Selegiline

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 medications 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 11months to about 18months after diagnosis. There is some evidence that selegiline acts as a neuroprotective and reduces the rate of disease progression, though this is disputed. There is evidence that selegiline may be more effective than rasagiline in the treatment of Parkinson's disease. This may be due to pharmacological differences between the drugs, such as the catecholaminergic activity enhancer (CAE) actions of selegiline which rasagiline lacks. 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. which is similar to that with transdermal selegiline. 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. These benefits were apparent in women but not in men. Transdermal selegiline patches have been underutilized in the treatment of depression compared to other antidepressants. • Oral tablets and capsules 5mg (brand names Eldepryl, Jumex, and generics) – indicated for Parkinson's disease • Orally disintegrating tablets (ODTs) 1.25mg (brand name Zelapar) – indicated for Parkinson's disease • Transdermal patches 6, 9, and 12mg/24hours (brand name Emsam) – indicated for major depressive disorder The transdermal patch form is also known as the "selegiline transdermal system" or "STS" and is applied once daily. They are 20, 30, or 40cm2 in size and contain a total of 20, 30, or 40mg selegiline per patch (so 20mg/20cm2, 30mg/30cm2, and 40mg/40cm2), respectively. The selegiline transdermal patch is a matrix-type adhesive patch with a three-layer structure. It is the only approved non-oral MAOI, having reduced dietary restrictions and side effects in comparison to oral MAOIs, and is also the only approved non-oral first-line antidepressant. The selegiline patch can be useful for those who have difficulty tolerating oral medications. ==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. Examples of other foods that may have high amounts of tyramine and similar substances include yeast products, chicken liver, snails, pickled herring, red wines, some beers, canned figs, broad beans, chocolate, and cream products. 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 (≥20mg/day) can cause such interactions, oral doses within the approved clinical range (≤10mg/day) appear to have little to no risk of these interactions. 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 12years 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. 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, 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 ( = 1.58), insomnia ( = 1.61, = 19), and application site reactions with the transdermal form ( = 1.81, = 7). The rates of other orthostatic hypotension-related side effects in this population were dizziness or vertigo 4.9% versus 3.1% with placebo and fainting 0.5% versus 0.0% with placebo. Meta-analyses published in the 1990s found that the addition of selegiline to levodopa increased mortality in people with Parkinson's disease. If selegiline does increase mortality, it has been theorized that this may be due to cardiovascular side effects, such as its amphetamine-related sympathomimetic effects and its MAO inhibition-related hypotension. Although selegiline does not seem to increase mortality, 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. However, MAO-B inhibitors like selegiline causing impulse control disorders is uncommon, controversial, and less frequent than with dopamine receptor agonists like pramipexole. Selegiline has also been reported to activate or worsen rapid eye movement (REM) sleep behavior disorder (RBD) in some people with Parkinson's disease. Selegiline has shown little or 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. ==Overdose==

Little information is available about clinically significant selegiline overdose. 10mg/day as an ODT, and 12mg/24hours as a transdermal patch. In addition, deprenyl (the racemic form) has been clinically studied orally at doses as large as 100mg/day. During clinical development of oral selegiline, some individuals who were exposed to doses of 600mg 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. Selegiline in combination with the opioid analgesic pethidine is not recommended, as it can lead to severe adverse effects. All three forms of selegiline carry warnings about food restrictions to avoid hypertensive crisis that are associated with MAOIs. 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. Likewise, oral selegiline at an MAO-B-selective dosage did not appear to modify the pharmacodynamic effects or pharmacokinetics of intravenous methamphetamine in another 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. Cautious safe combination of MAOIs like selegiline with stimulants like lisdexamfetamine has been reported. However, a hypertensive crisis with selegiline and ephedrine has also been reported. Selegiline can interact with exogenous dopamine, which is metabolized by MAO-A and MAO-B, and result in hypertensive crisis as well. Besides norepinephrine releasing agents, selective norepinephrine reuptake inhibitors (NRIs) may be safe in combination with MAOIs like selegiline. Potent NRIs, such as reboxetine, desipramine, protriptyline, and nortriptyline, can reduce or block the pressor effects of tyramine, including in those taking MAOIs. However, initiation at low doses and slow upward dose titration is advisable in the case of both NRIs and NDRIs due to possible potentiation of their effects and side effects by MAOIs. Cytochrome P450 inhibitors and inducers The cytochrome P450 enzymes involved in the metabolism of selegiline have not been fully elucidated. However, although most pharmacokinetic variables were unaffected, overall exposure to selegiline's metabolite levomethamphetamine was 46% higher in CYP2D6 poor metabolizers compared to extensive metabolizers and exposure to its metabolite desmethylselegiline was 68% higher in CYP2C19 poor metabolizers compared to extensive metabolizers. Birth control pills containing the synthetic estrogen 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. Hence, menopausal hormone therapy does not pose the same risk of interaction as ethinylestradiol-containing birth control pills when taken together with selegiline. The anticonvulsants included phenobarbital, phenytoin, carbamazepine, and amobarbital. It may inhibit the metabolism of bupropion, a major CYP2B6 substrate, into its active metabolite hydroxybupropion. In addition to CYP2B6 and other cytochrome P450 enzymes, selegiline is a potent mechanism-based inhibitor of CYP2A6 and may increase exposure to nicotine (a major CYP2A6 substrate). By inhibiting cytochrome P450 enzymes like CYP2B6 and CYP1A2, selegiline may inhibit its own metabolism and thereby interact with itself. Other interactions Dopamine antagonists like antipsychotics or metoclopramide, which block dopamine receptors and thereby antagonize the dopaminergic effects of selegiline, could potentially reduce the effectiveness of the medication. ==Pharmacology==

