Pharmacology of Selegiline

Introduction/Overview

Selegiline, also known by its chemical name L-deprenyl, represents a cornerstone agent in the management of Parkinson’s disease and occupies a unique niche in neuropsychopharmacology. Initially developed in the 1960s, its clinical introduction marked a significant advancement in the symptomatic treatment of neurodegenerative disorders. The drug’s primary mechanism involves the selective and irreversible inhibition of monoamine oxidase type B (MAO-B), an enzyme critical for the catabolism of dopamine within the central nervous system. This targeted action potentiates dopaminergic neurotransmission, which is fundamentally deficient in Parkinsonian pathology. Beyond its established role in movement disorders, the pharmacological profile of selegiline has prompted investigation into other potential therapeutic areas, including cognitive decline and certain mood disorders, though its use in these contexts remains more specialized.

The clinical relevance of selegiline is underscored by its utility as both monotherapy in early Parkinson’s disease and as an adjunct to levodopa in more advanced stages. Its ability to delay the need for levodopa initiation and to ameliorate motor fluctuations associated with long-term levodopa therapy has solidified its position in treatment algorithms. Furthermore, the transdermal formulation of selegiline, approved for major depressive disorder, exploits a different pharmacokinetic profile to achieve non-selective monoamine oxidase inhibition, representing a distinct clinical entity from the oral Parkinson’s disease formulation. Understanding the nuanced pharmacology of selegiline is therefore essential for optimizing its therapeutic benefits while mitigating risks, particularly those related to its irreversible enzyme inhibition and potential for serious drug and food interactions.

Learning Objectives

• Describe the molecular mechanism of action of selegiline as an irreversible, selective MAO-B inhibitor and differentiate this from the action of non-selective MAO inhibitors.
• Outline the key pharmacokinetic properties of oral and transdermal selegiline, including absorption, metabolism, and the clinical implications of its active metabolites.
• Identify the approved clinical indications for selegiline, including its roles in early and advanced Parkinson’s disease and in major depressive disorder (transdermal formulation).
• Analyze the major adverse effect profile and serious drug-drug and drug-food interactions associated with selegiline, with emphasis on serotonin syndrome and hypertensive crisis.
• Apply knowledge of selegiline pharmacology to special populations, including patients with renal or hepatic impairment, the elderly, and those taking concomitant medications.

Classification

Selegiline is systematically classified within multiple pharmacological and chemical hierarchies, each highlighting a different aspect of its properties and clinical use.

Pharmacotherapeutic Classification

The primary classification of selegiline is as an antiparkinson agent. More specifically, it is categorized as a monoamine oxidase inhibitor (MAOI). Crucially, at low oral doses used for Parkinson’s disease, it demonstrates selectivity for the MAO-B isoenzyme. This distinguishes it from classic, non-selective MAO inhibitors (e.g., phenelzine, tranylcypromine) which inhibit both MAO-A and MAO-B and are used primarily as antidepressants. The transdermal formulation, due to its delivery route achieving higher systemic exposure, is classified as an antidepressant and functions as a non-selective MAOI.

Chemical Classification

Chemically, selegiline is a propargylamine. Its full chemical name is (R)-N,α-dimethyl-N-2-propynylphenethylamine hydrochloride. The molecule is a derivative of methamphetamine and incorporates a propynyl (propargyl) group attached to the nitrogen atom. This propargyl moiety is integral to its mechanism of action, forming a covalent, irreversible bond with the flavin adenine dinucleotide (FAD) cofactor within the active site of the MAO-B enzyme. Selegiline is the L-isomer (or R-isomer) of deprenyl; the D-isomer possesses significantly less MAO-B inhibitory activity.

Mechanism of Action

The therapeutic effects of selegiline are primarily mediated through the irreversible inhibition of monoamine oxidase, with its selectivity and consequent clinical effects being highly dose- and route-dependent.

Monoamine Oxidase Inhibition

Monoamine oxidase (MAO) is a mitochondrial outer membrane enzyme responsible for the oxidative deamination of monoamine neurotransmitters and dietary amines. Two major isoenzymes exist: MAO-A and MAO-B. MAO-A preferentially metabolizes serotonin, norepinephrine, and dietary tyramine. MAO-B preferentially metabolizes dopamine, phenethylamine, and benzylamine. Both isoforms metabolize tyramine and dopamine to some degree. Selegiline acts as a mechanism-based inactivator (suicide inhibitor) of MAO. The drug is initially recognized as a substrate by the enzyme. During the catalytic cycle, the propargyl group of selegiline is activated, leading to the irreversible covalent modification and permanent inactivation of the enzyme’s FAD cofactor. Recovery of enzyme activity requires the synthesis of new MAO protein, a process that takes approximately 2-3 weeks following discontinuation of the drug.

