-dihydroxytryptamine (5,7-DHT) in C57BL/6 mice do not increase with age | journal = Brain Research | volume = 496 | issue = 1–2 | pages = 251–256 | date = September 1989 | pmid = 2804634 | doi = 10.1016/0006-8993(89)91072-x }}</ref>

Selegiline has also been reported to protect against [[methylenedioxymethamphetamine]] (MDMA)-induced serotonergic [[neurotoxicity]] in rodents.<ref name="MoratallaKhairnarSimola2017">{{cite journal | vauthors = Moratalla R, Khairnar A, Simola N, Granado N, García-Montes JR, Porceddu PF, Tizabi Y, Costa G, Morelli M | title = Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms | journal = Prog Neurobiol | volume = 155 | issue = | pages = 149–170 | date = August 2017 | pmid = 26455459 | doi = 10.1016/j.pneurobio.2015.09.011 | hdl = 10261/156486 | url =| hdl-access = free }}</ref><ref name="PuertaAguirre2011">{{cite journal | vauthors = Puerta E, Aguirre N | title=Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation | journal=Pharmaceuticals | volume=4 | issue=7 | pages=992–1018 | date=5 July 2011 | issn=1424-8247 | pmc=4058674 | doi=10.3390/ph4070992 | doi-access = free }}</ref><ref name="SpragueNichols1995a">{{cite journal | vauthors = Sprague JE, Nichols DE | title = Inhibition of MAO-B protects against MDMA-induced neurotoxicity in the striatum | journal = Psychopharmacology | volume = 118 | issue = 3 | pages = 357–359 | date = April 1995 | pmid = 7542394 | doi = 10.1007/BF02245967 }}</ref><ref name="SpragueNichols1995b">{{cite journal | vauthors = Sprague JE, Nichols DE | title = The monoamine oxidase-B inhibitor L-deprenyl protects against 3,4-methylenedioxymethamphetamine-induced lipid peroxidation and long-term serotonergic deficits | journal = J Pharmacol Exp Ther | volume = 273 | issue = 2 | pages = 667–673 | date = May 1995 | pmid = 7538579 | doi = 10.1016/S0022-3565(25)09490-X| url = }}</ref><ref name="AlvesSummavielleAlves2007">{{cite journal | vauthors = Alves E, Summavielle T, Alves CJ, Gomes-da-Silva J, Barata JC, Fernandes E, Bastos Mde L, Tavares MA, Carvalho F | title = Monoamine oxidase-B mediates ecstasy-induced neurotoxic effects to adolescent rat brain mitochondria | journal = J Neurosci | volume = 27 | issue = 38 | pages = 10203–10210 | date = September 2007 | pmid = 17881526 | pmc = 6672671 | doi = 10.1523/JNEUROSCI.2645-07.2007 | url = }}</ref> The serotonergic neurotoxicity of MDMA appears to be dependent on release of dopamine and its subsequent metabolism by MAO-B within serotonergic neurons into [[hydroxyl radical]]s, which is blocked by MAO-B inhibition.<ref name="MoratallaKhairnarSimola2017" /><ref name="PuertaAguirre2011" /> Likewise, selegiline prevented the serotonergic neurotoxicity of a combination of [[methylenedioxyaminoindane]] (MDAI) and [[dextroamphetamine]].<ref name="CorkeryElliottSchifano2013">{{cite journal | vauthors = Corkery JM, Elliott S, Schifano F, Corazza O, Ghodse AH | title = MDAI (5,6-methylenedioxy-2-aminoindane; 6,7-dihydro-5H-cyclopenta[f] [1,3]benzodioxol-6-amine; 'sparkle'; 'mindy') toxicity: a brief overview and update | journal = Hum Psychopharmacol | volume = 28 | issue = 4 | pages = 345–355 | date = July 2013 | pmid = 23881883 | doi = 10.1002/hup.2298 | url = }}</ref><ref name="JohnsonHuangNichols1991">{{cite journal | vauthors = Johnson MP, Huang XM, Nichols DE | title = Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue | journal = Pharmacol Biochem Behav | volume = 40 | issue = 4 | pages = 915–922 | date = December 1991 | pmid = 1726189 | doi = 10.1016/0091-3057(91)90106-c | url = }}</ref>

