Selegiline, also known as L-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.[1] It is provided in the form of a capsule or tablet taken by mouth or orally disintegrating tablets taken on the tongue for Parkinson's disease and as a patch applied to skin for depression.

Selegiline
Clinical data
Pronunciation/səˈlɛɪln/ sə-LEJ-i-leen
Trade namesEldepryl, Jumex, Zelapar, Emsam, others[1]
Other namesL-Deprenyl; (R)-(–)-N,α-Dimethyl-N-2-propynylphenethylamine; (R)-(–)-N-Methyl-N-2-propynylamphetamine; (R)-(–)-N-2-propynylmethamphetamine
AHFS/Drugs.comMonograph
MedlinePlusa697046
License data
Pregnancy
category
  • AU: B2
Routes of
administration
By mouth, transdermal (patch)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability10% (oral), 73% (patch)
Protein bindingUnknown[3]
MetabolismIntestines and liver
MetabolitesN-Desmethylselegiline, levoamphetamine, levomethamphetamine
Elimination half-life1.5–3.5 hours (oral),[4] 18–25 hours (transdermal)[5]
ExcretionUrine
Identifiers
  • (R)-N-methyl-N-(1-phenylpropan-2-yl)prop-3-yn-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.109.269 Edit this at Wikidata
Chemical and physical data
FormulaC13H17N
Molar mass187.286 g·mol−1
3D model (JSmol)
  • C#CCN([C@@H](Cc1ccccc1)C)C
  • InChI=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 checkY
  • Key:MEZLKOACVSPNER-GFCCVEGCSA-N checkY
  (verify)

Selegiline acts as a monoamine oxidase inhibitor, and increases levels of monoamine neurotransmitters in the brain. At typical clinical doses used for Parkinson's disease, selegiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B), increasing levels of dopamine in the brain. In larger doses (more than 20 mg/day), it loses its specificity for MAO-B and also inhibits MAO-A, which increases serotonin and norepinephrine levels in the brain. In addition to its monoamine oxidase inhibition, selegiline is a prodrug of levomethamphetamine and levoamphetamine, which act as norepinephrine releasing agents and may also be involved in its effects and side effects.[6][7][6] These metabolites are greatly minimized with the oral disintegrating tablet and transdermal patch formulations of selegiline.[8][9]

The racemic form of selegiline, deprenyl, was discovered and studied in the early 1960s.[10][11] Subsequently, selegiline was purified from deprenyl and was itself studied and developed.[10] Selegiline was approved as an oral pill for the treatment of Parkinson's disease in 1989[12] and as a patch for the treatment of depression in 2006.[11] In addition to its medical use, there has been interest in selegiline as a potential anti-aging and longevity drug and as a nootropic or "smart drug".[13]

Medical uses

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Parkinson's disease

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In its pill form, selegiline is used to treat symptoms of Parkinson's disease.[14] It is most often used as an adjunct to drugs such as levodopa (L-DOPA), although it has been used off-label as a monotherapy.[15][16] The rationale for adding selegiline to levodopa is to decrease the required dose of levodopa and thus reduce the motor complications of levodopa therapy.[17] Selegiline delays the point when levodopa treatment becomes necessary from about 11 months to about 18 months after diagnosis.[18] There is some evidence that selegiline acts as a neuroprotectant and reduces the rate of disease progression, though this is disputed.[16][17]

Selegiline has also been used off-label as a palliative treatment for dementia in Alzheimer's disease.[16]

Depression

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Selegiline is also delivered via a transdermal patch used as a treatment for major depressive disorder.[19][20] Administration of transdermal selegiline bypasses hepatic first pass metabolism. This avoids inhibition of gastrointestinal and hepatic MAO-A activity, which would result in an increase of food-borne tyramine in the blood and possible related adverse effects, while allowing for a sufficient amount of selegiline to reach the brain for an antidepressant effect.[9]

A quantitative review published in 2015 found that for the pooled results of the pivotal trials, the number needed to treat (a sign of effect size, so a low number is better) for the patch for symptom reduction was 11, and for remission, was 9.[20] The number needed to harm (inverse of the NNT, a high number here is better) ranged from 387 for sexual side effects to 7 for application site reaction.[20] With regard to the likelihood to be helped or harmed (LHH), the analysis showed that the selegiline patch was 3.6 times as likely to lead to a remission vs. a discontinuation due to side effects; the LHH for remission vs. incidence of insomnia was 2.1; the LHH for remission vs. discontinuation due to insomnia was 32.7. The LHH for remission vs. insomnia and sexual dysfunction were both very low.[20]

