Comprehensive Monograph: Selegiline (DB01037)

Section 1: Executive Summary

Selegiline is a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B) with a distinct and complex profile that spans the fields of neurology and psychiatry. Its primary therapeutic applications are as an adjunctive therapy for Parkinson's disease and, in a specific transdermal formulation, as a treatment for major depressive disorder. The clinical utility, efficacy, and safety profile of Selegiline are fundamentally dictated by its formulation and dosage, creating a unique pharmacological dichotomy. At low oral doses, it functions as a targeted neuro-enhancer, selectively inhibiting MAO-B to potentiate dopaminergic neurotransmission in the brain's nigrostriatal pathway. This action helps to alleviate the motor symptoms of Parkinson's disease and may delay the need for levodopa therapy.

As the dose is increased or when administered via a transdermal system that bypasses first-pass metabolism, Selegiline's selectivity for MAO-B diminishes, and it begins to inhibit monoamine oxidase type A (MAO-A) as well. This non-selective inhibition leads to increased synaptic levels of serotonin and norepinephrine, conferring an antidepressant effect. The development of the transdermal system (Emsam) represents a significant innovation in pharmaceutical science, as it largely mitigates the risk of tyramine-induced hypertensive crisis—a dangerous food interaction that severely limited the use of older, non-selective MAOIs. This formulation allows for the safe delivery of antidepressant doses of Selegiline by avoiding significant MAO-A inhibition in the gastrointestinal tract.

Despite its therapeutic benefits, Selegiline is an agent that requires careful clinical management due to a complex safety profile. It carries a U.S. Food and Drug Administration (FDA) Black Box Warning for an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults, a warning common to all antidepressant medications. Furthermore, its use is associated with a significant risk of potentially fatal drug interactions, most notably serotonin syndrome when combined with serotonergic agents (such as SSRIs, SNRIs, and certain opioids) and hypertensive crisis when combined with sympathomimetics or, at higher doses, with tyramine-rich foods. Other notable adverse effects include dopaminergic-related complications in Parkinson's patients, such as dyskinesia and hallucinations, as well as orthostatic hypotension and insomnia. This report provides an exhaustive analysis of Selegiline's chemical properties, pharmacology, clinical applications, safety considerations, and regulatory history, positioning it as a versatile but challenging therapeutic tool.

Section 2: Chemical Identity and Physicochemical Properties

A precise and unambiguous characterization of Selegiline is fundamental to understanding its pharmacology and clinical use. This section details its systematic nomenclature, structural features, identifiers across major chemical and drug databases, and essential safety information for handling.

2.1 Systematic Identification

Selegiline is identified through a variety of standardized naming and numbering systems to ensure its unique recognition in scientific literature, regulatory filings, and clinical practice. Its formal chemical name, as defined by the International Union of Pure and Applied Chemistry (IUPAC), is (2R)-N-methyl-1-phenyl-N-prop-2-ynylpropan-2-amine.[1]

The most common identifier in chemical commerce and research is its Chemical Abstracts Service (CAS) Registry Number. The CAS number for the selegiline free base is 14611-51-9.[1] It is crucial to distinguish this from the CAS number for its hydrochloride salt, 14611-52-0, which is the form predominantly used in pharmaceutical preparations to enhance stability and solubility.[1] Other key identifiers include its DrugBank Accession Number, DB01037, and its Unique Ingredient Identifier (UNII) from the FDA's Global Substance Registration System, 2K1V7GP655.[1]

2.2 Chemical Structure and Formula

Selegiline is a small molecule with the molecular formula C13​H17​N and a molecular weight of approximately 187.28 g/mol.[1] Structurally, it is classified as a substituted phenethylamine and is a derivative of amphetamine, specifically the levorotatory enantiomer of methamphetamine containing a propargyl group.[8] This propargyl group (a prop-2-yn-1-yl moiety) is essential for its mechanism of action, as it forms a covalent bond with the MAO enzyme, leading to irreversible inhibition.

The stereochemistry of Selegiline is a critical feature. It is the purified levorotatory, or (R)-, enantiomer, designated as (-)-selegiline.[1] This distinguishes it from its dextrorotatory enantiomer and from deprenyl, which is the racemic mixture of both enantiomers and was the original compound studied in the 1960s.[8] The isolation of the specific (R)-enantiomer was a key step in its development, as enantiomers can possess significantly different pharmacological and toxicological properties.