Selectivity for MAO-B

At low oral doses (e.g., 10 mg/day in divided doses), selegiline exhibits a high degree of selectivity for MAO-B. This selectivity is relative, not absolute, and is influenced by several factors. The concentration of the drug in tissues, the relative abundance of MAO-A versus MAO-B in different organs, and individual patient variability all contribute. In the human brain, where MAO-B is the predominant form in glial cells and serotonergic neurons, low-dose selegiline effectively inhibits dopamine catabolism without significantly affecting the metabolism of serotonin or norepinephrine. This selective inhibition potentiates dopaminergic neurotransmission in the striatum, compensating for the neuronal loss characteristic of Parkinson’s disease. The selectivity diminishes as the dose increases. At the higher systemic levels achieved with the transdermal formulation (e.g., 6 mg/24 hours), significant inhibition of both MAO-A and MAO-B occurs, which is the intended mechanism for its antidepressant effect, increasing the availability of serotonin, norepinephrine, and dopamine in synaptic clefts.

Neuroprotective and Neurorescue Hypotheses

Beyond symptomatic relief, preclinical evidence has suggested that selegiline may possess neuroprotective or neurorescue properties. Proposed mechanisms include the reduction of oxidative stress from dopamine metabolism, induction of antioxidant enzymes like superoxide dismutase and catalase, anti-apoptotic effects via stabilization of mitochondrial membrane potential, and upregulation of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). The metabolite L-desmethylselegiline (also known as L-methamphetamine) may contribute to some of these effects independently of MAO inhibition. However, translation of these observations into definitive clinical neuroprotection in humans has not been conclusively demonstrated in large-scale trials, and its primary clinical benefit remains symptomatic.

Other Pharmacodynamic Effects

Selegiline is metabolized to L-amphetamine and L-methamphetamine. These metabolites are less potent as central nervous system stimulants than their D-isomers but may contribute to reported side effects such as insomnia, agitation, or euphoria. They possess minimal activity at MAO but have weak sympathomimetic properties. The overall clinical effect of selegiline in Parkinson’s disease is a modest increase in “on” time and a reduction in motor fluctuations when used as an adjunct to levodopa, attributable to more stable dopaminergic tone.

Pharmacokinetics

The pharmacokinetics of selegiline are complex, characterized by extensive first-pass metabolism, active metabolites, and significant differences between oral and transdermal routes of administration.

Absorption

Oral selegiline is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations (C_max) occurring within 0.5 to 2 hours post-administration. However, its oral bioavailability is low, estimated at approximately 10%, due to extensive first-pass metabolism in the liver. Absorption is not significantly affected by food. The transdermal system delivers selegiline continuously through the skin into the systemic circulation, bypassing first-pass hepatic metabolism. This results in a much higher systemic bioavailability (approximately 70-75% for the transdermal system) and a different metabolic profile. Steady-state plasma concentrations are typically achieved within 3-5 days of initiating transdermal therapy.

Distribution

Selegiline is a lipophilic base and is widely distributed throughout the body. It readily crosses the blood-brain barrier, which is essential for its central effects in Parkinson’s disease. The volume of distribution is large, exceeding total body water. The drug and its metabolites are extensively bound to plasma proteins, though the exact percentage is not well characterized. The high lipophilicity and brain penetration are key factors in its central nervous system efficacy.

Metabolism

Selegiline undergoes extensive hepatic metabolism primarily via the cytochrome P450 system, with CYP2B6 and CYP2C19 playing major roles, and CYP3A4/5 contributing to a lesser extent. The primary metabolic pathways are N-dealkylation and demethylation. This produces three major metabolites:

1. N-Desmethylselegiline (L-methamphetamine): Further metabolized to L-amphetamine.
2. L-Amphetamine: Both L-methamphetamine and L-amphetamine are active metabolites with longer half-lives than the parent compound (10-30 hours).
3. Selegiline-N-oxide

The formation of these amphetamine derivatives is clinically significant as they may contribute to both therapeutic effects (mild stimulation, possible neuroprotective effects) and adverse effects (insomnia, cardiovascular stimulation). With transdermal administration, the first-pass effect is avoided, leading to lower relative levels of these amphetamine metabolites and higher levels of parent drug and other metabolites like the N-oxide.