Conversely, selegiline failed to reduce the serotonergic neurotoxicity caused by [[fenfluramine]] and either did not affect or potentiated the serotonergic neurotoxicity caused by [[para-chloroamphetamine|''para''-chloroamphetamine]] (PCA).<ref name="Bentué-FerrerMénardAllain1996">{{cite journal | vauthors = Bentué-Ferrer D, Ménard G, Allain H | title=Monoamine Oxidase B Inhibitors: Current Status and Future Potential | journal=CNS Drugs | volume=6 | issue=3 | date=1996 | issn=1172-7047 | doi=10.2165/00023210-199606030-00005 | pages=217–236 }}</ref><ref name="HalladayKirschnerHesse2001">{{cite journal | vauthors = Halladay AK, Kirschner E, Hesse K, Fisher H, Wagner GC | title = Role of monoamine oxidase inhibition and monoamine depletion in fenfluramine-induced neurotoxicity and serotonin release | journal = Pharmacol Toxicol | volume = 89 | issue = 5 | pages = 237–248 | date = November 2001 | pmid = 11881977 | doi = 10.1034/j.1600-0773.2001.d01-154.x | doi-broken-date = August 21, 2025 | url = }}</ref><ref name="BenmansourBrunswick1994">{{cite journal | vauthors = Benmansour S, Brunswick DJ | title = The MAO-B inhibitor deprenyl, but not the MAO-A inhibitor clorgyline, potentiates the neurotoxicity of p-chloroamphetamine | journal = Brain Res | volume = 650 | issue = 2 | pages = 305–312 | date = July 1994 | pmid = 7953696 | doi = 10.1016/0006-8993(94)91796-5 | url = }}</ref><ref name="SpragueJohnsonSchmidt1996">{{cite journal | vauthors = Sprague JE, Johnson MP, Schmidt CJ, Nichols DE | title = Studies on the mechanism of p-chloroamphetamine neurotoxicity | journal = Biochem Pharmacol | volume = 52 | issue = 8 | pages = 1271–1277 | date = October 1996 | pmid = 8937435 | doi = 10.1016/0006-2952(96)00482-0 | url = }}</ref> In addition, findings are mixed and conflicting on whether selegiline prevents [[amphetamine]]- and [[methamphetamine]]-induced dopaminergic neurotoxicity in rodents.<ref name="GoldbergYasar1997">{{cite book | vauthors = Goldberg SR, Yasar S | title=Neurochemistry: Cellular, Molecular, and Clinical Aspects | chapter=Methamphetamine Administration and Associated Neurotoxicity: Effects of Selegiline (l-Deprenyl) | publisher=Springer US | publication-place=Boston, MA | date=1997 | isbn=978-1-4613-7468-8 | doi=10.1007/978-1-4615-5405-9_55 | pages=327–330}}</ref><ref name="WanShiahLin2000">{{cite journal | vauthors = Wan FJ, Shiah IS, Lin HC, Huang SY, Tung CS | title = Nomifensine attenuates d-amphetamine-induced dopamine terminal neurotoxicity in the striatum of rats | journal = Chin J Physiol | volume = 43 | issue = 2 | pages = 69–74 | date = June 2000 | pmid = 10994696 | doi = | url = }}</ref><ref name="GrasingAzevedoKaruppan2001">{{cite journal | vauthors = Grasing K, Azevedo R, Karuppan S, Ghosh S | title = Biphasic effects of selegiline on striatal dopamine: lack of effect on methamphetamine-induced dopamine depletion | journal = Neurochem Res | volume = 26 | issue = 1 | pages = 65–74 | date = January 2001 | pmid = 11358284 | doi = 10.1023/a:1007632700126 | url = }}</ref><ref name="DavidsonChenZhang2007">{{cite journal | vauthors = Davidson C, Chen Q, Zhang X, Xiong X, Lazarus C, Lee TH, Ellinwood EH | title = Deprenyl treatment attenuates long-term pre- and post-synaptic changes evoked by chronic methamphetamine | journal = Eur J Pharmacol | volume = 573 | issue = 1–3 | pages = 100–110 | date = November 2007 | pmid = 17651730 | doi = 10.1016/j.ejphar.2007.06.046 | url = }}</ref>

