Selegiline

Selegiline

Clinical data
Pronunciation	/səˈlɛdʒɪliːn/ sə-LEJ-i-leen ("seh-LEH-ji-leen")
Trade names	Eldepryl, Jumex, Zelapar, Emsam, others
Other names	L-Deprenyl; (R)-(–)-N,α-Dimethyl-N-2-propynylphenethylamine; (R)-(–)-N-Methyl-N-2-propynylamphetamine; (R)-(–)-N-2-Propynylmethamphetamine
AHFS/Drugs.com	Monograph
MedlinePlus	a697046
License data	US FDA: Selegiline
Pregnancy category	AU: B2
Routes of administration	• Oral (tablet, capsule) • Buccal (ODTTooltip orally disintegrating tablet) • Transdermal (patch)
Drug class	Monoamine oxidase inhibitor; Catecholaminergic activity enhancer; Norepinephrine releasing agent; Antiparkinsonian; Antidepressant; Neuroprotective
ATC code	N04BD01 (WHO) QN06AX90 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	Oral: 4–10% ODT: ~5–8× oral Patch: 75%
Protein binding	85–90%
Metabolism	Liver, other tissues (CYP2B6, CYP2C19, others)
Metabolites	• Desmethylselegiline (DMS) • Levomethamphetamine (L-MA) • Levoamphetamine (L-A)
Elimination half-life	Oral: • S (single): 1.2–3.5 h • S (multi): 7.7–9.7 h • DMS (single): 2.2–3.8 h • DMS (multi): 9.5 h • L-MA: 14–21 h • L-A: 16–18 h ODT: • S (single): 1.3 h • S (multi): 10 h Patch: • S: 20 h
Excretion	Urine (87%): • L-MA: 20–63% • L-A: 9–26% • DMS: 1% • S: 0.01–0.03% Feces: 15%
Identifiers
IUPAC name (R)-N-methyl-N-(1-phenylpropan-2-yl)prop-3-yn-1-amine
CAS Number	14611-51-9 Y 14611-52-0 (HCl)
PubChem CID	26757
IUPHAR/BPS	6639
DrugBank	DB01037 Y
ChemSpider	24930 Y
UNII	2K1V7GP655
KEGG	D03731 Y
ChEBI	CHEBI:9086 Y
ChEMBL	ChEMBL972 Y
CompTox Dashboard (EPA)	DTXSID6023575
ECHA InfoCard	100.109.269
Chemical and physical data
Formula	C13H17N
Molar mass	187.286 g·mol−1
3D model (JSmol)	Interactive image
SMILES C#CCN([C@@H](Cc1ccccc1)C)C
InChI 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 Y Key:MEZLKOACVSPNER-GFCCVEGCSA-N Y
(verify)

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. It has also been studied for a variety of other indications, but has not been formally approved for any other use. The medication in the form licensed for depression has modest effectiveness for this condition that is similar to that of other antidepressants. Selegiline is provided as a swallowed tablet or capsule or an orally disintegrating tablet (ODT) for Parkinson's disease and as a patch applied to skin for depression.

Side effects of selegiline occurring more often than with placebo include insomnia, dry mouth, dizziness, nervousness, abnormal dreams, and application site reactions with the patch form, among others. At high doses, selegiline has the potential for dangerous food and drug interactions, such as the tyramine-related "cheese reaction" or hypertensive crisis and risk of serotonin syndrome. However, doses within the approved clinical range appear to have little to no risk of these interactions. In addition, the ODT and transdermal patch forms of selegiline have reduced risks of such interactions compared to the conventional oral form. Selegiline has no known misuse potential or dependence liability.

Selegiline acts as a monoamine oxidase inhibitor (MAOI) and thereby 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 brain levels of dopamine. 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. In addition to its MAOI activity, selegiline is a catecholaminergic activity enhancer (CAE) and enhances the impulse-mediated release of dopamine and norepinephrine in the brain. This action may be mediated by TAAR1 agonism. Selegiline is also a prodrug of levomethamphetamine and levoamphetamine in small amounts, which act as norepinephrine releasing agents (NRAs) and might be involved in its effects and side effects as well. The levels of these metabolites are much lower with the ODT and transdermal patch forms of selegiline. Chemically, selegiline is a substituted amphetamine, a derivative of methamphetamine, and the purified levorotatory enantiomer of deprenyl (the racemic form).

Deprenyl was discovered and studied in the early 1960s. Subsequently, selegiline was purified from deprenyl and was studied and developed itself. Selegiline was first introduced for medical use in Hungary in 1977. It was subsequently approved in the United Kingdom in 1982 and in the United States in 1989. The ODT was approved in the United States in 2006 and in the European Union in 2010, while the patch was introduced in the United States in 2006. In addition to its medical use, there has been interest in selegiline as a potential anti-aging drug and as a nootropic or "smart drug". However, effects of this sort are controversial and uncertain. 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.

Medical uses

Parkinson's disease

In its oral and ODT forms, selegiline is used to treat symptoms of Parkinson's disease (PD). 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. The rationale for adding selegiline to levodopa is to decrease the required dose of levodopa and thus reduce the motor complications of levodopa therapy. Selegiline delays the point when levodopa treatment becomes necessary from about 11 months to about 18 months after diagnosis. There is some evidence that selegiline acts as a neuroprotective and reduces the rate of disease progression, though this is disputed. In addition to parkinsonism, selegiline can improve symptoms of depression in people with Parkinson's disease. There is evidence that selegiline may be more effective than rasagiline in the treatment of Parkinson's disease, which may be due to pharmacological differences between the drugs.

Depression

Selegiline is used as an antidepressant in the treatment of major depressive disorder (MDD). Both the oral selegiline and transdermal selegiline patch formulations are used in the treatment of depression. However, oral selegiline is not approved for depression and is used off-label for this indication, while the transdermal patch is specifically licensed for treatment of depression. Both standard clinical doses of oral selegiline (up to 10 mg/day) and higher doses of oral selegiline (e.g., 30 to 60 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. Unlike oral selegiline, transdermal selegiline bypasses first-pass metabolism, thereby avoiding inhibition of gastrointestinal and hepatic MAO-A and minimizing the risk of food and drug interactions whilst still allowing for selegiline to reach the brain and inhibit MAO-B.