Pharmacodynamics Selegiline has multiple known mechanisms of action in terms of its pharmacodynamic activity. However, these theoretical effects of selegiline have not been clearly demonstrated in humans as of present and remain to be substantiated. Through its active metabolites levomethamphetamine (L-MA) and levoamphetamine (L-A), selegiline acts as a weak norepinephrine and/or dopamine releasing agent (NDRA). Levels of selegiline's metabolites are much lower with the ODT and transdermal patch forms of selegiline than with the oral form and this may result in differences in its effects and side effects. ==Chemistry==

Selegiline is a substituted phenethylamine and amphetamine derivative. Selegiline is a small-molecule compound, with the molecular formula C13H17N and a low molecular weight of 187.281g/mol. Besides selegiline and pargyline, another clinically used MAOI of the phenylalkylamine and amphetamine families is the antidepressant tranylcypromine (trans-2-phenylcyclopropylamine). Another notable analogue of selegiline is 4-fluoroselegiline, a variation of selegiline in which one of the hydrogen atoms of the phenyl ring has been replaced with a fluorine atom. A large number of other analogues of selegiline derived via structural modification have been synthesized and characterized. Rasagiline ((R)-N-propargyl-1-aminoindan) is an analogue of selegiline in which the amphetamine base structure has been replaced with a 1-aminoindan structure and the N-methyl group has been removed. Synthesis Selegiline can be 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. Deprenyl was initially referred to by the chemical name phenylisopropylmethylpropinylamine and the developmental code name E-250. In 1968, it was discovered by J. P. 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. Selegiline was the first selective MAO-B inhibitor to be discovered Deprenyl and selegiline were initially studied as antidepressants for treatment of depression. 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 phenylalanine reported remarkably high effectiveness in the treatment of depression similar to that with electroconvulsive therapy (ECT). Speculation, by József Knoll, that selegiline could be useful as an anti-aging and pro-sexual agent, began in the 1980s. Selegiline was first introduced for clinical use in Hungary in 1977. While the NDA was under review, Somerset was acquired in a joint venture by two generic drug companies, Mylan and Bolan Pharmaceuticals. The involvement of these metabolites in the effects and side effects of selegiline has remained controversial and unresolved in the decades afterwards. The catecholaminergic activity enhancer (CAE) effects of selegiline became well-characterized and distinctly named in 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 monoaminergic activity enhancers (MAEs), like phenylpropylaminopentane (PPAP) and benzofuranylpropylaminopentane (BPAP), were derived from selegiline and other compounds and were first described in 1988 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. 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. ==Society and culture==

Names Selegiline is the generic name of the drug and its , , and , while selegiline hydrochloride is the . The word "selegiline" is pronounced () 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. Selegiline has been marketed under more than 70brand names worldwide. Generic forms Generic forms of oral selegiline are available in the United States. 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. 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 10years. He is also known to have simultaneously taken Adderall for treatment of attention deficit hyperactivity disorder (ADHD) 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 Selegiline in non-pharmaceutical form is sold on the Internet without a prescription by online vendors for uses such as purported cognitive enhancement (i.e., as a so-called "smart drug" or nootropic) and anti-aging effects. 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. Such actions may have performance-enhancing effects. They are classified as "Stimulants", alongside a variety of other amphetamines, under Article2 of Japan's Narcotics and Psychotropics Control Law. ==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: Despite claims that selegiline and other claimed nootropics have cognitive-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. The effectiveness was modest, with a reduction in social anxiety scores from baseline of 32% over 6weeks of treatment. 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 6weeks 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. In case reports and small clinical studies, selegiline has been reported to improve disorders of diminished motivation like apathy and abulia due to conditions such as traumatic brain injury. In accordance with the preceding findings, selegiline, along with other dopaminergic and activating agents, may be useful in the treatment of disorders of diminished motivation, including apathy, abulia, and akinetic mutism. Studies are mixed on whether selegiline, at MAO-B-selective doses, reduces the effects of cocaine in humans. It also did not improve sexual function in men with depression, but did improve several domains of sexual function in women with depression. However, it failed to significantly reduce positive or negative symptoms of schizophrenia in meta-analyses of these studies. It was found to be effective in these studies. It was reported to be effective as assessed by polysomnography, reducing periodic limb movements during sleep by about 60%. Dementia and stroke Selegiline has also been used off-label as a palliative treatment for dementia in Alzheimer's disease. 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. 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. 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 MAOIs, including selegiline, can produce serious complications, including serotonin syndrome, hypertensive crisis, and death. Other formulations The original oral formulation of selegiline was developed for the treatment of depression. ==Veterinary use==

In veterinary medicine, selegiline is sold under the brand name Anipryl and is manufactured by Zoetis. It is available in the form of 2, 5, 10, 15, and 30mg oral tablets for use in animals. CCD is a form of dementia that mimics Alzheimer's disease in humans. Geriatric dogs treated with selegiline show improvements in sleeping pattern, reduced urinary incontinence, and increased activity level, with most showing improvements by one month of treatment. Though it is labeled for use in dogs only, selegiline has been used off-label for geriatric cats with cognitive dysfunction. PDH is a hormonal disorder and is analogous to pituitary-dependent Cushing's syndrome in humans. The greatest sign of improvement is lessening of PDH-related 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 has been limitedly studied in large animals like horses and its dosage in these animals has not been established. In preliminary research, a dose of selegiline of 30mg orally or intravenously in horses had no observable effects on behavior or locomotor activity. The doses of selegiline used in animals are described as extremely high relative to those used in humans (which are ~0.1mg/kg body weight). ==References==