Special populations

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For all human uses and all forms, selegiline is pregnancy category C: studies in pregnant lab animals have shown adverse effects on the fetus but there are no adequate studies in humans.[14][19]

Available forms

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Selegiline is available in the form of 5 mg oral tablets and capsules (brand name Eldepryl and generics), 1.25 mg orally disintegrating tablets (brand name Zelapar), and 6 mg/24-hour, 9 mg/24-hour, and 12 mg/24-hour transdermal patches (brand name Emsam).[21]

Side effects

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Side effects of the tablet form in conjunction with levodopa include, in decreasing order of frequency, nausea, hallucinations, confusion, depression, loss of balance, insomnia, increased involuntary movements, agitation, slow or irregular heart rate, delusions, hypertension, new or increased angina pectoris, and syncope.[14] Most of the side effects are due to a high dopamine signaling, and can be alleviated by reducing the dose of levodopa.[1]

The main side effects of the patch form for depression include application-site reactions, insomnia, diarrhea, and sore throat.[19] The selegiline patch carries a black box warning about a possible increased risk of suicide, especially for young people,[19] as do all antidepressants since 2007.[22]

Interactions

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Both the oral and patch forms come with strong warnings against combining selegiline with drugs that could produce serotonin syndrome, such as SSRIs and the cough medicine dextromethorphan.[14][19][23] Selegiline in combination with the opioid analgesic pethidine is not recommended, as it can lead to severe adverse effects.[23] Several other synthetic opioids such as tramadol and methadone, as well as various triptans, are contraindicated due to potential for serotonin syndrome.[24][25]

Birth control pills containing ethinylestradiol and a progestin increase the bioavailability of selegiline by 10- to 20-fold.[26] High levels can lead to loss of MAO-B selectivity, and selegiline may begin inhibiting MAO-A as well. This increases susceptibility to side effects of non-selective MAOIs, such as tyramine-induced hypertensive crisis and serotonin toxicity when combined with serotonergic medications.[26]

Both forms of the drug carry warnings about food restrictions to avoid hypertensive crisis that are associated with MAO inhibitors.[14][19] The patch form was created in part to overcome food restrictions; clinical trials showed that it was successful. Additionally, in post-marketing surveillance from April 2006 to October 2010, only 13 self-reports of possible hypertensive events or hypertension were made out of 29,141 exposures to the drug, and none were accompanied by objective clinical data.[20] The lowest dose of the patch method of delivery, 6 mg/24 hours, does not require any dietary restrictions.[27] Higher doses of the patch and oral formulations, whether in combination with the older non-selective MAOIs or in combination with the reversible MAO-A inhibitor moclobemide, require a low-tyramine diet.[23]

Selegiline "potently" or "strongly" inhibits the cytochrome P450 enzyme CYP2B6 in vitro.[28][29][30] It can inhibit the metabolism of bupropion, a major CYP2B6 substrate, into its active metabolite hydroxybupropion.[28][29][30] One small study observing three patients found that selegiline was safe in combination with bupropion.[30][31]

Pharmacology

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Pharmacodynamics

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Selegiline is a selective inhibitor of MAO-B, irreversibly inhibiting it by binding to it covalently.[1][32] It is generally believed to exert its effects by blocking the breakdown of dopamine, thus increasing its activity;[33] however, recent evidence suggests that MAO-A is solely or almost entirely responsible for the metabolism of dopamine.[34] Its possible neuroprotective properties may be due to protecting nearby neurons from the free oxygen radicals that are released by MAO-B activity. At higher doses, selegiline loses its selectivity for MAO-B and inhibits MAO-A as well.[1] Selegiline has been called the "first synthetic catecholaminergic activity enhancer substance".[35][36]

Following a single 5 or 10 mg oral dose of selegiline, 86% to 90% of MAO-B activity in blood platelets was inhibited within 2 to 4 hours and 98% of activity was inhibited after 24 hours.[3][37] Inhibition of platelet MAO-B activity persisted at above 90% for 5 days and almost 14 days were required before activity returned to baseline.[3][37] A lower dose of selegiline of 1 mg/day also inhibits MAO-B activity by 70 to 100%.[37] However, despite this potent and long-lasting inhibition, optimal effectiveness in Parkinson's disease requires 10 mg/day and the effectiveness lasts only about 2 to 3 days with discontinuation of selegiline.[37] Taken together, selegiline almost completely inhibits platelet MAO-B act a dosage of 10 mg/day.[8] It is assumed that peripheral and brain MAO-B are inhibited with selegiline to very similar extents, although this is also not certain.[38][39][37]