A 2023 systematic review and meta-analysis evaluated the effectiveness and safety of selegiline in the treatment of psychiatric disorders including depression. It included both randomized and non-randomized published clinical studies. The meta-analysis found that selegiline was more effective than placebo 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). 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). However, this was largely due to older and less methodologically rigorous trials at high risk for bias. Oral selegiline studies also often employed much higher doses than usual, for instance 20 to 60 mg/day. 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. For comparison, meta-analyses of other antidepressants for depression have found a mean effect size of about 0.3 (a small effect), similar to that with transdermal selegiline.

In two pivotal regulatory clinical trials of 6 to 8 weeks duration, selegiline decreased scores on depression rating scales (specifically the 17- and -28-item HDRSTooltip Hamilton Depression Rating Scale) by 9.0 to 10.9 points, whereas placebo decreased scores by 6.5 to 8.6 points, giving placebo-subtracted differences attributable to selegiline of 2.4 to 2.5 points. A 2013 quantitative review of transdermal selegiline 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 MADRSTooltip Montgomery–Åsberg Depression Rating Scale). For comparison, other antidepressants, including fluoxetine, paroxetine, duloxetine, vilazodone, 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. On the basis of these results, it was concluded transdermal selegiline has similar effectiveness to other antidepressants. 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. 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). The effectiveness of transdermal selegiline for depression relative to side effects and discontinuation was considered to be favorable.

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. Although multiple doses of transdermal selegiline were assessed, a dose–response relationship for depression was never established. Transdermal selegiline has shown similar clinical effectiveness in the treatment of atypical depression relative to typical depression and in the treatment of anxious depression relative to non-anxious depression.

Transdermal selegiline does not cause sexual dysfunction and may improve certain domains of sexual function, for instance sexual interest, maintaining interest during sex, and sexual satisfaction. These benefits were apparent in women but not in men. The lack of sexual dysfunction with transdermal selegiline is in contrast to many other antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), which are associated with high rates of sexual dysfunction.

Transdermal selegiline patches have been underutilized in the treatment of depression compared to other antidepressants. A variety of factors contributing to this underutilization have been identified. One major factor is the very high cost of transdermal selegiline, which is often not covered by insurance and frequently proves to be prohibitive. Conversely, other widely available antidepressants are much cheaper in comparison.

Available forms

Selegiline is available in the following three pharmaceutical forms:

• Oral tablets and capsules 5 mg (brand names Eldepryl, Jumex, and generics)
• Orally disintegrating tablets (ODTs) 1.25 mg (brand names Zelapar)
• Transdermal patches 6, 9, and 12 mg/24 hours (brand name Emsam)

The transdermal patch form is also known as the "selegiline transdermal system" or "STS" and is applied once daily.

Contraindications

Selegiline is contraindicated with serotonergic antidepressants including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), with serotonergic opioids like meperidine, tramadol, and methadone, with other monoamine oxidase inhibitors (MAOIs) such as linezolid, phenelzine, and tranylcypromine, and with dextromethorphan, St. John's wort, cyclobenzaprine, pentazocine, propoxyphene, and carbamazepine. Combination of selegiline with serotonergic agents may cause serotonin syndrome, while combination of selegiline with adrenergic or sympathomimetic agents like ephedrine or amphetamines may cause hypertensive crisis. Long washout periods are required before starting and stopping these medications with discontinuation or initiation of selegiline.

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. 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 means, chocolate, and cream products.

The preceding drug and food contraindications are dependent on selegiline dose and route, and hence are not necessarily absolute contraindications. While high oral doses of selegiline (≥20 mg/day) can cause such interactions, oral doses within the approved clinical range (≤10 mg/day) appear to have little to no risk of these interactions. In addition, the ODT and transdermal forms of selegiline have reduced risks of such interactions compared to the conventional oral form.

Selegiline is also contraindicated in children less than 12 years of age and in people with pheochromocytoma, both due to heightened risk of hypertensive crisis. For all human uses and all forms, selegiline is pregnancy category C, meaning that studies in pregnant animals have shown adverse effects on the fetus but there are no adequate studies in humans.

Side effects

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. Most of the side effects are due to a high dopamine signaling, and can be alleviated by reducing the dose of levodopa. Selegiline can also cause cardiovascular side effects such as orthostatic hypotension, hypertension, atrial fibrillation, and other types of cardiac arrhythmias.

The main side effects of the patch form for depression include application-site reactions, insomnia, dry mouth, dizziness, nervousness, and abnormal dreams. The selegiline patch carries a black box warning about a possible increased risk of suicide, especially for young people, as do all antidepressants since 2007.

Side effects of selegiline that have been identified as occurring significantly more often than with placebo in meta-analyses for psychiatric disorders have included dry mouth (RRTooltip Risk ratio = 1.58), insomnia (RR = 1.61, NNHTooltip Number needed to harm = 19), and application site reactions with the transdermal form (RR = 1.81, NNH = 7). No significant diarrhea, headache, dizziness, nausea, sexual dysfunction, or weight gain were apparent in these meta-analyses.

Selegiline does not appear to increase mortality in people with Parkinson's disease. However, it appears to worsen cognition in people with Parkinson's disease over time. Conversely, rasagiline does not seem to do so and can enhance cognition.

Rarely, selegiline has been reported to induce or exacerbate impulse control disorders, hypersexuality, and paraphilias in people with Parkinson's disease. However, MAO-B inhibitors like selegiline causing impulse control disorders is uncommon and controversial. Selegiline has also been reported to activate or worsen rapid eye movement (REM) sleep behavior disorder in some people with Parkinson's disease.

Selegiline has shown no misuse potential in humans or monkeys. Likewise, it has no dependence potential in rodents. This is in spite of its amphetamine active metabolites, levomethamphetamine and levoamphetamine, and is in contrast to agents like dextroamphetamine and dextromethamphetamine. However, selegiline can strongly potentiate the reinforcing effects of exogenous β-phenethylamine by inhibiting its MAO-B-mediated metabolism. Misuse of the combination of selegiline and β-phenethylamine has been reported.

Overdose

Little information is available about clinically significant selegiline overdose. The drug has been studied clinically at doses as high as 60 mg/day orally, 10 mg/day as an ODT, and 12 mg/24 hours as a transdermal patch. In addition, deprenyl (the racemic form) has been clinically studied at doses as large as 100 mg/day. During clinical development of oral selegiline, some individuals who were exposed to doses of 600 mg developed severe hypotension and psychomotor agitation. 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 inhibitors (MAOIs) like phenelzine, isocarboxazid, and tranylcypromine. Serotonin syndrome, hypertensive crisis, and/or death may occur with overdose. No specific antidote to selegiline overdose is available.

