Deprenyl was discovered and studied as an antidepressant in the early 1960s by Zoltan Ecseri,József Knoll, and other colleagues atChinoin Pharmaceutical Company inHungary.[44][23] Subsequently, selegiline waspurified from deprenyl and was studied and developed itself.[44] Selegiline was first introduced for medical use, to treat Parkinson's disease, in Hungary in 1977.[45] It was subsequently approved in theUnited Kingdom in 1982 and in theUnited States in 1989.[45][46] The ODT was approved for Parkinson's disease in the United States in 2006 and in theEuropean Union in 2010, while the patch was introduced for depression in the United States in 2006.[45][23] Selegiline was the first selective MAO-B inhibitor to be discovered and marketed.[13][47][48] In addition to its medical use, there has been interest in selegiline as a potentialanti-aging drug andnootropic.[49][50][51] However, effects of this sort are controversial and uncertain.[49][52][53][54]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.[55][56]
Selegiline is used as anantidepressant in the treatment ofmajor depressive disorder (MDD).[8][24] Both the oral selegiline and transdermal selegiline patch formulations are used in the treatment of depression.[24] However, oral selegiline is not approved for depression and is usedoff-label for this indication, while the transdermal patch is specifically licensed for treatment of depression.[4][8] Both standard clinical doses of oral selegiline (up to 10mg/day) and higher doses of oral selegiline (e.g., 30 to 60mg/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.[9][24] Unlike oral selegiline, transdermal selegiline bypassesfirst-pass metabolism, thereby avoiding inhibition ofgastrointestinal andhepatic MAO-A and minimizing the risk offood and drug interactions, whilst still allowing for selegiline to reach the brain and inhibit MAO-B.[9]
A 2023systematic review andmeta-analysis evaluated the effectiveness and safety of selegiline in the treatment ofpsychiatric disorders including depression.[24] It included both randomized and non-randomized published clinical studies.[24] The meta-analysis found that selegiline was more effective thanplacebo in terms of reduction in depressive symptoms (SMDTooltip standardized mean difference = −0.96, k = 10, n = 1,308),response rates for depression improvement (RRTooltip risk ratio = 1.61, k = 9, n = 1,238), and response rates for improvement of depression with atypical features (RR = 2.23, k = 3, n = 136).[24] Oral selegiline was significantly more effective than the selegiline patch in terms of depressive symptom improvement (SMD = −1.49, k = 6, n = 282 vs.SMD = −0.27, k = 4, n = 1,026, respectively; p = 0.03).[24] However, this was largely due to older and lessmethodologically rigorous trials that were at high risk forbias.[24] Oral selegiline studies also often employed much higher doses than usual, for instance 20 to 60mg/day.[24] Thequality of evidence of selegiline for depression was rated as very low overall, very low for oral selegiline, and low to moderate for transdermal selegiline.[24] For comparison, meta-analyses of other antidepressants for depression have found a meaneffect size of about 0.3 (a small effect),[26][64] which is similar to that with transdermal selegiline.[24]
In twopivotal regulatory clinical trials of 6 to 8weeks duration, the selegiline transdermal patch decreased scores ondepression rating scales (specifically the 17- and 28-itemHDRSTooltip Hamilton Depression Rating Scale) by 9.0 to 10.9points, whereas placebo decreased scores by 6.5 to 8.6points, giving placebo-subtracted differences attributable to selegiline of 2.4 to 2.5points.[8] A 2013quantitativereview of the transdermal selegiline patch for depression, which pooled the results of these two trials, found that the placebo-subtractednumber 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 theMADRSTooltip Montgomery–Åsberg Depression Rating Scale).