Although MAO-B-selective doses of selegiline protect against MDMA-induced serotonergic neurotoxicity in rodents, combination of [[amphetamine-type stimulant|amphetamine]]s like MDMA with MAOIs, including selegiline, can produce serious complications, including [[serotonin syndrome]], [[hypertensive crisis]], and death.<ref name="CarvalhoCarmoCosta2012">{{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 = 1167–231 | date = August 2012 | pmid = 22392347 | doi = 10.1007/s00204-012-0815-5 | bibcode = 2012ArTox..86.1167C | url =  }}</ref><ref name="EdinoffSwinfordOdisho2022">{{cite journal | vauthors = Edinoff AN, Swinford CR, Odisho AS, Burroughs CR, Stark CW, Raslan WA, Cornett EM, Kaye AM, Kaye AD | title = Clinically Relevant Drug Interactions with Monoamine Oxidase Inhibitors | journal = Health Psychol Res | volume = 10 | issue = 4 | article-number = 39576 | date = 2022 | pmid = 36425231 | pmc = 9680847 | doi = 10.52965/001c.39576 | url = }}</ref>

===Other formulations===
The original oral formulation of selegiline was developed for the treatment of [[depression (mood)|depression]].<ref name="Knoll2001" /> However, it ended up being developed and approved for the treatment of [[Parkinson's disease]] instead.<ref name="Knoll2001" /><ref name="TábiVécseiYoudim2020" /><ref name="PillLabel" /> In any case, oral selegiline has been widely used [[off-label use|off-label]] to treat depression.<ref name="RossanoCaiazzaSobrino2023" /> The transdermal patch form of selegiline was developed and approved specifically for the treatment of depression.<ref name="AdisInsight-Patch">{{cite web | title=Selegiline transdermal (Emsam) - Somerset Pharmaceuticals | website=AdisInsight | date=5 November 2023 | url=https://adisinsight.springer.com/drugs/800013559 | access-date=15 July 2024}}</ref><ref name="PaeLimHan2007" /><ref name="LeeChen2007" /><ref name="PatchLabel" /> It was also under development for the treatment of [[Alzheimer's disease]], [[attention deficit hyperactivity disorder]] (ADHD), [[cognition disorder]]s, and Parkinson's disease, but development for these indications was discontinued.<ref name="AdisInsight-Patch" /> The ODT form of selegiline was developed and licensed exclusively for the treatment of Parkinson's disease.<ref name="AdisInsight-ODT">{{cite web | title=Selegiline orally disintegrating tablet (Efupi; FPF 1100 NW) - FP Pharmaceutical | website=AdisInsight | date=3 June 2016 | url=https://adisinsight.springer.com/drugs/800045473 | access-date=15 July 2024}}</ref><ref name="PostonWaters2007" /><ref name="ODTLabel" />

==Veterinary use==
In [[veterinary medicine]], selegiline is sold under the brand name Anipryl and is manufactured by [[Zoetis]].<ref name="BruyetteRuehlEntriken1997">{{cite journal | vauthors = Bruyette DS, Ruehl WW, Entriken T, Griffin D, Darling L | title = Management of canine pituitary-dependent hyperadrenocorticism with l-deprenyl (Anipryl) | journal = Vet Clin North Am Small Anim Pract | volume = 27 | issue = 2 | pages = 273–286 | date = March 1997 | pmid = 9076907 | doi = 10.1016/s0195-5616(97)50031-3 | url = }}</ref> It is available in the form of 2, 5, 10, 15, and 30{{nbsp}}mg [[oral administration|oral]] [[tablet (pharmacy)|tablet]]s for use in animals.<ref name="BruyetteRuehlEntriken1997" /> Selegiline is used in [[dogs]] to treat [[canine cognitive dysfunction]] (CCD) and, at higher doses, to treat [[Cushing's syndrome|pituitary-dependent hyperadrenocorticism]] (PDH).<ref name="BraddockChurchRobertson2004">{{cite web|url=http://www.lloydinc.com/pdfs/Endocrinology/Vol14_issue3_2004.pdf|title=Selegiline Treatment of Canine Pituitary-Dependent Hyperadrenocorticism|vauthors=Braddock JA, Church DB, Robertson ID|year=2004|publisher=Australian Veterinary Journal|access-date=April 8, 2011|archive-url=https://web.archive.org/web/20101129015812/http://www.lloydinc.com/pdfs/Endocrinology/Vol14_issue3_2004.pdf|archive-date=November 29, 2010}} ([[PDF]])</ref><ref name="Eghianruwa2014">{{cite book|url=https://books.google.com/books?id=CtfIAgAAQBAJ&pg=PA127|title=Essential Drug Data for Rational Therapy in Veterinary Practice| vauthors = Eghianruwa K |publisher=AuthorHouse|year=2014|isbn=978-1-4918-0010-2|pages=127–128}}</ref>