In vitro, selegiline is about 1,000 times more potent in inhibiting platelet MAO-B relative to intestinal MAO-A.[37] The clinical selectivity of selegiline for MAO-B is lost at doses of the drug above 20 mg/day.[37] In a study of post-mortem individuals who took selegiline 10 mg/day for an average of 6 days prior to death, MAO-A activity in the brain was inhibited by 38 to 86%.[37][40] More recent studies have also found inhibition of brain MAO-A by 33 to 70% in humans.[41][42][43] However, while brain dopamine and phenethylamine levels are substantially increased (by 40–350% and 1,300%, respectively), brain serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels remain unchanged or 5-HIAA levels were only somewhat decreased.[40][37] It has been shown that MAO-A in the brain must be inhibited by nearly 85% before serotonin, norepinephrine, or dopamine levels increase and result in increased functional activity.[40] Selegiline at an oral dosage of 10 mg/day does not cause the "cheese effect" as assessed by oral tyramine and phenethylamine challenge tests.[3] These findings indicate that selegiline does not importantly inhibit MAO-A at a dosage of 10 mg/day.[3] However, a dosage of 20 mg/day selegiline did increase the pressor effect of tyramine, indicating that doses this high and above can significantly inhibit MAO-A.[40]

Besides increasing brain dopamine levels via MAO-B inhibition, selegiline strongly increases endogenous levels of β-phenethylamine (PEA), a major substrate of MAO-B.[37] Levels in of PEA in the brain are increased 10- to 30-fold and levels in urine are increased 20- to 90-fold.[37] PEA is normally present in small amounts in the brain and urine and has been referred to as "endogenous amphetamine".[37] Similarly to amphetamines, it induces the release of norepinephrine and dopamine and produces psychostimulant effects.[37] Selegiline also strongly increases levels of PEA with exogenous administration of PEA.[37] The increase in endogenous levels of PEA with selegiline might be involved in its effects, for instance claimed "psychic energizing" and mood-lifting effects.[13] In contrast to amphetamine psychostimulants however, selegiline has no misuse potential.[13]

Selegiline has potent pro-sexual effects in rodents, which are apparently not shared with other MAO-B inhibitors or clorgiline (an MAO-A inhibitor).[37] The pro-sexual effects are stronger than those of dopamine agonists like apomorphine and bromocriptine and high doses of amphetamine.[37] However, these pro-sexual effects in rodents were not subsequently confirmed in primates.[37]

Selegiline also inhibits the cytochrome P450 enzymes CYP2A6 and CYP2B6.[44][29] The CYP2A6 inhibition can increase the effects of nicotine.[44] Selegiline additionally appears to activate σ1 receptors, having a relatively high affinity for these receptors of approximately 400 nM.[45][46] The drug has a weak dopamine releasing effect, weakly blocks dopamine receptors, and weakly inhibits the reuptake of norepinephrine, but these actions are all of very low potency and are of questionable clinical significance.[37] Selegiline does not significantly inhibit the brain dopamine transporter in humans at clinical doses.[43]

Besides selegiline itself, its three major metabolites, desmethylselegiline, levomethamphetamine, and levoamphetamine, are pharmacologically active.[6] Compared to selegiline, desmethylselegiline is 60-fold less potent in inhibiting MAO-B in vitro, but is only 3- to 6-fold less potent in vivo.[3] Although desmethylselegiline levels with selegiline therapy are low, selegiline and desmethylselegiline are highly potent MAO-B inhibitors due to the irreversible nature of their inhibition.[37] As such, desmethylselegiline may contribute significantly to the MAO-B inhibition with selegiline.[37] Levomethamphetamine and levoamphetamine are sympathomimetic agents that work by inducing the release of norepinephrine.[6] They might improve fatigue, but can also produce cardiovascular side effects like increased heart rate and blood pressure and reportedly may be able to cause insomnia, psychiatric disturbances, and psychosis.[6][8] They are ten times less potent at stimulating locomotor activity (a measure of psychostimulant effect) than dextromethamphetamine and dextroamphetamine in rodents.[6][47] It is unknown what concentrations of levomethamphetamine and levoamphetamine produce sympathomimetic and other effects in humans and whether such concentrations are achieved with selegiline therapy.[6] However, cardiovascular side effects of selegiline have been found clinically and have been attributed to its amphetamine metabolites.[48][38] For comparison, rasagiline, which lacks amphetamine metabolites, has shown fewer adverse effects in clinical studies.[48][38][49]