For computational and structural chemistry applications, its structure is represented by the Simplified Molecular-Input Line-Entry System (SMILES) string C[C@H](CC1=CC=CC=C1)N(C)CC#C and the IUPAC International Chemical Identifier Key (InChIKey) MEZLKOACVSPNER-GFCCVEGCSA-N.[1]

2.3 Synonyms and Trade Names

Selegiline's long history is reflected in its numerous synonyms. It is widely known in scientific literature by the name L-deprenyl, a reference to its levorotatory nature and its origin as a derivative of deprenyl.[1] Other common synonyms include L-deprenalin and (-)-selegiline.[1] In international contexts, it may be referred to by its Latin name, Selegilinum, or its Spanish name, Selegilina.[1]

Commercially, Selegiline is marketed under several brand names, which often correspond to specific formulations and indications. The most prominent trade names include:

• Eldepryl: Conventional oral capsules, primarily for Parkinson's disease.[8]
• Zelapar: Orally disintegrating tablets (ODT), also for Parkinson's disease.[8]
• Emsam: A transdermal patch system, approved for the treatment of major depressive disorder.[3]
• Other brand names include Selgene, Carbex, and Jumex.[1]

2.4 Physicochemical Characteristics and Safety Data

Selegiline is available for laboratory and manufacturing use as a neat (pure) substance or as a certified reference material, often dissolved in methanol.[2] For optimal stability, it is typically stored under refrigeration at 2-8°C.[2]

According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), selegiline presents several hazards. It is classified as a highly flammable liquid and vapor (H225) and is toxic if swallowed, in contact with skin, or if inhaled (H301+H311+H331).[3] Furthermore, it is known to cause damage to organs, with the eyes being a specific target organ (H370).[3] These classifications necessitate careful handling procedures, including the use of personal protective equipment and storage in well-ventilated, flame-proof areas, for individuals working with the bulk chemical.

Table 2.1: Chemical and Physical Identifiers of Selegiline

Identifier Type	Value	Source(s)
IUPAC Name	(2R)-N-methyl-1-phenyl-N-prop-2-ynylpropan-2-amine	1
CAS Number (Base)	14611-51-9	1
CAS Number (HCl Salt)	14611-52-0	1
DrugBank ID	DB01037	1
Molecular Formula	C13​H17​N	1
Molecular Weight	187.28 g/mol	1
UNII	2K1V7GP655	1
ChEBI ID	CHEBI:9086	1
SMILES	C[C@H](CC1=CC=CC=C1)N(C)CC#C	1
InChIKey	MEZLKOACVSPNER-GFCCVEGCSA-N	1

Section 3: Comprehensive Pharmacology

The clinical effects of Selegiline are a direct consequence of its complex interactions with the monoamine oxidase enzyme system and other neurotransmitter pathways. Its pharmacological profile is uniquely characterized by a dose-dependent duality, functioning as two distinct therapeutic agents depending on the administered dose and route of administration. This section provides a detailed analysis of its mechanism of action, pharmacodynamic effects, and the comparative pharmacokinetics of its different formulations.

3.1 Mechanism of Action

The primary mechanism of action for Selegiline is the selective, irreversible inhibition of monoamine oxidase type B (MAO-B).[6] MAO-B is one of two key isoenzymes (the other being MAO-A) responsible for the oxidative deamination and subsequent degradation of monoamine neurotransmitters. In the human brain, particularly within the nigrostriatal pathways of the central nervous system, MAO-B is the predominant enzyme responsible for the breakdown of dopamine.[3] Selegiline binds to the active site of the MAO-B enzyme, and its propargyl group forms a covalent adduct with the enzyme's flavin cofactor, leading to irreversible inactivation. Because the inhibition is irreversible, the enzyme's function is only restored through the synthesis of new enzyme molecules, a process that can take up to two weeks. This is the cornerstone of its therapeutic effect in Parkinson's disease, as blocking dopamine metabolism increases the synaptic concentration and prolongs the action of both endogenous dopamine and dopamine derived from levodopa therapy.[3]

A critical feature of Selegiline's pharmacology is the dose-dependent loss of its selectivity for MAO-B.[3] At the typical doses used for Parkinson's disease (e.g., 10 mg/day oral), it maintains a high degree of selectivity for MAO-B. However, as the dose escalates beyond this therapeutic window, Selegiline begins to inhibit MAO-A as well.[6] MAO-A is the primary enzyme responsible for metabolizing serotonin, norepinephrine, and dietary tyramine. The non-selective inhibition of both MAO-A and MAO-B at higher doses is the basis for Selegiline's antidepressant effects, but it also introduces the significant safety risks associated with traditional, non-selective MAOIs, such as hypertensive crisis and serotonin syndrome.[6]

Beyond its direct effects on MAO, Selegiline exhibits secondary mechanisms that may contribute to its overall clinical profile. It has been identified as a catecholaminergic activity enhancer (CAE), promoting the impulse-mediated release of dopamine and norepinephrine from nerve terminals.[8] This action may be mediated through agonism at the trace amine-associated receptor 1 (TAAR1), suggesting a more complex, multi-target mechanism than simple enzyme inhibition.[8]