[25] For comparison, other antidepressants, includingfluoxetine,paroxetine,duloxetine,vilazodone,adjunctivearipiprazole,olanzapine/fluoxetine, andextended-releasequetiapine, have NNTs ranging from 6 to 8 in terms of depression response and 7 to 14 in terms of depression remission.[25] On the basis of these results, it was concluded that transdermal selegiline has similar effectiveness to other antidepressants.[25][65] 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.[25] Lower NNTs are better, and NNTs corresponding toCohen'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).[25] The effectiveness of transdermal selegiline for depression relative toside effects anddiscontinuation was considered to be favorable.[25]
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.[56][65] Although multiple doses of transdermal selegiline were assessed, adose–response relationship for depression was never established.[56][65] Transdermal selegiline has shown similar clinical effectiveness in the treatment ofatypical depression relative to typical depression and in the treatment ofanxious depression relative to non-anxious depression.[56][66][65]
Transdermal selegiline patches have been underutilized in the treatment of depression compared to other antidepressants.[56][65] A variety of factors contributing to this underutilization have been identified.[56] One major factor is the very high cost of transdermal selegiline, which is often not covered byinsurance and frequently proves to be prohibitive.[56][65] Conversely, other widely available antidepressants are much cheaper in comparison.[56][65]
The transdermal patch form is also known as the "selegiline transdermal system" or "STS" and is applied once daily.[9][12][27][65][8] They are 20, 30, or 40cm2 in size and contain a total of 20, 30, or 40mg selegiline per patch (so 20mg/20cm2, 30mg/30cm2, and 40mg/40cm2), respectively.[8][65] The selegiline transdermal patch is amatrix-type adhesive patch with a three-layer structure.[8][65] It is the only approved non-oral MAOI, having reduceddietary restrictions andside effects in comparison to oral MAOIs, and is also the only approved non-oralfirst-line antidepressant.[65] The selegiline patch can be useful for those who have difficulty tolerating oral medications.[65]
Consumption oftyramine-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.[6][11][47][15] 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.[15]
The preceding drug and food contraindications are dependent on selegiline dose and route, and hence are not necessarily absolute contraindications.[4][6][5][7][9] While high oral doses of selegiline (≥20mg/day) can cause such interactions, oral doses within the approved clinical range (≤10mg/day) appear to have little to no risk of these interactions.[9][28][5] In addition, the ODT and transdermal forms of selegiline have reduced risks of such interactions compared to the conventional oral form.[7][9]
Selegiline is also contraindicated in children less than 12years of age and in people withpheochromocytoma, both due to heightened risk of hypertensive crisis.[8] For all human uses and all forms, selegiline ispregnancy category C, meaning that studies inpregnant animals have shown adverse effects on thefetus but there are no adequate studies in humans.[4][8]
Selegiline, including in its oral, ODT, and patch forms, has been found to causehypotension ororthostatic hypotension in some individuals.[4][6][8] 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.[6] The risk of hypotension is greater at the start of treatment and in the elderly (3% vs. 0% with placebo).[6] 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.[27] Significant orthostatic blood pressure changes (≥10mmHg decrease) occurred in 9.8% versus 6.7% with placebo, but most of these cases were asymptomatic andheart rate was unchanged.[27][71] The rates of other orthostatic hypotension-related side effects in this population weredizziness orvertigo 4.9% versus 3.1% with placebo andfainting 0.5% versus 0.0% with placebo.[27] It is said that orthostatic hypotension is rarely seen with the selegiline transdermal patch compared to oral MAOIs.[56] 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.[6][30][71]Falls are of particular concern in the elderly.[71] MAOIs like selegiline may lowerblood pressure by increasing dopamine levels and activatingdopamine receptors, by increasing levels of thefalse neurotransmitteroctopamine, and/or by other mechanisms.[72]