It is unknown whether selegiline's amphetamine metabolites are involved in its effectiveness in the treatment of Parkinson's disease.[37] However, this has been deemed unlikely.[37] High doses of levoamphetamine, for instance 50 mg/day, have been reported to have some degree of effectiveness in the treatment of Parkinson's disease.[37] However, this could not be relevant to selegiline, which is administered at a dose of 10 mg/day.[37] Accordingly, relatively low levels of levoamphetamine occur with selegiline.[37] In one clinical study, levels of the amphetamine metabolites of selegiline were manipulated and there were no changes in clinical symptoms of Parkinson's disease.[37] This led the researchers to conclude that the beneficial clinical effects of selegiline in Parkinson's disease were not due to its amphetamine metabolites.[37] It is possible that there could be some small synergistic beneficial effect of selegiline with its amphetamine metabolites, but this has been considered improbable.[37] In any case, as previously mentioned, the amphetamine metabolites of selegiline might produce other effects, like reduced fatigue, as well as side effects.[6][8][48] Newer formulations of selegiline, such as the orally disintegrating tablet and the transdermal patch, have been developed which strongly reduce formation of the amphetamine metabolites and their associated effects.[8][9] In addition, other MAO-B inhibitors that do not metabolize into amphetamines, like rasagiline, have been developed and introduced.[6]

Pharmacokinetics

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Absorption

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Selegiline has an oral bioavailability of about 10%.[3] The average time to peak levels of selegiline is 0.6 to 1.4 hours, with a range in one study of about 0.5 to 1.5 hours.[3]

The circulating levels of selegiline and its metabolites following a single 10 mg oral dose have been studied.[3] The metabolites of selegiline include desmethylselegiline, levomethamphetamine, and levoamphetamine.[3] The average peak concentrations of selegiline across several studies ranged from 0.84 ± 0.6 μg/L to 2.2 ± 1.2 μg/L and the AUC levels ranged from 1.26 ± 1.19 μg⋅h/L to 2.17 ± 2.59 μg⋅h/L.[3] In the case of desmethylselegiline, the time to peak has been reported to be 0.8 ± 0.2 hours, the peak levels were 7.84 ± 2.11 μg/L to 13.4 ± 3.2 μg/L, and the area-under-the-curve (AUC) levels were 15.05 ± 4.37 μg⋅h/L to 40.3 ± 10.7 μg⋅h/L.[3] For levomethamphetamine, the peak levels were 10.2 ± 1.5 μg/L and the AUC levels were 150.2 ± 21.6 μg⋅h/L, whereas for levoamphetamine, the peak levels were 3.6 ± 2.9 μg/L and the AUC levels were 61.7 ± 44.0 μg⋅h/L.[3] For comparison, following a single 10 mg oral dose of dextromethamphetamine or dextroamphetamine, peak levels of these agents have been reported to range from 14 to 90 μg/L and from 15 to 34 μg/L, respectively.[50] Levels of desmethylselegiline and levomethamphetamine are 10- to 20-fold higher than selegiline levels with oral selegiline therapy.[51]

With repeated administration of selegiline, there is an accumulation of selegiline and its metabolites.[3] With a dosage of 10 mg once a day or 5 mg twice daily, peak levels of selegiline were 1.59 ± 0.89 μg/L to 2.33 ± 1.76 μg/L and AUC levels of selegiline were 6.92 ± 5.39 μg⋅h/L to 7.84 ± 5.43 μg⋅h/L after 1 week of treatment.[3] This equated to a 1.9- to 2.6-fold accumulation in peak levels and a 3.6- to 5.5-fold accumulation in AUC levels.[3] The metabolites of selegiline accumulate to a smaller extent than selegiline.[3] The AUC levels of desmethylselegiline increased by 1.5-fold and the peak and AUC levels of levomethamphetamine and levoamphetamine increased by 2-fold following 1 week of treatment with selegiline.[3]