Excretion

Following metabolism, the drug and its metabolites are eliminated primarily via the kidneys. Less than 5% of an oral dose is excreted unchanged in the urine. The elimination of selegiline itself is rapid, with a terminal half-life (t_1/2) of approximately 1.5 to 2 hours for the oral formulation. However, due to its irreversible mechanism of action, its pharmacodynamic effect persists long after the drug is cleared from plasma. The pharmacological activity is determined by the rate of synthesis of new MAO enzyme. The metabolites, particularly L-amphetamine, have much longer half-lives (up to 30 hours), which can influence the duration of some side effects. For the transdermal system, the apparent half-life at steady state is longer, ranging from 18 to 25 hours.

Dosing Considerations

The standard oral dose for Parkinson’s disease is 5 mg twice daily, taken at breakfast and lunch. Dosing later in the day is typically avoided to minimize the risk of insomnia from the amphetamine metabolites. A once-daily orally disintegrating tablet formulation (Zydis selegiline) is also available, which is absorbed buccally, further reducing first-pass metabolism and amphetamine metabolite production. The transdermal patch for depression is applied once daily, with doses ranging from 6 mg/24 hours to 12 mg/24 hours. Dosing must be individualized, and the principle of “start low, go slow” is often employed, especially with the transdermal formulation to minimize adverse effects.

Therapeutic Uses/Clinical Applications

Selegiline is employed in distinct clinical contexts depending on its formulation and resultant pharmacodynamic profile.

Approved Indications

Parkinson’s Disease: Oral selegiline is approved as an adjunct to levodopa/carbidopa in the treatment of Parkinson’s disease for patients experiencing motor fluctuations (“wearing-off” phenomena). It is also approved as monotherapy for the symptomatic treatment of early, mild Parkinson’s disease. As monotherapy, it provides modest symptomatic benefit and may delay the need to initiate levodopa by several months. As an adjunct to levodopa, it can reduce “off” time, smooth out motor responses, and permit a modest reduction in levodopa dose in some patients.

Major Depressive Disorder (MDD): The transdermal selegiline system is approved for the treatment of major depressive disorder in adults. This indication utilizes the non-selective MAO inhibition achieved through systemic delivery. It is generally considered after failure of first-line antidepressant therapies (e.g., SSRIs, SNRIs) due to its more complex safety profile regarding interactions.

Off-Label and Investigational Uses

Neuroprotection in Parkinson’s Disease: Based on preclinical data, high-dose oral selegiline was investigated in large trials (e.g., DATATOP) to determine if it could slow disease progression. While initial analyses were suggestive, later follow-up indicated the primary effect was symptomatic, and conclusive evidence for disease modification remains elusive.

Attention-Deficit/Hyperactivity Disorder (ADHD): Limited studies and anecdotal reports have explored its use, possibly related to its dopaminergic and noradrenergic effects from metabolites, but it is not a standard treatment.

Negative Symptoms of Schizophrenia: Small studies have investigated its adjunctive use to address avolition and apathy, with mixed results.

Cognitive Decline and Alzheimer’s Disease: Some studies have explored its potential in mild cognitive impairment and dementia, given its effects on monoamines and proposed neurotrophic properties, but it is not an approved therapy for these conditions.

Smoking Cessation: Its dopaminergic action has been theorized to help with nicotine withdrawal, but evidence is insufficient to support this use.

Adverse Effects

The adverse effect profile of selegiline varies between formulations and is influenced by its dose-dependent selectivity, its active metabolites, and its potentiation of monoaminergic transmission.

Common Side Effects

Common adverse reactions are often extensions of its pharmacological activity. For the oral formulation in Parkinson’s disease, these may include:

• Dopaminergic Effects: Nausea, dizziness, orthostatic hypotension, confusion, hallucinations (particularly in the elderly or those with cognitive impairment), increased dyskinesias when used with levodopa.
• Stimulant-like Effects (from metabolites): Insomnia, agitation, anxiety, vivid dreams, dry mouth. Taking the last dose no later than early afternoon can mitigate insomnia.
• Other: Headache, gastrointestinal upset, arthralgia.

For the transdermal formulation used in depression, application site reactions (rash, pruritus) are very common. Other frequent side effects include insomnia, dizziness, orthostatic hypotension, and gastrointestinal disturbances similar to other MAOIs and antidepressants.