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 inhibitors (SSRIs) and the cough medicine dextromethorphan (DXM). Selegiline in combination with the opioid analgesic pethidine is not recommended, as it can lead to severe adverse effects. Several other synthetic opioids such as tramadol and methadone, as well as various triptans, are also contraindicated due to potential for serotonin syndrome.

All three forms of selegiline carry warnings about food restrictions to avoid hypertensive crisis that are associated with MAOIs. 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. The lowest dose of the patch method of delivery, 6 mg/24 hours, does not require any dietary restrictions. 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 (RIMA) moclobemide, require a low-tyramine diet.

Cytochrome P450 inhibitors and inducers

The cytochrome P450 enzymes involved in the metabolism of selegiline have not been fully elucidated. CYP2D6 and CYP2C19 metabolizer phenotypes did not significantly affect the pharmacokinetics of selegiline, suggesting that these enzymes are minimally involved in its metabolism and that inhibitors and inducers of these enzymes would not importantly affect its pharmacokinetics. Likewise, 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. On the other hand, the anticonvulsant carbamazepine, which is known to act as a strong inducer of CYP3A enzymes, 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). One enzyme thought to be majorly involved in the metabolism of selegiline based on in-vitro studies is CYP2B6. However, there are no clinical studies of different CYP2B6 metabolizer phenotypes or of CYP2B6 inhibitors or inducers on the pharmacokinetics of selegiline. In addition to CYP2B6, CYP2A6 may be involved in the metabolism of selegiline to a lesser extent.

Birth control pills containing ethinylestradiol and a progestin like gestodene or levonorgestrel have been found to increase peak levels and overall exposure to oral selegiline by 10- to 20-fold. High levels of selegiline can lead to loss of MAO-B selectivity and inhibition of MAO-A as well. This increases susceptibility to side effects and interactions of non-selective monoamine oxidase inhibitors (MAOIs), such as tyramine-induced hypertensive crisis and serotonin toxicity when combined with serotonergic medications. However, this study had a small sample size of 4 individuals as well as other methodological limitations. 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. In contrast to birth control pills containing ethinylestradiol, menopausal hormone therapy with estradiol and levonorgestrel did not modify peak levels of selegiline and only modestly increased overall exposure (+59%). Hence, menopausal hormone therapy does not pose the same risk of interaction as ethinylestradiol-containing birth control pills when taken together with selegiline.

Selegiline inhibition of cytochrome P450 enzymes

Selegiline has been reported to inhibit several cytochrome P450 enzymes, including CYP2D6, CYP3A4/5, CYP2C19, CYP2B6, and CYP2A6. It is a mechanism-based inhibitor of CYP2B6 and has been said to "potently" or "strongly" inhibit this enzyme in vitro. It may inhibit the metabolism of bupropion, a major CYP2B6 substrate, into its active metabolite hydroxybupropion. However, a study predicted that inhibition of CYP2B6 by selegiline would non-significantly affect exposure to bupropion. Selegiline has not been listed or described as a clinically significant CYP2B6 inhibitor by the Food and Drug Administration (FDA) as of 2023. One small study observing three patients found that selegiline was safe and well-tolerated in combination with bupropion. Selegiline is also a potent mechanism-based inhibitor of CYP2A6 and may increase exposure to nicotine. By inhibiting cytochrome P450 enzymes like CYP2B6 and CYP1A2, selegiline may inhibit its own metabolism and thereby interact with itself.

Other interactions

Selegiline, at an MAO-B-selective dosage, did not appear to modify the pharmacological effects or pharmacokinetics of intravenous methamphetamine in one study. 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.

Dopamine antagonists like antipsychotics or metoclopramide, which block dopamine receptors and thereby antagonize the dopaminergic effects of selegiline, could potentially reduce the effectiveness of selegiline.

Pharmacology

Pharmacodynamics

Monoamine oxidase inhibitor

Selegiline acts as an enzyme inhibitor of the enzyme monoamine oxidase (MAO) and hence is known as a monoamine oxidase inhibitor (MAOI). There are two types of MAO, MAO-A and MAO-B. MAO-A metabolizes the monoamine neurotransmitters serotonin, dopamine, and norepinephrine as well as trace amines like tyramine, whereas MAO-B metabolizes dopamine and the trace amine β-phenethylamine. At lower concentrations and at typical clinical doses (≤10 mg/day), selegiline selectively inhibits MAO-B. Conversely, at higher concentrations and doses (≥20 mg/day), selegiline additionally inhibits MAO-A. By selectively inhibiting MAO-B, selegiline increases levels of dopamine in the brain and thereby increases dopaminergic neurotransmission. At higher doses, by inhibiting both MAO-A and MAO-B, selegiline increases brain levels of serotonin, dopamine, and norepinephrine and thereby increases serotonergic, dopaminergic, and noradrenergic neurotransmission. Selegiline is an irreversible mechanism-based inhibitor of MAO that acts by covalently binding to the active site of the protein and thereby disabling it.

Selegiline is thought to exert its therapeutic effects in the treatment of the motor symptoms of Parkinson's disease by increasing dopamine levels in the substantia nigra pars compacta (SNpc) of the basal ganglia, which projects to the caudate nucleus and putamen of the striatum, thereby enhancing the signaling of the nigrostriatal pathway. In addition to the nigrostriatal pathway, selegiline may also influence and potentiate other dopaminergic pathways and areas, including the mesolimbic pathway, mesocortical pathway, tuberoinfundibular pathway, and chemoreceptor trigger zone, which may also be involved in its effects as well as side effects. Selegiline and other MAO-B inhibitors may additionally improve non-motor symptoms in Parkinson's disease, for instance depression and motivational deficits, by increasing dopamine levels. Selegiline may have some disease-modifying neuroprotective effects in Parkinson's disease by inhibiting the MAO-B-mediated oxidation of dopamine into reactive oxygen species that damage dopaminergic neurons in the nigrostriatal pathway via oxidative stress. However, the pathophysiology of Parkinson's disease is complex and multifacted, and MAO-B inhibitors may only slow the progression of the disease and do not halt it.