The oral bioavailability of selegiline increases when it is ingested together with a fatty meal, as the molecule is fat-soluble.[1][52] There is a 3-fold increase in peak levels of selegiline and a 5-fold increase in AUC levels when it is taken orally with food.[3] The elimination half-life of selegiline is unchanged when it is taken with food.[3] In contrast to selegiline itself, the pharmacokinetics of its metabolites, desmethylselegililne, levomethamphetamine, and levoamphetamine, are unchanged when selegiline is taken with food.[3]

A buccal formulation of selegiline was found to have 5-fold higher bioavailability, more consistent blood levels, and to produce fewer amphetamine metabolites than the standard oral tablet form.[53]

Distribution

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No data were originally available on the plasma protein binding of selegiline.[3] It has been stated that the plasma protein binding of selegiline is 94%, but there is no actual evidence to support this figure.[3] Subsequent research found that its plasma protein binding is 89%.[9] The apparent volume of distribution of selegiline is 1,854 ± 824 L.[3] Selegiline and its metabolites cross the blood–brain barrier and enter the brain, where they most concentrated at the thalamus, basal ganglia, midbrain, and cingulate gyrus.[16][19] It especially accumulates in brain areas with high MAO-B content, such as the thalamus, striatum, cortex, and brainstem.[40] Concentrations of selegiline's metabolites in cerebrospinal fluid (CSF) are similar to those in blood, suggesting that accumulation in the brain does not occur.[40]

Metabolism

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Selegiline is mostly metabolized in the intestines and liver; it and its metabolites are excreted in the urine.[1] Selegiline is metabolized by cytochrome P450 to L-desmethylselegiline and levomethamphetamine.[54][55] Desmethylselegiline has some activity against MAO-B, but much less than that of selegiline.[33][32] It is thought to be further metabolized by CYP2C19.[56] Levomethamphetamine (the less potent of the two enantiomers of methamphetamine) is converted to levoamphetamine (the less potent of the two enantiomers of amphetamine, with regards to psychological effects).

Due to the presence of these metabolites, people taking selegiline may test positive for "amphetamine" or "methamphetamine" on drug screening tests.[57] While the amphetamine metabolites may contribute to selegiline's ability to inhibit reuptake of the neurotransmitters dopamine and norepinephrine, they have also been associated with orthostatic hypotension and hallucinations.[55][58][7] The recovery of selegiline from urine is high at 87%, which has caused some researchers to question the clinical relevance of its amphetamine metabolites.[59] The amphetamine metabolites are hydroxylated and, in phase II, conjugated by glucuronyltransferase.

The cytochrome P450 enzymes CYP2B6, CYP2C9, and CYP3A are thought to be significantly involved in the metabolism of selegiline on the basis of in vitro studies.[9][60][61] Other cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP2C8, CYP2D6, CYP2C19, and CYP2E1, may also be involved.[9][62][60][61] One review concluded that CYP2B6 and CYP2C19 are the leading candidates in selegiline metabolism.[63] CYP2B6 is thought to N-demethylate selegiline into desmethylselegiline and CYP2B6 and CYP2C19 are thought to N-depropargylate selegiline into levomethamphetamine.[9][60] Additionally, CYP2B6 and CYP2C19 are thought to metabolize desmethylselegiline into levoamphetamine and CYP2B6 is thought to N-demethylate levomethamphetamine into levoamphetamine.[9][60] CYP2D6 and CYP2C19 metabolizer phenotypes did not significantly affect the pharmacokinetics of selegiline, suggesting that these enzymes are minimally involved in its metabolism.[63][61][51] However, although most pharmacokinetic variables were unaffected, AUC levels of levomethamphetamine were 46% higher in CYP2D6 poor metabolizers compared to extensive metabolizers and desmethylselegiline AUC levels were 68% in CYP2C19 poor metabolizers compared to extensive metabolizers.[61][51] As with CYP2D6 and CYP2C19, CYP3A4 and CYP3A5 are unlikely to be majorly involved in the metabolism of selegiline as the strong inhibitor itraconazole has minimal impact on its pharmacokinetics.[63][64] Besides its major metabolites of desmethylselegiline, levomethamphetamine, and levoamphetamine, selegiline-N-oxide and formaldehyde are formed.[65] In addition, more than 40 minor metabolites of selegiline have been either detected or proposed.[65]