Serious/Rare Adverse Reactions

Serotonin Syndrome: This is a potentially life-threatening condition resulting from excessive serotonergic activity in the central nervous system. The risk is highest when selegiline (particularly the transdermal form or high oral doses) is combined with other serotonergic agents (e.g., SSRIs, SNRIs, TCAs, tramadol, meperidine, dextromethorphan, triptans). Symptoms range from autonomic instability (hyperthermia, tachycardia, diaphoresis), neuromuscular abnormalities (hyperreflexia, myoclonus, tremor), and altered mental status (agitation, confusion).

Hypertensive Crisis (Tyramine Reaction): This classic MAOI reaction occurs due to inhibition of intestinal and hepatic MAO-A, which normally inactivates dietary tyramine. Ingesting tyramine-rich foods (aged cheeses, cured meats, fermented products, tap beers, soy products) can lead to a massive release of norepinephrine, causing a sudden, severe hypertension characterized by occipital headache, palpitations, neck stiffness, nausea, vomiting, and potentially intracranial hemorrhage. The risk with low-dose oral selegiline (≤10 mg/day) is considered very low due to MAO-B selectivity, and strict dietary restrictions are not typically mandated. However, with the transdermal formulation, dietary modification is required as per non-selective MAOI guidelines.

Increased Suicidality: As with all antidepressants, transdermal selegiline carries a black box warning regarding the increased risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18-24) during initial treatment.

Mania/Hypomania: Can be induced in susceptible individuals, particularly those with bipolar disorder.

Severe Orthostatic Hypotension and Syncope: Can occur, especially during initial dose titration.

Black Box Warnings

The transdermal selegiline product carries two black box warnings:

1. Suicidality in Children and Young Adults: Antidepressants may increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Close monitoring for clinical worsening or behavioral changes is essential.
2. Hypertensive Crisis from Drug Interactions and Tyramine: The warning emphasizes the risk of potentially fatal hypertensive crises, which can occur from interactions with sympathomimetic amines (e.g., in decongestants) or tyramine-rich foods and beverages. It stresses the importance of patient education on avoidance and the required 2-week washout period when switching to or from other antidepressants.

Oral selegiline for Parkinson’s disease does not carry these black box warnings, reflecting its different risk profile at selective MAO-B inhibiting doses.

Drug Interactions

Drug interactions with selegiline are among the most critical aspects of its pharmacology, often being severe and potentially life-threatening. The risk profile is formulation- and dose-dependent.

Major Drug-Drug Interactions

Contraindicated Combinations (Absolute or Relative):

• Other Serotonergic Agents: Concurrent use with SSRIs (e.g., fluoxetine, sertraline), SNRIs (e.g., venlafaxine, duloxetine), TCAs (particularly clomipramine, imipramine), serotonin precursors (tryptophan), and strong serotonin receptor agonists (triptans) is contraindicated due to high risk of serotonin syndrome. A lengthy washout period (at least 2 weeks, 5 weeks for fluoxetine due to its long half-life) is required when switching between these agents and transdermal selegiline or high-dose oral selegiline.
• Other MAO Inhibitors: Concurrent use with other MAOIs (e.g., phenelzine, tranylcypromine, linezolid, methylene blue) is contraindicated due to additive monoaminergic effects and dramatically increased risk of hypertensive crisis and serotonin syndrome.
• Sympathomimetic Amines: Drugs such as pseudoephedrine, phenylephrine, epinephrine (in local anesthetics), and amphetamines can provoke hypertensive crises. These are found in many over-the-counter cough, cold, and allergy products.
• Meperidine (Pethidine) and Other Opioids: Meperidine is absolutely contraindicated due to a high risk of fatal serotonin syndrome and excitatory reactions. Caution is also advised with tramadol, methadone, and dextromethorphan.
• Carbamazepine and Oxcarbazepine: May reduce selegiline levels via CYP450 induction.

Other Significant Interactions

• CYP450 Inhibitors: Drugs like fluoxetine, paroxetine, or ketoconazole may increase selegiline plasma levels, potentially reducing its selectivity and increasing the risk of adverse effects.
• Levodopa: The combination is therapeutic but can potentiate levodopa’s dopaminergic adverse effects, such as dyskinesias, nausea, orthostatic hypotension, and hallucinations. A reduction in levodopa dose by 10-30% may be necessary when selegiline is added.
• General Anesthetics: May interact unpredictably; selegiline should be discontinued if possible prior to elective surgery, with adequate time for MAO regeneration (approximately 2-3 weeks).