Meta-analyses published in the 1990s found that the addition of selegiline tolevodopa increasedmortality in people with Parkinson's disease.[30] However, several subsequent meta-analyses with more trials and patients found no increase in mortality with selegiline added to levodopa.[30][73][74] 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.[75] Although selegiline does not seem to increase mortality, it appears to worsencognition in people with Parkinson's disease over time.[76] Conversely, rasagiline does not seem to do so and can enhance cognition.[76]
All three forms of selegiline carry warnings aboutfood restrictions to avoid hypertensive crisis that are associated with MAOIs.[4][6][8] The patch form was created in part to overcome food restrictions; clinical trials showed that it was successful.[25][8] Additionally, inpost-marketing surveillance from April 2006 to October 2010, only 13self-reports of possiblehypertensive events or hypertension were made out of 29,141exposures to the drug, and none were accompanied by objective clinical data.[25] The lowest dose of the patch method of delivery, 6mg/24hours, does not require anydietary restrictions.[101] Higher doses of the patch and oral formulations, whether in combination with the older non-selective MAOIs or in combination with thereversible MAO-A inhibitor (RIMA)moclobemide, require a low-tyramine diet.[98]
A study found that selegiline in transdermal patch form did not importantly modify thepharmacodynamic effects orpharmacokinetics of thesympathomimetic agentspseudoephedrine andphenylpropanolamine.[9][102] Likewise, oral selegiline at an MAO-B-selective dosage did not appear to modify the pharmacodynamic effects or pharmacokinetics ofintravenousmethamphetamine in another study.[103][104] Conversely, selegiline, also at MAO-B-selective doses, has been found to reduce the physiological and euphoric subjective effects ofcocaine whilst not affecting its pharmacokinetics in some studies but not in others.[105][106][107][108][109][110] Cautious safe combination of MAOIs like selegiline withstimulants likelisdexamfetamine has been reported.[111][112][113] However, a hypertensive crisis with selegiline andephedrine has also been reported.[4] 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 monitoringblood pressure with such combinations.[6][8] The combination of selegiline with certain other medications, likephenylephrine andbuspirone, is also warned against for similar reasons.[8][12][114][71] In the case of phenylephrine, this drug is substantially metabolized by monoamine oxidase, including by bothMAO-A andMAO-B.[115][116] Selegiline can interact withexogenousdopamine, which is metabolized by MAO-A and MAO-B, and result in hypertensive crisis as well.[117][118]
Thecytochrome P450enzymes involved in the metabolism of selegiline have not been fully elucidated.[5][21]CYP2D6 andCYP2C19metabolizerphenotypes did not significantly affect thepharmacokinetics of selegiline, suggesting that these enzymes are minimally involved in its metabolism and thatinhibitors andinducers of these enzymes would not importantly affect its pharmacokinetics.[21][43][126][127] However, although most pharmacokinetic variables were unaffected,overall exposure to selegiline's metabolitelevomethamphetamine was 46% higher in CYP2D6poor metabolizers compared toextensive metabolizers and exposure to its metabolitedesmethylselegiline was 68% higher in CYP2C19 poor metabolizers compared to extensive metabolizers.[43][126][127] As with the cases of CYP2D6 and CYP2C19, the strongCYP3A4 andCYP3A5 inhibitoritraconazole has minimal impact on the pharmacokinetics of selegiline, suggesting lack of major involvement of this enzyme as well.