The oral clearance of selegiline is 59.4 ± 43.7 L/min.[3] This is described as very high and as almost 30-fold higher than hepatic blood flow.[3] The renal clearance of selegiline is 0.0072 L/h and is very low compared to its oral clearance.[3] These findings suggest that selegiline is extensively metabolized not only by the liver but also by non-hepatic tissues.[3]

A newer anti-Parkinson MAO-B inhibitor, rasagiline, metabolizes into 1(R)-aminoindan, which has no amphetamine-like characteristics.[66]

Elimination

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The average elimination half-life of selegiline after a single oral dose ranges from 1.2 hours to 1.9 hours across studies.[3] With repeated administration, the half-life of selegiline increases to 7.7 ± 12.6 hours to 9.6 ± 13.6 hours.[3] The elimination half-life of selegiline's metabolite, desmethylselegiline, has been reported to range from 2.2 ± 0.6 hours to 3.8 hours.[3] The half-lives of its metabolites levomethamphetamine and levoamphetamine have been reported to be 14 hours and 16 hours, respectively.[3] Following repeated administration, the half-life of desmethylselegiline increased from 3.8 hours with the first dose to 9.5 hours following 1 week of daily selegiline doses.[3]

Approximately 0.01% to 0.03% unchanged selegiline is excreted in urine with an oral dose.[3] This indicates that selegiline is essentially completely metabolized prior to excretion.[3]

Orally disintegrating tablet

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Selegiline as an orally disintegrating tablet (ODT) achieves blood levels of selegiline at a dose of 1.25 mg/day that are similar to those with conventional oral selegiline at a dose of 10 mg/day.[8] In addition, there is an at least 90% reduction in metabolites of selegiline including desmethylselegiline, levomethamphetamine, and levoamphetamine with the ODT formulation of selegiline compared to conventional oral selegiline.[8] Hence, levels of these metabolites are 10-fold lower with the ODT formulation.[48] This formulation of selegiline retains selectivity for MAO-B over MAO-A and likewise does not cause the "cheese effect" with consumption of tyramine-rich foods.[8]

Transdermal patch

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Following application of the patch to humans, an average of 25% to 30% of the selegiline content is delivered systemically over 24 hours.[9] This equates to about 0.3 mg selegiline per cm2 over 24 hours.[9] Transdermal dosing results in significantly higher exposure to selegiline and lower exposure to all metabolites when compared to oral dosing.[9] Selegiline levels are 50-fold higher and exposure to metabolites 70% lower with transdermal administration compared to oral administration at equivalent doses.[9] The patch has approximately 75% bioavailability, compared to 10% with the conventional oral form.[9] These differences are due to the extensive first-pass metabolism of the pill form and low first-pass metabolism of the patch form. The site of application is not a significant factor in how the drug is distributed. In humans, selegiline does not accumulate in the skin, nor is it metabolized there.[19]

Chemistry

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Selegiline belongs to the phenethylamine and amphetamine chemical families. It is also known as L-deprenyl, as well as (R)-(–)-N,α-dimethyl-N-(2-propynyl)phenethylamine or (R)-(–)-N-methyl-N-2-propynylamphetamine. The compound is a derivative of levomethamphetamine (L-methamphetamine) with a propargyl group attached to the nitrogen atom. It is also known as N-propargyl-L-methamphetamine.[8] This detail is borrowed from pargyline, an older MAO-B inhibitor of the phenylalkylamine group.[35] Selegiline is the levorotatory enantiomer of the racemic mixture deprenyl.

Selegiline is synthesized by the alkylation of (–)-methamphetamine using propargyl bromide.[67][68][69][70]

 

Another clinically used MAOI of the amphetamine class is tranylcypromine.

History

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Following the discovery in 1952 that the tuberculosis drug iproniazid elevated the mood of people taking it, and the subsequent discovery that the effect was likely due to inhibition of MAO, many people and companies started trying to discover MAO inhibitors to use as antidepressants. Deprenyl (the racemic form of selegiline) was discovered by Zoltan Ecseri at the Hungarian drug company, Chinoin (part of Sanofi since 1993),[71] which they called E-250.[72]: 66–67  Chinoin received a patent on the drug in 1962 and the compound was first published in the scientific literature in English in 1965.[72]: 67 [73] 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.[72]: 67 

 
Emsam transdermal patch, 6mg/24hr dose

Deprenyl is a racemic compound (a mixture of two isomers called enantiomers). Further work determined that the levorotatory enantiomer was a more potent MAO-inhibitor, which was published in 1967, and subsequent work was done with the single enantiomer L-deprenyl.[72]: 67 [74][75]