Contraindications

Selegiline is contraindicated in patients with:

• Known hypersensitivity to the drug or any component of the formulation.
• Concomitant use with contraindicated medications as listed above.
• Pheochromocytoma (due to risk of catecholamine crisis).
• For transdermal selegiline: its use in children under 12 years is contraindicated.

Special Considerations

The use of selegiline requires careful evaluation in specific patient populations due to its potent and irreversible mechanism of action.

Pregnancy and Lactation

Pregnancy (Category C): Animal reproduction studies have shown adverse effects, but adequate and well-controlled studies in humans are lacking. Selegiline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The amphetamine metabolites raise additional concerns. In pregnant patients with Parkinson’s disease, the risks of untreated motor disability must be weighed against medication risks.

Lactation: It is not known whether selegiline or its metabolites are excreted in human milk. Given the potential for serious adverse reactions in nursing infants from amphetamine derivatives and MAO inhibition, a decision should be made to discontinue nursing or discontinue the drug.

Pediatric and Geriatric Considerations

Pediatric: Oral selegiline is not indicated for use in children. Transdermal selegiline is contraindicated in children under 12 and carries increased suicidality risks in adolescents. Safety and efficacy in pediatric populations are not established.

Geriatric: This is the primary population for oral selegiline in Parkinson’s disease. Elderly patients are more susceptible to its adverse effects, particularly orthostatic hypotension, confusion, hallucinations, and falls. Dose selection should start at the low end of the dosing range. Cognitive status and concomitant medications must be carefully assessed. The amphetamine metabolites may exacerbate insomnia or anxiety.

Renal and Hepatic Impairment

Renal Impairment: Since the drug and its active metabolites are renally excreted, patients with severe renal impairment may experience accumulation of these compounds. Caution is advised, and dose reduction may be necessary. Monitoring for increased stimulant or dopaminergic side effects is recommended.

Hepatic Impairment: Selegiline is extensively metabolized by the liver. Patients with significant hepatic impairment (e.g., cirrhosis) may have reduced first-pass metabolism, leading to higher and more sustained plasma levels of the parent drug. This could theoretically reduce its selectivity for MAO-B and increase the risk of adverse reactions, including hypertensive crisis. Use in patients with severe hepatic impairment is not recommended, and caution is warranted in mild to moderate impairment.

Summary/Key Points

• Selegiline is an irreversible inhibitor of monoamine oxidase. At low oral doses (≤10 mg/day), it is relatively selective for the MAO-B isoenzyme, enhancing dopaminergic transmission for the symptomatic treatment of Parkinson’s disease.
• The transdermal formulation achieves systemic levels that inhibit both MAO-A and MAO-B, acting as a non-selective MAOI for the treatment of major depressive disorder. This fundamental difference dictates distinct clinical use, dietary restrictions, and interaction profiles.
• Pharmacokinetically, oral selegiline undergoes extensive first-pass metabolism to active amphetamine derivatives (L-methamphetamine, L-amphetamine), which contribute to its effects and side effects. The transdermal route bypasses this, altering the metabolite profile.
• Major serious risks include serotonin syndrome (when combined with other serotonergic agents) and hypertensive crisis (primarily with the transdermal formulation or high doses due to tyramine ingestion or sympathomimetic drug interactions).
• Oral selegiline is used as monotherapy in early Parkinson’s disease or as an adjunct to levodopa to reduce motor fluctuations. Its role in neuroprotection remains unproven despite preclinical promise.
• Critical management aspects include careful patient selection, thorough review of concomitant medications, appropriate counseling on dietary restrictions (for the transdermal form), and vigilant monitoring for adverse effects, especially in the elderly and those with comorbid conditions.

Clinical Pearls

• When prescribing oral selegiline for Parkinson’s, advise patients to take the second dose no later than early afternoon to minimize insomnia from amphetamine metabolites.
• Strict dietary tyramine restrictions are generally not required for patients on low-dose oral selegiline (10 mg/day or less) for Parkinson’s, but they are mandatory for patients using the transdermal patch for depression.
• Always observe the recommended washout periods (at least 2 weeks, longer for fluoxetine) when switching between selegiline (especially transdermal) and other serotonergic antidepressants to avoid serotonin syndrome.
• In an elderly Parkinson’s patient who develops new or worsening hallucinations or confusion after starting selegiline, consider dose reduction or discontinuation before attributing it solely to disease progression.
• The irreversible nature of MAO inhibition means that the pharmacological effects and interaction risks persist for weeks after the last dose, until new enzyme is synthesized. This must be considered in perioperative management or when changing therapies.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.