[21][128][6] On the other hand, theanticonvulsantcarbamazepine, which is known to act as a strong inducer of CYP3A enzymes,[129] has paradoxically been found to increase exposure to selegiline and its metabolites levomethamphetamine andlevoamphetamine by approximately 2-fold (with selegiline used as the transdermal patch form).[8][9] One enzyme thought to be majorly involved in the metabolism of selegiline based onin-vitro studies isCYP2B6.[5][21][9][22] However, there are no clinical studies of different CYP2B6 metabolizer phenotypes or of CYP2B6 inhibitors or inducers on the pharmacokinetics of selegiline.[47] In addition to CYP2B6,CYP2A6 may be involved in the metabolism of selegiline to a lesser extent.[47][130]
Birth control pills containing thesyntheticestrogenethinylestradiol and aprogestin likegestodene orlevonorgestrel have been found to increasepeak levels and overall exposure to oral selegiline by 10- to 20-fold.[21][131][132] High levels of selegiline can lead to loss of MAO-B selectivity and inhibition of MAO-A as well.[21][132] This increases susceptibility to side effects and interactions of non-selectivemonoamine oxidase inhibitors (MAOIs), such astyramine-inducedhypertensive crisis and serotonin toxicity when combined withserotonergic medications.[21][132] However, this study had a smallsample size of four individuals as well as othermethodological limitations.[21][132] The precise mechanism underlying the interaction is unknown, but is likely related to cytochrome P450 inhibition and consequent inhibition of selegilinefirst-pass metabolism by ethinylestradiol.[21] In contrast to birth control pills containing ethinylestradiol,menopausal hormone therapy withestradiol and levonorgestrel did not modify peak levels of selegiline and only modestly increased overall exposure (+59%).[21][131][133] Hence, menopausal hormone therapy does not pose the same risk of interaction as ethinylestradiol-containing birth control pills when taken together with selegiline.[131][133]
Overall exposure to selegiline with oral selegiline has been found to be 23-fold lower in people takinganticonvulsants known to strongly activatedrug-metabolizing enzymes.[134] The anticonvulsants includedphenobarbital,phenytoin,carbamazepine, andamobarbital.[134] In a previous study however, carbamazepine specifically did not reduce selegiline exposure.[8][9] Phenobarbital and certain other anticonvulsants are known to strongly induce CYP2B6, one of the major enzymes believed to be involved in selegiline metabolism.[134] As such, it was concluded that strong CYP2B6 induction was most likely responsible for the dramatically reduced exposure to selegiline observed in the study.[134]
Selegiline has been reported to inhibit several cytochrome P450 enzymes, including CYP2D6, CYP3A4/5, CYP2C19, CYP2B6, and CYP2A6.[8][135] It is amechanism-based inhibitor (suicide inhibitor) of CYP2B6 and has been said to "potently" or "strongly" inhibit this enzymein vitro.[136][135][137][138] It may inhibit the metabolism ofbupropion, a major CYP2B6substrate, into itsactive metabolitehydroxybupropion.[136][135][137] However, a study predicted that inhibition of CYP2B6 by selegiline would non-significantly affect exposure to bupropion.[138] Selegiline has not been listed or described as a clinically significant CYP2B6 inhibitor by theFood and Drug Administration (FDA) as of 2023.[129][8] One small study observing three patients found that selegiline was safe and well-tolerated in combination with bupropion.[137][139] In addition to CYP2B6 and other cytochrome P450 enzymes, selegiline is a potent mechanism-based inhibitor of CYP2A6 and may increase exposure tonicotine (a major CYP2A6 substrate).[140][141] By inhibiting cytochrome P450 enzymes like CYP2B6 and CYP1A2, selegiline may inhibit its own metabolism and thereby interact with itself.[141][142]
Metabolism of selegiline.(R)-Methamphetamine (levomethamphetamine) and(R)-amphetamine (levoamphetamine) are not extensively metabolized and are excreted substantially unchanged so their metabolic profiles are omitted.