In 1971, Knoll showed that selegiline 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 consuming foods containing tyramine) that occurs with non-selective MAO inhibitors. A few years later, 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, Prof. 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.[75][76]

In the 1970s there was speculation that it could be useful as an anti-aging drug or aphrodisiac.[77]

In 1987 Somerset Pharmaceuticals in New Jersey, which had acquired the US rights to develop selegiline, filed a new drug application (NDA) with the FDA to market the drug for Parkinson's disease in the US.[12] While the NDA was under review, Somerset was acquired in a joint venture by two generic drug companies, Mylan and Bolan Pharmaceuticals.[12] Selegiline was approved for Parkinson's disease by the FDA in 1989.[12]

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 dietary restrictions of MAO inhibitors.[77][78][79] Somerset obtained FDA approval to market the patch in 2006.[80]

Non-medical use

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Anti-aging and longevity

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Joseph Knoll and his team are credited with having developed selegiline. Although selegeline's development as a potential treatment for Parkinson's, Alzheimer's, and major depressive disorder 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.[81][82][83] Knoll published How Selegiline ((-)-Deprenyl) Slows Brain Aging (2018) wherein he claims that:

"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".[84]

The mechanism of selegiline's longevity-promoting effect has been researched by several groups, including Joseph Knoll and his associates at Semmelweis University, Budapest.[11] 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:

" ... 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 catcholaminergic 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 neurnsn 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."[84]

Nootropic or "smart drug"

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Selegiline is considered by some to be a nootropic,[85] both at clinical and sub-clinical dosages, and has been used off-label to improve cognitive performance. It has been shown to have protective activity against a range of neurotoxins and to increase the production of several brain growth factors, such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor.[11] It has been demonstrated in numerous animal models to improve learning ability and preserve it during both ischemia and aging.[86][87][88][89]

Society and culture

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In E for Ecstasy (a book examining the uses of the street drug ecstasy in the UK) the writer, activist and ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained selegiline.[90] 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.[91]

David Pearce wrote The Hedonistic Imperative[92] six weeks after starting taking selegiline.[93]

In Gregg Hurwitz's novel Out of the Dark,[94] selegiline (Emsam) and tyramine-containing food were used to assassinate the president of the United States.

Veterinary use

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In veterinary medicine, selegiline is sold under the brand name Anipryl (manufactured by Zoetis). It is used in dogs to treat canine cognitive dysfunction and, at higher doses, pituitary-dependent hyperadrenocorticism (PDH).[95][96] Canine cognitive dysfunction is a form of dementia that mimics Alzheimer's disease in humans. Geriatric dogs treated with selegiline show improvements in sleeping pattern, reduced incontinence, and increased activity level; most show improvements by one month.[97][98] Though it is labeled for dog use only, selegiline has been used off-label for geriatric cats with cognitive dysfunction.[99]

Selegiline's efficacy in treating pituitary-dependent hyperadrenocorticism has been disputed.[95] Theoretically, it works by increasing dopamine levels, which downregulates the release of ACTH, eventually leading to reduced levels of cortisol.[99] Some claim that selegiline is only effective at treating PDH caused by lesions in the anterior pituitary (which comprise most canine cases).[100] The greatest sign of improvement is lessening of abdominal distention.[97]

Side effects in dogs are uncommon, but they include vomiting, diarrhea, diminished hearing, salivation, decreased weight and behavioral changes such as hyperactivity, listlessness, disorientation, and repetitive motions.[96][100]

Selegiline does not appear to have a clinical effect on horses.[100]

Research

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ADHD

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Selegiline has been limitedly studied in the treatment of attention deficit hyperactivity disorder (ADHD) in both children/adolescents and adults.[101][102] 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.[103] 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.[104] In another small randomized controlled trial of selegiline for the treatment of adult ADHD, a high dose of the medication for 6 weeks was not significantly more effective than placebo in improving symptoms.[102][105][106]

Motivational disorders

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Selegiline has been found to increase effort expenditure and to reverse pharmacologically-induced motivational deficits in rodents.[107][108][109] In case reports and small clinical studies, selegiline has been reported to improve apathy in people with traumatic brain injury and schizophrenia.[107] However, no evidence of benefit was found with selegiline in people with Alzheimer's disease.[107]

References

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