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. Inhibition of platelet MAO-B activity persisted at above 90% for 5 days and almost 14 days were required before activity returned to baseline. A lower dose of selegiline of 1 mg/day also inhibits platelet MAO-B activity by 70 to 100%. However, despite this potent and long-lasting inhibition, optimal effectiveness in Parkinson's disease requires a dosage of 10 mg/day and the effectiveness lasts only about 2 to 3 days with discontinuation of selegiline. Based on the preceding findings, selegiline almost completely inhibits platelet MAO-B act a dosage of 10 mg/day. It is assumed that peripheral and brain MAO-B are inhibited with selegiline to similar extents. Accordingly, selegiline at an MAO-B-selective dosage of 10 mg/day has been found to inhibit brain MAO-B by more than 90% in postmortem individuals with Parkinson's disease. This dosage of selegiline has been found in such individuals to produce increases in brain levels of dopamine of 23 to 350% and of β-phenethylamine of 1,200 to 3,400% depending on the brain area and the study. Brain MAO-B levels recover slowly upon discontinuation of selegiline, with a half-time of brain MAO-B synthesis and recovery of approximately 40 days in humans.

Selegiline is about 500 to 1,000 times more potent in inhibiting MAO-B than MAO-A in vitro and about 100 times more potent in vivo in rodents. The clinical selectivity of selegiline for MAO-B is lost at doses of the drug above 20 mg/day. In a study of post-mortem individuals who were on selegiline 10 mg/day, MAO-A activity in the brain was inhibited by 38 to 86%. A more recent study using positron emission tomography (PET) imaging similarly found inhibition of brain MAO-A by 33 to 70% in humans. However, while brain dopamine and β-phenethylamine levels are substantially increased at this dosage, brain levels of serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) remain unchanged. It has been found in animal studies that brain MAO-A must be inhibited by nearly 85% before serotonin, norepinephrine, or dopamine levels increase and result in increased functional activity as well as accompanying behavioral changes. Selegiline at an oral dosage of 10 mg/day does not cause the "cheese effect" as assessed by oral tyramine and β-phenethylamine challenge tests. These findings indicate that selegiline does not importantly inhibit MAO-A at a dosage of 10 mg/day. 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. The "cheese reaction" is known to be specifically dependent on inhibition of intestinal MAO-A.

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

Besides selegiline itself, its major metabolite desmethylselegiline is pharmacologically active. 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. 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. As such, desmethylselegiline may contribute significantly to the MAO-B inhibition with selegiline.

Findings from a 2021 study suggest that MAO-A is solely or almost entirely responsible for the striatal metabolism of dopamine rather than MAO-B. Conversely, MAO-B was found to regulate tonic GABA levels and to indirectly enhance dopaminergic neurotransmission. These findings warrant a rethinking of the pharmacological actions of MAO-B inhibitors like selegiline in the treatment of Parkinson's disease.

Catecholaminergic activity enhancer

Selegiline has been found to act as a catecholaminergic activity enhancer (CAE). It selectively enhances the activity of noradrenergic and dopaminergic neurons and does not affect the activity of serotonergic neurons. The CAE actions of selegiline are distinct from those of catecholamine releasing agents like amphetamines. Conversely, the actions are shared with certain trace amines like β-phenethylamine and tryptamine. Selegiline and other CAEs enhance only impulse propogation-mediated release of catecholamines. In relation to this, they lack the misuse potential of amphetamines. Selegiline is active as a CAE at far lower concentrations and doses than those at which it starts to inhibit the monoamine oxidases. For example, selegiline given subcutaneously in rodents selectively inhibits MAO-B with a single dose of at least 0.2 mg/kg, whereas CAE effects are apparent for noradrenergic neurons at a dose of 0.01 mg/kg (+42% activity) and for dopaminergic neurons at a dose of 0.025 mg/kg (+17% activity). Selegiline is presently the only registered pharmaceutical medication with CAE actions that lacks concomitant potent catecholamine releasing effects.

Other monoamine activity enhancers (MAEs) besides selegiline, like phenylpropylaminopentane (PPAP) and benzofuranylpropylaminopentane (BPAP), have been developed. PPAP was derived from selegiline (and by extension from β-phenethylamine), while BPAP was derived from tryptamine. These compounds are more potent and selective in their MAE actions than selegiline. In addition, BPAP is an activity enhancer of not only catecholaminergic neurons but also of serotonergic neurons. Unlike selegiline, PPAP and BPAP lack the MAO inhibition and amphetamine metabolites of selegiline.

The actions of MAEs including selegiline may be due to TAAR1 agonism. TAAR1 agonists have been found to enhance the release of monoamine neurotransmitters like dopamine and serotonin analogously to MAEs, trace amines like β-phenethylamine and tryptamine are known to act as both TAAR1 agonists and MAEs, and the TAAR1 antagonist EPPTB has been shown to reverse the CAE effects of BPAP and selegiline. However, it has yet to be determined whether MAEs like BPAP and selegiline actually directly bind to and activate the TAAR1. In any case, selegiline's active metabolites levomethamphetamine and levoamphetamine have been confirmed to bind to and activate the TAAR1. As with selegiline, levomethamphetamine is also a CAE, although it is about 10-fold less potent in this action than selegiline itself.

In contrast to selegiline, rasagiline is devoid of CAE actions. In fact, it actually inhibits the CAE effects of selegiline. This may explain differences in effectiveness between selegiline and rasagiline in the treatment of Parkinson's disease. According to József Knoll, one of the original developers of selegiline, the CAE effect of selegiline may be more important than MAO-B inhibition in terms of effectiveness for Parkinson's disease. Rasagiline may act as a TAAR1 antagonist to mediate its anti-CAE effects. However, as with selegiline, binding to and modulation of the TAAR1 by rasagiline still requires confirmation.

TAAR1 agonists like ulotaront and ralmitaront are under investigation for treatment of a variety of psychiatric disorders, such as depression and schizophrenia.

Selegiline has potent pro-sexual or aphrodisiac effects in male rodents. The pro-sexual effects of selegiline are stronger than those of dopamine agonists like apomorphine and bromocriptine and high doses of amphetamine. These effects are not shared with other MAO-B inhibitors or the MAO-A inhibitor clorgiline and hence do not appear to be related to MAO inhibition. Instead, the CAE actions of selegiline have been implicated in the pro-sexual effects. Although selegiline has shown potent pro-sexual effects in rodents, these effects were not subsequently confirmed in primates. In humans, selegiline for depression shows minimal pro-sexual effects in men, though it did significantly enhance several areas of sexual function in women.