CCD is a form of [[dementia]] that mimics [[Alzheimer's disease]] in humans.<ref name="PrparMihevcMajdič2019">{{cite journal | vauthors = Prpar Mihevc S, Majdič G | title = Canine Cognitive Dysfunction and Alzheimer's Disease - Two Facets of the Same Disease? | journal = Front Neurosci | volume = 13 | issue = | article-number = 604 | date = 2019 | pmid = 31249505 | pmc = 6582309 | doi = 10.3389/fnins.2019.00604 | doi-access = free | url = }}</ref> [[Geriatric]] dogs treated with selegiline show improvements in [[sleep|sleeping pattern]], reduced [[urinary incontinence]], and increased [[locomotor activity|activity level]], with most showing improvements by one month of treatment.<ref name="Drugs.com-Vet">{{cite web|url=https://www.drugs.com/vet/anipryl-tablets.html|title=Anipryl Tablets for Animal Use|work=Drugs.com|access-date=August 31, 2017}}</ref><ref name="Lundgren2013">{{cite web|url=http://www.veterinarypartner.com/Content.plx?P=A&A=2549|title=Canine Cognitive Dysfunction| vauthors = Lundgren B |publisher=Veterinary Partner|access-date=April 8, 2011}}</ref> Though it is labeled for use in dogs only, selegiline has been used [[off-label use|off-label]] for geriatric [[cats]] with [[cognitive dysfunction]].<ref name="RivierePapich2013">{{cite book|url=https://books.google.com/books?id=xAPa4WDzAnQC&pg=PA530|title=Veterinary Pharmacology and Therapeutics| vauthors = Riviere JE, Papich MG |publisher=John Wiley & Sons|year=2013|isbn=978-1-118-68590-7|page=530}}</ref>

PDH is a [[hormonal disorder]] and is analogous to [[pituitary gland|pituitary]]-dependent [[Cushing's syndrome]] in humans.<ref name="BruyetteRuehlEntriken1997" /> Selegiline's effectiveness in treating PDH has been disputed.<ref name="BraddockChurchRobertson2004" /> Theoretically, it works by increasing [[dopamine]] levels, which [[downregulation|downregulates]] the [[secretion]] of [[adrenocorticotropic hormone]] (ACTH) from the [[brain]], eventually leading to reduced levels of [[cortisol]].<ref name="RivierePapich2013" /> Some claim that selegiline is only effective at treating PDH caused by [[lesion]]s in the [[anterior pituitary]] (which comprise most canine cases).<ref name="Papich2015">{{cite book|url=https://books.google.com/books?id=ip8_CwAAQBAJ&pg=PA722|title=Saunders Handbook of Veterinary Drugs: Small and Large Animal| vauthors = Papich MG |publisher=Elsevier Health Sciences|year=2015|isbn=978-0-323-24485-5|page=722}}</ref> The greatest sign of improvement is lessening of PDH-related [[abdominal distention]].<ref name="Drugs.com-Vet" />

[[Side effect]]s in dogs are uncommon, but they include [[vomiting]], [[diarrhea]], [[hearing loss|diminished hearing]], [[salivation]], [[weight loss|decreased weight]], and [[behavior|behavioral changes]] such as [[hyperactivity]], [[listlessness]], [[disorientation]], and [[stereotypy|repetitive motions]].<ref name="Eghianruwa2014" /><ref name="Papich2015" />

Selegiline has been limitedly studied in large animals like [[horse]]s and its dosage in these animals has not been established.<ref name="Papich2015" /> In preliminary research, a dose of selegiline of 30{{nbsp}}mg orally or [[intravenous injection|intravenously]] in horses had no observable effects on behavior or locomotor activity.<ref name="Papich2015" />

The doses of selegiline used in animals are described as extremely high relative to those used in humans (which are ~0.1{{nbsp}}mg/kg body weight).<ref name="KalászMagyarSzőke2014" />

==References==
{{Reflist}}

==External links==
* [https://www.selegiline.com/ Selegiline (l-deprenyl) (from The Good Drug Guide) - David Pearce - BLTC Research]

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