Rasagiline ((R)-N-propargyl-1-aminoindan) is an analogue of selegiline in which the amphetamine base structure has been replaced with a1-aminoindan structure and theN-methyl group has been removed.[41] Like selegiline, it is also a selective MAO-B inhibitor and used to treat Parkinson's disease.[41] In contrast to selegiline however, rasagiline lacks the amphetamine metabolites and activity of selegiline.[41] A further derivative of rasagiline,ladostigil ([N-propargyl-(3R)-aminoindan-5-yl]-N-propylcarbamate), a dual MAO-B inhibitor andacetylcholinesterase inhibitor, was developed for treatment ofAlzheimer's disease and other conditions but was ultimately never introduced for medical use.[169]
Deprenyl is aracemic compound (a mixture of twoisomers calledenantiomers).[11][15] The racemic form has mild amphetamine-likepsychostimulant effects that are diminished compared to those of amphetamine but are still present.[15] Thelevorotatory enantiomer has further reduced stimulant effects, and further work, published in 1967, determined that the levorotatory enantiomer was a more potent MAOI than thedextrorotatory enantiomer.[11][15][178][179] As a result, subsequent work was done with the single enantiomerL-deprenyl.[11][15][178][179] In 1968, it was discovered by J. P. Johnston that monoamine oxidase exists in multiple forms.[11][15][180] 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 crisis resulting from consumingfoods containing tyramine) that occurs with non-selective MAOIs.[11][15][181] 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.[11][15][182] Selegiline was the first selective MAO-B inhibitor to be discovered[13] and hence is described as prototypical of these agents.[47][48]
Deprenyl and selegiline were initially studied asantidepressants for treatment ofdepression.[50][176] Deprenyl was first found to be effective for depression from 1965 to 1967,[50][183][184] while selegiline was first found to be effective for depression in 1971 and this was further corroborated in 1980.[50][185][186] A 1984 study that combined selegiline withphenylalanine reported remarkably high effectiveness in the treatment of depression similar to that withelectroconvulsive therapy (ECT).[50][187] However, selegiline in its original oral form was never further developed or approved for the treatment of depression.[50]
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.[178][188]
Selegiline was first introduced for clinical use inHungary in 1977.[45] It was approved in the oral pill form under the brand name Jumex to treat Parkinson's disease.[45] The drug was then introduced in theUnited Kingdom in 1982.[45] In 1987, Somerset Pharmaceuticals in New Jersey, which had acquired the rights to develop selegiline in theUnited States, filed aNew Drug Application (NDA) with theFood and Drug Administration (FDA) to market the drug for Parkinson's disease in this country.[46] While the NDA was under review, Somerset was acquired in a joint venture by twogeneric drug companies,Mylan and Bolan Pharmaceuticals.[46] Selegiline was approved for Parkinson's disease by the FDA in 1989.[46]
It had been known since the mid-1960s that high doses of deprenyl hadpsychostimulant effects.[17][11][176][184] Selegiline was first shown tometabolize intolevomethamphetamine andlevoamphetamine in humans in 1978.[31][194] The involvement of these metabolites in the effects and side effects of selegiline has remained controversial and unresolved in the decades afterwards.[31][41] In any case, concerns about these metabolites have contributed to the development of newer MAO-B inhibitors likerasagiline andsafinamide that lack such metabolites.[41][195]
Binding to and agonism of thetrace amine-associated receptors (TAARs) as themechanism 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.[39][145][40] Activation of theTAAR1 as the mechanism of the MAE effects was first clearly substantiated in 2022.[205][38]
Selegiline is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française, whileselegiline hydrochloride is theUSANTooltip United States Adopted Name.[206][207][161] The word "selegiline" is pronounced/səˈlɛdʒɪliːn/ (sə-LEJ-i-leen) or as "seh-LEH-ji-leen".[1][2] Selegiline is also known asL-deprenyl,L-deprenil,L-deprenalin,L-deprenaline,L-phenylisopropylmethylpropinylamine, andL-E-250.[23][206][207][161][176] It should not be confused with theracemic form,deprenyl (E-250), or with thedextrorotatoryenantiomer,D-deprenyl, which are distinct substances.[206][44][23]
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).[3][161][155] Selegiline has been marketed under more than 70brand names worldwide.[208][3] 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.[65][209]