Catecholamine releasing agent

Two of selegiline's major metabolites, levomethamphetamine and levoamphetamine, are pharmacologically active. Levomethamphetamine and levoamphetamine are sympathomimetic agents that work by inducing the release of norepinephrine and dopamine. However, whereas the psychostimulants dextromethamphetamine and dextroamphetamine are relatively balanced releasers of dopamine and norepinephrine, levomethamphetamine is about 15-fold more potent in releasing norepinephrine relative to dopamine in vitro. Similarly, levomethamphetamine and levoamphetamine are 10 times less potent at stimulating locomotor activity (a measure of psychostimulant effect) than dextromethamphetamine and dextroamphetamine in rodents. Hence, these agents act more as selective norepinephrine releasing agents than as dual releasers of norepinephrine and dopamine. The involvement of these metabolites in the effects of selegiline is controversial. Both beneficial and harmful effects of these metabolites have been postulated. It is unknown whether selegiline's amphetamine metabolites are involved in its effectiveness in the treatment of Parkinson's disease.

It has been said that the amphetamine metabolites of selegiline might improve fatigue, but could also produce cardiovascular side effects like increased heart rate and blood pressure and reportedly may be able to cause insomnia, euphoria, psychiatric disturbances, and psychosis. 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. However, cardiovascular side effects of selegiline have been found clinically and have been attributed to its amphetamine metabolites. For comparison, rasagiline, which lacks amphetamine metabolites, has shown fewer adverse effects in clinical studies. Animal studies suggest that selegiline's amphetamine metabolites may indeed be involved in its effects, such as arousal, wakefulness, and locomotor activity.

In clinical studies, levomethamphetamine at oral doses of 1 to 10 mg has been found not to affect subjective drug responses, heart rate, blood pressure, core temperature, electrocardiography, respiration rate, oxygen saturation, or other clinical parameters. As such, doses of levomethamphetamine of less than or equal to 10 mg have no significant physiological or subjective effects. However, higher doses of levomethamphetamine, for instance 0.25 to 0.5 mg/kg (mean doses of ~18–37 mg) intravenously, have been reported to produce significant pharmacological effects, including increased heart rate and blood pressure, increased respiration rate, and subjective effects like intoxication and drug liking. On the other hand, in contrast to dextroamphetamine and dextromethamphetamine, levomethamphetamine also produces subjective "bad" or aversive drug effects. As with levomethamphetamine, oral doses of levoamphetamine of 20 to 60 mg have been reported to produce significant effects, for instance on wakefulness and mood. With a 10 mg oral dose of selegiline, about 2 to 6 mg levomethamphetamine and 1 to 3 mg levoamphetamine is excreted in urine.

The amphetamine metabolites of selegiline being involved in its effectiveness in the treatment of Parkinson's disease has been deemed unlikely. High doses of levoamphetamine, for instance 50 mg/day, have been reported to be slightly effective in the treatment of Parkinson's disease. It has been postulated that amphetamines are limitedly effective for Parkinson's disease as there is inadequate presynaptic dopamine to be released in patients with the condition. In any case, this effectiveness of high doses of levoamphetamine could not be relevant to selegiline, which is administered at a dose of 10 mg/day. Accordingly, relatively low levels of levoamphetamine occur with selegiline. 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. This led the researchers to conclude that the beneficial clinical effects of selegiline in Parkinson's disease were not due to its amphetamine metabolites. It is possible that there could be some small synergistic beneficial effect of selegiline with its amphetamine metabolites, but this has been considered improbable.

Dextromethamphetamine and dextroamphetamine are known to produce dopaminergic neurotoxicity at high doses. Such toxicity would be especially unfavorable in the context of Parkinson's disease. However, levomethamphetamine and levoamphetamine are much weaker releasers of dopamine than the corresponding dextrorotatory enantiomers and have differing actions. The levels of levomethamphetamine and levoamphetamine with typical clinical doses of selegiline are far lower than the levels of the corresponding dextrorotatory enantiomers that are known to produce clear signs of neurotoxicity. As such, dopaminergic neurotoxicity with selegiline due to its amphetamine metabolites and consequent aggravation of Parkinson's disease is unlikely.

Newer formulations of selegiline, such as the ODT and transdermal patch forms, have been developed which strongly reduce formation of the amphetamine metabolites and their associated effects. In addition, other MAO-B inhibitors that do not metabolize into amphetamines, like rasagiline and safinamide, have been developed and introduced.

Dopaminergic neuroprotection

Starting around the age of 45, dopamine content in the caudate nucleus decreases at a rate of about 13% per decade, and this neurodegeneration extends to the nigrostriatal dopaminergic pathway in general. This is a very high rate of neuronal decay relative to brain aging generally. Similarly, age-related decay of mesolimbic dopaminergic neurons as well as noradrenergic neurons is substantially slower than in the nigrostriatal pathway. Symptoms of Parkinson's disease are known to develop when the dopamine content of the caudate nucleus drops below 30% of the normal level. Loss of striatal dopamine reaches a level of 40% in healthy people by the age of 75, whereas in people with Parkinson's disease, the loss is around 70% at diagnosis and more than 90% at death. Only about 0.1% of the human population develops Parkinson's disease. In these individuals, the nigrostriatal pathway deteriorates more rapidly and prematurely than usual, for instance at a rate of 30 to 90% loss of dopamine content per decade. However, it is thought that if humans lived much longer than the average lifespan, everyone would eventually develop Parkinson's disease. Besides the nigrostriatal pathway, there is also considerable, albeit lesser, loss of dopaminergic neurons in people with Parkinson's disease in other pathways and areas, like the mesolimbic and mesocortical pathways. There is even substantial loss of dopamine in non-brain tissues, like the adrenal cortex and retina, implicating a generalized degeneration of the whole dopamine system.

The progressive loss of dopaminergic neurons in the nigrostriatal pathway as well as other areas has implications not only for motor control and risk of Parkinson's disease but also for cognition, emotions, learning, sexual activity, and other processes. Dopamine itself is thought to play a major role in this degeneration by metabolism into reactive oxygen species that damage dopaminergic neurons. Age-related degeneration of nigrostriatal dopaminergic neurons is similar in rodents and humans. Selegiline has been found to prevent the age-related morphological changes in the nigrostriatal pathway of rodents and to produce accompanying preservations of cognitive and sexual functions. These protective effects may be mediated by actions of selegiline including MAO-B inhibition, its catetcholaminergic activity enhancer activity, and other actions. According to József Knoll and Ildikó Miklya, two of the developers of selegiline, the drug may act as a neuroprotective and may be able to slow the rate of age-related dopaminergic neurodegeneration in humans. Knoll has advocated for the widespread use of a low dose of selegiline (1 mg/day or 10–15 mg/week) in the healthy population for such purposes. However, antiaging and anti-neurodegenerative effects of selegiline in humans have not been clearly demonstrated as of present and this theory remains to be demonstrated.

Other actions

Selegiline has a weak dopamine releasing effect, weakly blocks dopamine receptors, and weakly inhibits the reuptake of norepinephrine. However, these actions are all of very low potency and are of questionable clinical significance. On the basis of positron emission tomography research, selegiline does not significantly inhibit the brain dopamine transporter in humans at clinical doses. The ODT and patch formulations of selegiline were used in this study.

Selegiline appears to activate σ₁ receptors, having a relatively high affinity for these receptors of approximately 400 nM.

Unlike some of the hydrazine MAOIs like phenelzine and isocarboxazid, selegiline does not inhibit semicarbazide-sensitive amine oxidase (SSAO; also known as primary amine oxidase (PrAO) or as diamine oxidase (DAO)) nor does it pose a risk of vitamin B6 deficiency. As a result, selegiline does not have risks of the side effects of these actions.

Selegiline has been reported to inhibit several cytochrome P450 enzymes, including CYP2D6, CYP3A4/5, CYP2C19, CYP2B6, and CYP2A6.

Pharmacokinetics

Absorption

Selegiline has an oral bioavailability of about 4 to 10%. 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.

The circulating levels of selegiline and its metabolites following a single 10 mg oral dose have been studied. The metabolites of selegiline include desmethylselegiline, levomethamphetamine, and levoamphetamine. 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. 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. 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. 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. Levels of desmethylselegiline and levomethamphetamine are 10- to 20-fold higher than selegiline levels with oral selegiline therapy.

With repeated administration of selegiline, there is an accumulation of selegiline and its metabolites. 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. 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. The metabolites of selegiline accumulate to a smaller extent than selegiline. 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. Selegiline appears to inhibit its own metabolism and that of desmethylselegiline with continuous use.

The oral bioavailability of selegiline increases when it is ingested together with a fatty meal, as the molecule is fat-soluble. 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. The elimination half-life of selegiline is unchanged when it is taken with food. In contrast to selegiline itself, the pharmacokinetics of its metabolites, desmethylselegililne, levomethamphetamine, and levoamphetamine, are unchanged when selegiline is taken with food.

Distribution

The apparent volume of distribution of selegiline is 1,854 ± 824 L. Selegiline and its metabolites rapidly cross the blood–brain barrier and enter the brain, where they most concentrated at the thalamus, basal ganglia, midbrain, and cingulate gyrus. Selegiline especially accumulates in brain areas with high MAO-B content, such as the thalamus, striatum, cortex, and brainstem. Concentrations of selegiline's metabolites in cerebrospinal fluid (CSF) are similar to those in blood, suggesting that accumulation in the brain over peripheral tissues does not occur.

No data were originally available on the plasma protein binding of selegiline. It has been stated that the plasma protein binding of selegiline is 94%, but there is no actual evidence to support this figure. Subsequent research found that its plasma protein binding is 85 to 90%.

Metabolism

Selegiline is metabolized in the intestines, liver, and other tissues. More than 90% of orally administered selegiline is metabolized prior to reaching the bloodstream due to strong first-pass metabolism. Selegiline (L-N-propargylmethamphetamine) is metabolized by N-demethylation into levomethamphetamine and by N-depropargylation into desmethylselegiline (L-N-propargylamphetamine). Subsequently, levomethamphetamine is further metabolized into levoamphetamine by N-demethylation and desmethylselegiline is further metabolized into levoamphetamine by N-depropargylation. Levomethamphetamine, levoamphetamine, and desmethylselegiline constitute the three major or primary metabolites of selegiline. No racemization occurs in the metabolism of selegiline or its metabolites; that is, the levorotatory enantiomers are not converted into the dextrorotatory enantiomers, such as D-deprenyl, dextromethamphetamine, or dextroamphetamine. Following their formation, the amphetamine metabolites of selegiline are also metabolized via hydroxylation and then conjugation via glucuronidation. Besides the preceding metabolites, selegiline-N-oxide and formaldehyde are also known to be formed. More than 40 minor metabolites of selegiline have been either detected or proposed. Due to the amphetamine metabolites of selegiline, people taking selegiline may test positive for "amphetamine" or "methamphetamine" on drug screening tests.

The exact cytochrome P450 enzymes responsible for the metabolism of selegiline have not been fully elucidated. CYP2B6, CYP2C9, and CYP3A are thought to be significantly involved in the metabolism of selegiline on the basis of in vitro studies. Other cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP2C8, CYP2D6, CYP2C19, and CYP2E1, may also be involved. One review concluded that CYP2B6 and CYP2C19 are the leading candidates in selegiline metabolism. CYP2B6 is thought to N-demethylate selegiline into desmethylselegiline and CYP2B6 and CYP2C19 are thought to N-depropargylate selegiline into levomethamphetamine. Additionally, CYP2B6 and CYP2C19 are thought to metabolize desmethylselegiline into levoamphetamine and CYP2B6 is thought to N-demethylate levomethamphetamine into levoamphetamine. CYP2D6 and CYP2C19 metabolizer phenotypes did not significantly affect the pharmacokinetics of selegiline, suggesting that these enzymes are minimally involved in its metabolism. 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. 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.

Elimination

Selegiline administered orally is recovered 87% in urine and 15% in feces as the unchanged parent drug and its metabolites. Of selegiline excreted in urine, 20 to 63% is excreted as levomethamphetamine, 9 to 26% as levoamphetamine, 1% as desmethylselegiline, and 0.01 to 0.03% at unchanged selegiline. In the case of levomethamphetamine and levoamphetamine, with an oral dose of 10 mg selegiline, this would be amounts of about 2 to 6 mg levomethamphetamine and about 1 to 3 mg levoamphetamine. The near-absence of unchanged excreted selegiline indicates that selegiline is essentially completely metabolized prior to its excretion.

The average elimination half-life of selegiline after a single oral dose ranges from 1.2 hours to 1.9 hours across studies. With repeated administration, the half-life of selegiline increases to 7.7 ± 12.6 hours to 9.6 ± 13.6 hours. The elimination half-life of selegiline's metabolite, desmethylselegiline, has been reported to range from 2.2 ± 0.6 hours to 3.8 hours. The half-lives of its metabolites levomethamphetamine and levoamphetamine have been reported to be 14 hours and 16 hours, respectively. 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. Selegiline is a known inhibitor of several cytochrome P450 enzymes, such as CYP2B6 and CYP2A6. It appears to inhibit its own metabolism and the metabolism of its metabolite desmethylselegiline.