Generic forms of oral selegiline are available in theUnited States.[55] However, generic forms of the orally disintegrating tablet and the transdermal patch are not available in this country.[55][56] The latter formulations of selegiline are very expensive, and this can be prohibitive to their use.[56][210] There has been poorinsurance 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.[56] It is expected that generics of the transdermal patch will become available at some point in the future.[56]
Conventional oral selegiline (brand names Eldepryl, Jumex) is widely marketed throughout the world, including in over 70countries.[3][161][23][208] Conversely, the selegiline transdermal patch (brand name Emsam) is only marketed in theUnited States, while the selegiline orally disintegrating tablet (brand name Zelapar) is marketed in the United States, theUnited Kingdom, and theEuropean Union.[3][45][23]
József Knoll, one of the developers of selegiline, began taking a low 1mg daily dose of selegiline on January 1, 1989, at the age of 64.[147]: 92 [178] He reported in 2012 that this had continued for 22years uninterrupted.[147]: 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.[147]: 92 [178] Knoll later died in 2018 at the age of 93.[211]
David Pearce, a Britishtranshumanistphilosopher, wrote his self-published book-length internet manifestoThe Hedonistic Imperative[212] six weeks after starting to take selegiline.[213]
InGregg Hurwitz's novelOut of the Dark, selegiline (Emsam) andtyramine-containing food were used to assassinate the president of the United States.[217]
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" ornootropic) and anti-aging effects.[218][153][219] It is widely available for such purposes, for instance under informal brand names like Dep-Pro, Selepryl, and Cyprenil, which are oral liquidsolutions of selegiline at a concentration of 1mg per drop.[153][219][147]: 86
In his 1993 bookE for Ecstasy examining the uses of the street drugecstasy in theUnited Kingdom, the writer, activist, and ecstasy advocateNicholas Saunders highlighted test results showing that certain consignments of the drug also contained selegiline.[220] Consignments of ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination ofketamine,ephedrine and selegiline," as did a consignment of "Sitting Duck" Ecstasy tablets.[221]
József Knoll and his team are credited with having developed selegiline. Although selegiline's development as a potential treatment forParkinson'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.[211][227][228] Knoll published his 2012 bookHow Selegiline ((–)-Deprenyl) Slows Brain Aging wherein he claims that:[147]: 90
"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".
The mechanism of selegiline's longevity-promoting effect has been researched by several groups, including Knoll and his associates at Semmelweis University, Budapest.[23] The drug has been determined to be acatecholaminergic 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 unknowntrace 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:[147]: 70, 43
"[...] 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."
"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."
Despite findings by Knoll that selegiline can prolong lifespan in rodents by 35% however, other studies have had conflicting findings and have even found increasedmortality with selegiline in rodents.[54] In humans with Parkinson's disease, selegiline has been associated withcardiovascular andpsychiatric complications and has not been found to reduce mortality in long-term studies.[54] As such, the claimed anti-aging and longevity benefits of selegiline have yet to be substantiated in humans and are controversial and uncertain.[54][53]
A small clinical study found that oral selegiline (10mg/day) reduced symptoms ofsocial anxiety disorder.[12][24][237] The effectiveness was modest, with a reduction in social anxiety scores from baseline of 32% over 6weeks of treatment.[12][24][237] It was seemingly less effective than certain other agents used in the treatment of social anxiety, such as the non-selective MAOIphenelzine (45% symptom reduction) and thebenzodiazepineclonazepam (51% symptom reduction), though it was similar to the SSRIsertraline (32% symptom decrease).[237]
Selegiline has been limitedly studied in the treatment ofattention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults.[24][238][239][240] 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.[241] 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.[242] In another small randomized controlled trial of selegiline for the treatment of adult ADHD, a high dose of the medication for 6weeks was not significantly more effective than placebo in improving symptoms.[239][243][244] Selegiline in its transdermal patch form (brand name Emsam) has also been assessed in the treatment of ADHD in children and adolescents in a smallopen-labelpilot study sponsored by the manufacturer in 2003.[12][245] However, there was a high rate ofdiscontinuation and development was not further pursued.[12][245]