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

Orally disintegrating tablet

Selegiline as an orally disintegrating tablet (ODT) is absorbed primarily buccally instead of being swallowed orally. It was found to have 5- to 8-fold higher bioavailability, more consistent blood levels, and to produce fewer amphetamine metabolites than the standard oral tablet form. It 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. 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. Hence, levels of these metabolites are 10-fold lower with the ODT formulation. The levels of amphetamine metabolites with the ODT formulation have been regarded as negligible. 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.

Transdermal patch

The selegiline transdermal patch is indicated for application to the upper torso, upper thigh, or the outer upper arm once every 24 hours. With application, an average of 25 to 30% (range 10 to 14%) of the selegiline content of the patch is delivered systemically over 24 hours. This equates to about 0.3 mg selegiline per cm² over 24 hours. The patch has approximately 75% bioavailability, compared to 4 to 10% with the conventional oral form. Transdermal selegiline results in significantly higher exposure to selegiline and lower exposure to all metabolites compared to conventional oral selegiline. Selegiline levels are 50-fold higher and exposure to its metabolites 70% lower with the transdermal patch compared to oral administration at equivalent doses. These differences are due to extensive first-pass metabolism with the oral form and the bypassing and absence of the first pass with the patch form. Selegiline absorption and levels have been found to be equivalent when applied to the upper torso versus the upper thigh. The drug does not accumulate in skin and is not significantly metabolized in skin.

Chemistry

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. This detail is borrowed from pargyline, an older MAO-B inhibitor of the phenylalkylamine group. Selegiline is the levorotatory enantiomer of the racemic mixture deprenyl. D-deprenyl is the dextrorotatory enantiomer. Another clinically used MAOI of the amphetamine class is tranylcypromine.

Synthesis

Selegiline is synthesized by the alkylation of levomethamphetamine using propargyl bromide.

History

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 monoamine oxidase (MAO) and elevation of monoamine neurotransmitters in the brain, many people and companies started trying to discover monoamine oxidase inhibitors (MAOIs) to use as antidepressants. Deprenyl, the racemic form of selegiline, was synthesized and discovered by Zoltan Ecseri at the Chinoin Pharmaceutical Company (part of Sanofi since 1993) in Budapest, Hungary. Chinoin received a patent on the drug in 1962 and the compound was first published in the scientific literature in English in 1965. Chinoin researchers had been studying substituted amphetamines since 1960, and decided to try synthesizing amphetamines that acted as MAOIs. It had been known that methamphetamine was a reversible inhibitor of MAO. Deprenyl, also known as N-propargyl-N-methylamphetamine, is closely related to and inspired by pargyline (N-propargyl-N-methylbenzylamine), another MAOIs that had been synthesized earlier. Deprenyl was initially referred to by the chemical name phenylisopropylmethylpropinylamine and the developmental code name E-250. 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.

Deprenyl is a racemic compound (a mixture of two isomers called enantiomers). Further work determined that the levorotatory enantiomer was a more potent MAOI, which was published in 1967, and subsequent work was done with the single enantiomer L-deprenyl. In 1968, it was discovered by Johnston that monoamine oxidase exists in multiple forms. 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 consuming foods containing tyramine) that occurs with non-selective MAOIs. 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.

Deprenyl and selegiline were initially studied as antidepressants for treatment of depression. Deprenyl was first found to be effective for depression from 1965 to 1967, while selegiline was first found to be effective for depression in 1971 and this was further corroborated in 1980. A 1984 study that combined selegiline with β-phenethylamine reported remarkably high effectiveness in the treatment of depression similar to that with electroconvulsive therapy (ECT). However, selegiline in its original oral form was never further developed or approved for the treatment of depression.

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.

In the 1970s, there was also speculation that selegiline could be useful as an anti-aging drug or aphrodisiac.

Selegiline was first introduced for clinical use in Hungary in 1977. It was approved in the oral pill form under the brand name Jumex to treat Parkinson's disease. The drug was then introduced in the United Kingdom in 1982. 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. While the NDA was under review, Somerset was acquired in a joint venture by two generic drug companies, Mylan and Bolan Pharmaceuticals. Selegiline was approved for Parkinson's disease by the FDA in 1989.

Selegiline was first shown to metabolize into levomethamphetamine and levoamphetamine in humans in 1978. The involvement of these metabolites in the effects and side effects of selegiline has remained controversial and unresolved in the decades afterwards. 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.

The catecholaminergic activity enhancer (CAE) effects of selegiline became well-characterized and distinctly named by 1994. 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. More potent, selective, and/or expansive monoamine activity enhancers (MAEs), like phenylpropylaminopentane (PPAP) and benzofuranylpropylaminopentane (BPAP), were derived from selegiline and other compounds and were first described in 1992 and 1999, respectively. 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.

Emsam transdermal patch, 6 mg/24 hours dose.

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 MAOIs. Somerset obtained FDA approval to market the patch for depression in 2006. 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.

Binding to and agonism of the TAAR1 as the mechanism responsible for the MAE effects of selegiline and related MAEs like PPAP and BPAP was first suggested by 2007 and was first substantiated in 2022. TAAR1 agonists like ulotaront and ralmitaront are under development for treatment of various psychiatric disorders as of 2023.

Society and culture

Names

Selegiline is the generic name of the drug and its INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française, while selegiline hydrochloride is the USANTooltip United States Adopted Name. The word "selegiline" is pronounced /səˈlɛdʒɪliːn/ (sə-LEJ-i-leen) or as "seh-LEH-ji-leen". Selegiline is also known as L-deprenyl, L-deprenil, L-deprenalin, L-deprenaline, L-phenylisopropylmethylpropinylamine, and L-E-250. It should not be confused with the racemic form, deprenyl (E-250), or with the dextrorotatory enantiomer, D-deprenyl, which are distinct substances.

Major brand names of selegiline include Eldepryl and Jumex (oral tablet and capsule), Zelapar (orally disintegrating tablet or ODT), and Emsam (transdermal patch). The brand name "Emsam" was derived from the names of two children, Emily and Samuel, of one of the employees at Somerset Pharmaceuticals, the developer of Emsam.

Generic forms

Generic forms of oral selegiline are available in the United States. However, generic forms of the orally disintegrating tablet and the transdermal patch are not available in this country. The latter formulations of selegiline are very expensive, and this can be prohibitive to their use. There has been poor 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. It is expected that generics of the transdermal patch will become available at some point in the future.

Availability

Conventional oral selegiline (brand names Eldepryl, Jumex) is widely marketed throughout the world, including in over 60 countries. 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.