Selegiline has been evaluated forsmoking cessation both as a monotherapy and in combination withnicotine replacement therapy in five clinical studies.[256][257][24] However, it is limitedly or not effective for this use.[256][257][24] It was also evaluated for treatment ofcocaine dependence in one study, but was similarly not effective.[258] Studies are mixed on whether selegiline, at MAO-B-selective doses, reduces the effects of cocaine in humans.[105][106][107][108][109][110] Selegiline, also at an MAO-B-selective dosage, did not modify or potentiate the pharmacological effects ofintravenousmethamphetamine in a small clinical study.[103][104]
Selegiline has been assessed for treatment ofsexual dysfunction induced byantipsychotics in people withschizophrenia, but was not effective in a single small clinical study.[259][260] It also did not improve sexual function in men with depression, but did improve several domains of sexual function in women with depression.[67]
Selegiline has been evaluated for the treatment ofnarcolepsy in three small clinical studies.[262][263][264] It was found to be effective in these studies.[262][263] A dosage of 10mg/day had no effect on symptoms, but 20 to 30mg/day improvedalertness,mood, and somewhat reducedcataplexy, clinical effects that have been described as comparable to the same dosages ofamphetamine.[263]Animal research indicates that the beneficial effects of high doses of selegiline in narcolepsy are likely due to conversion into itsactive metabolites,levoamphetamine andlevomethamphetamine.[263][264] Selegiline has also been evaluated for treatment ofhypersomnia (excessive sleeping or sleepiness) in people withmyotonic dystrophy, but its effectiveness was very uncertain.[265][262]
Selegiline has been studied in the treatment ofperiodic limb movement disorder (PLMD) in a single smallopen-label clinical study.[266][267][268] It was reported to be effective as assessed bypolysomnography, reducing periodic limb movements during sleep by about 60%.[266][268] Selegiline has not been studied for the related conditionrestless legs syndrome (RLS) as of 2023.[266][267] The drug has not been studied well enough in PLMD or RLS to be widely used in their treatment.[266]
Selegiline has also been usedoff-label as a palliative treatment fordementia inAlzheimer's disease.[58] However, its clinical effectiveness is limited or lacking for this use.[270][271][272][273] It was also ineffective in the treatment ofLewy body dementia.[274] Selegiline has been used to support motor rehabilitation instroke recovery, but evidence for this use is inadequate and no recommendation can be made for or against it.[275]
Conversely, selegiline failed to reduce the serotonergic neurotoxicity caused byfenfluramine and either did not affect or potentiated the serotonergic neurotoxicity caused bypara-chloroamphetamine (PCA).[280][291][292][293] In addition, findings are mixed and conflicting on whether selegiline preventsamphetamine- andmethamphetamine-induced dopaminergic neurotoxicity in rodents.[294][295][296][297]
Although MAO-B-selective doses of selegiline protect against MDMA-induced serotonergic neurotoxicity in rodents, combination ofamphetamines like MDMA with MAOIs, including selegiline, can produce serious complications, includingserotonin syndrome,hypertensive crisis, and death.[298][299]
The original oral formulation of selegiline was developed for the treatment ofdepression.[50] However, it ended up being developed and approved for the treatment ofParkinson's disease instead.[50][45][4] In any case, oral selegiline has been widely usedoff-label to treat depression.[24] The transdermal patch form of selegiline was developed and approved specifically for the treatment of depression.[300][12][9][8] It was also under development for the treatment ofAlzheimer's disease,attention deficit hyperactivity disorder (ADHD),cognition disorders, and Parkinson's disease, but development for these indications was discontinued.[300] The ODT form of selegiline was developed and licensed exclusively for the treatment of Parkinson's disease.[301][7][6]
Selegiline has been limitedly studied in large animals likehorses and its dosage in these animals has not been established.[309] In preliminary research, a dose of selegiline of 30mg orally orintravenously in horses had no observable effects on behavior or locomotor activity.[309]
The doses of selegiline used in animals are described as extremely high relative to those used in humans (which are ~0.1mg/kg body weight).[155]
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Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages. See also:Receptor/signaling modulators