Notable users

David Pearce, a British transhumanist philosopher, wrote his self-published book-length internet manifesto The Hedonistic Imperative six weeks after starting to take selegiline.

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 years. He is also known to have simultaneously taken Adderall for treatment of attention deficit hyperactivity disorder (ADHD) and to have possessed non-pharmaceutical adrafinil, a prodrug of modafinil.

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.

Internet vendors

Selegline in non-pharmaceutical form is sold on the Internet without a prescription by online vendors for uses such as purported cognitive enhancement and anti-aging effects.

Presence in ecstasy

In his 1993 book E for Ecstasy examining the uses of the street drug ecstasy in the United Kingdom, the writer, activist, and ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained selegiline. 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.

Doping in sport

Selegline is on the World Anti-Doping Agency (WADA)'s list of prohibited substances. It is classified as a stimulant in this list, along with various amphetamines, methylphenidate, adrenergic sympathomimetics, modafinil, and other agents. 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 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 tests.

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. Knoll published his 2012 book How Selegiline ((-)-Deprenyl) Slows Brain Aging 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".

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

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 with selegiline in rodents. In humans with Parkinson's disease, selegline has been associated with cardiovascular and psychiatric complications and has not been found to reduce mortality in long-term studies. As such, the claimed anti-aging and longevity benefits of selegiline are controversial and uncertain.

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 and non-medically to improve cognitive performance. It is one of the most popular such agents. Selegiline has been found to have neuroprotective activity against certain neurotoxins and to increase the production of several brain growth factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF). The drug has also been found in animal models to improve learning ability and to help preserve it during ischemia and aging. Despite claims that selegiline and other claimed nootropics have cogintive-enhancing effects however, these effects are controversial and their benefits versus risks are uncertain.

Research

Depression

Selegiline has been clinically studied in combination with oral L-phenylalanine or β-phenethylamine in the treatment of depression and was reported to be effective. L-Phenylalanine is known to be metabolized into β-phenethylamine, selegiline is known to strongly inhibit the metabolism of β-phenethylamine, and β-phenethylamine has been implicated in having psychostimulant-like mood-lifting effects.

Anxiety

A small clinical study found that oral selegiline (10 mg/day) reduced symptoms of social anxiety disorder. The effectiveness was modest, with a reduction in social anxiety scores from baseline of 32% over 6 weeks of treatment.

ADHD

Selegiline has been limitedly studied in the treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults. 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. 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. 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. 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 pilot study sponsored by the manufacturer in 2003. However, there was a high rate of discontinuation and development was not further pursued.

Motivational disorders

Selegiline has been found to increase effort expenditure and to reverse pharmacologically-induced motivational deficits in rodents. In case reports and small clinical studies, selegiline has been reported to improve apathy in people with traumatic brain injury, stroke, and schizophrenia. In accordance with the preceding findings, selegiline, along with other dopaminergic and activating agents, is a potentially promising treatment for disorders of diminished motivation, including apathy, abulia, and akinetic mutism.

Addiction

Selegiline has been evaluated for smoking cessation both as a monotherapy and in combination with nicotine replacement therapy in five clinical studies. However, it is limitedly or not effective for this use. It was also evaluated for treatment of cocaine dependence in one study, but was similarly not effective. Studies are mixed on whether selegiline, at MAO-B-selective doses, reduces the effects of cocaine in humans. Selegiline, also at an MAO-B-selective dosage, did not modify or potentiate the pharmacological effects of intravenous methamphetamine in a small clinical study.

Sexual dysfunction

Selegiline has been assessed for treatment of sexual dysfunction induced by antipsychotics in people with schizophrenia, but was not effective in a single small clinical study. It also did not improve sexual function in men with depression, but did improve several domains of sexual function in women with depression.

Psychosis

Selegiline has been studied as an adjunct to antipsychotics in the treatment of schizophrenia in four clinical studies. However, it failed to significantly reduce positive or negative symptoms of schizophrenia in meta-analyses of these studies.

Excessive sleepiness

Selegiline has been evaluated for the treatment of narcolepsy in three small clinical studies. It was found to be effective in these studies. Selegiline has also been evaluated for treatment of hypersomnia (excessive sleeping or sleepiness) in people with myotonic dystrophy, but was not effective in a single small clinical study.

Periodic limb movement disorder

Selegiline has been studied in the treatment of periodic limb movement disorder (PLMD) in a single small open-label clinical study. It was reported to be effective as assessed by polysomnography, reducing periodic limb movements during sleep by about 60%. Selegiline has not been studied for the related condition restless legs syndrome (RLS) as of 2023. The drug has not been studied well enough in PLMD or RLS to be widely used in their treatment.

Tardive dyskinedia

Selegiline was studied in the treatment of antipsychotic-induced tardive dyskinesia in one small clinical study, but was ineffective.

Dementia and stroke

Selegiline has also been used off-label as a palliative treatment for dementia in Alzheimer's disease. However, its clinical effectiveness is limited or lacking for this use. It was also ineffective in the treatment of Lewy body dementia. 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.

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 clinical study. It was found to be effective in enhancing arousal and promoting recovery of consciousness in some of these individuals.

Neurotoxicity

Selegiline has been reported to protect against the damage caused by the potent dopaminergic and/or noradrenergic neurotoxins 6-hydroxydopamine (6-OHDA), N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in animals. Conversely, selegiline is ineffective in protecting against the serotonergic and noradrenergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT).

Selegiline has also been reported to protect against methylenedioxymethamphetamine (MDMA)-induced serotonergic neurotoxicity in rodents. 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 radicals, which is blocked by MAO-B inhibition. Likewise, selegiline prevented the serotonergic neurotoxicity of a combination of methylenedioxyaminoindane (MDAI) and dextroamphetamine.

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 (PCA). In addition, findings are mixed and conflicting on whether selegiline prevents amphetamine- and methamphetamine-induced dopaminergic neurotoxicity in rodents.

Although MAO-B-selective doses of selegiline protect against MDMA-induced serotonergic neurotoxicity in rodents, combination of amphetamines like MDMA with monoamine oxidase inhibitors, including selegiline, can produce serious complications, including serotonin syndrome, hypertensive crisis, and death.

Veterinary use

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). 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. Though it is labeled for dog use only, selegiline has been used off-label for geriatric cats with cognitive dysfunction.

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

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.

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

External links

• Selegiline (l-deprenyl) (from The Good Drug Guide) - David Pearce - BLTC Research