3.2 Pharmacodynamics

The primary pharmacodynamic consequence of Selegiline's MAO-B inhibition is the potentiation of dopaminergic activity within the substantia nigra and other dopamine-rich areas of the brain.[6] This enhanced dopaminergic tone leads to improvements in the cardinal motor symptoms of Parkinson's disease, including bradykinesia, rigidity, and tremor.[14] When used as an adjunct to levodopa, it helps to smooth out motor fluctuations by extending the duration of action of each levodopa dose.[14]

At higher, non-selective doses used for depression, the concurrent inhibition of MAO-A leads to a significant increase in the synaptic concentrations of serotonin and norepinephrine, in addition to dopamine.[8] This broad enhancement of monoamine neurotransmission is the presumed mechanism underlying its antidepressant action, similar to that of older MAOIs.[16]

There has been considerable investigation into a potential neuroprotective effect of Selegiline. The hypothesis is that by inhibiting the MAO-B-mediated metabolism of dopamine, Selegiline reduces the production of neurotoxic byproducts, such as hydrogen peroxide and other reactive oxygen species.[3] While some preclinical and early clinical studies suggested it might slow the progression of Parkinson's disease, this effect remains controversial and has not been definitively established in long-term clinical trials.[3]

3.3 Pharmacokinetics

The pharmacokinetic profile of Selegiline varies substantially between its different formulations, a factor that is central to their distinct clinical applications and safety profiles.

Absorption:

• Conventional Oral (Eldepryl): Selegiline is rapidly absorbed from the gastrointestinal tract but undergoes extensive first-pass metabolism in the gut wall and liver.[6]
• Orally Disintegrating Tablet (Zelapar): This formulation is designed for pre-gastric absorption through the buccal mucosa. By dissolving on the tongue, a portion of the dose is absorbed directly into the systemic circulation, which reduces the extent of first-pass metabolism compared to conventional tablets.[18]
• Transdermal System (Emsam): The transdermal patch delivers Selegiline directly into the systemic circulation, completely bypassing gastrointestinal and hepatic first-pass metabolism.[8] This is a crucial feature that allows for antidepressant efficacy while minimizing the inhibition of gut MAO-A, thereby reducing the risk of tyramine-induced hypertensive crisis at lower doses.

Distribution:

Selegiline is highly lipophilic and widely distributed throughout the body. It exhibits very high plasma protein binding, with over 99.5% of the drug bound to proteins.6

Metabolism:

Selegiline is extensively metabolized, primarily in the liver. During the regulatory review of the Zelapar formulation, the FDA required extensive studies to identify the responsible enzymes. These studies confirmed that metabolism is mediated primarily by the cytochrome P450 enzyme CYP2B6, with smaller contributions from CYP3A4 and CYP2A6.19

A clinically significant aspect of its metabolism is the formation of three major active metabolites: N-desmethylselegiline, L-amphetamine (levoamphetamine), and L-methamphetamine (levomethamphetamine).[6] These amphetamine metabolites are pharmacologically active stimulants and are thought to contribute to some of Selegiline's adverse effects, particularly insomnia and anxiety.[8] The development of the ODT and transdermal formulations was, in part, a deliberate strategy to alter the metabolic pathway and reduce the formation of these metabolites. By minimizing first-pass metabolism, both the Zelapar and Emsam formulations result in significantly lower plasma concentrations of L-amphetamine and L-methamphetamine compared to equivalent doses of conventional oral Selegiline, thereby improving the drug's tolerability.[8]

Elimination:

The parent drug has a relatively short elimination half-life of 1.2 to 2 hours.6 However, this pharmacokinetic parameter is misleading with respect to the duration of the drug's effect. Because Selegiline is an irreversible inhibitor, its pharmacodynamic effect persists long after the drug has been cleared from the plasma. The clinical effect is terminated not by drug elimination but by the de novo synthesis of the MAO-B enzyme, which can take up to 14 days. This disconnect between pharmacokinetics and pharmacodynamics explains the need for extended washout periods when switching to or from other interacting medications.

Table 3.1: Comparative Pharmacokinetic Profile of Selegiline Formulations

Pharmacokinetic Parameter	Conventional Oral (e.g., Eldepryl)	Orally Disintegrating Tablet (Zelapar)	Transdermal System (Emsam)
Primary Absorption Route	Gastrointestinal	Buccal Mucosa & Gastrointestinal	Transdermal
First-Pass Metabolism	Extensive	Reduced	Bypassed
Amphetamine Metabolites	Highest Levels	Intermediate Levels	Lowest Levels
Plasma Half-life (Parent)	1.2 - 2 hours	Similar to Oral	Longer due to continuous absorption
Protein Binding	>99.5%	>99.5%	>99.5%
Primary Metabolizing Enzymes	CYP2B6, CYP3A4, CYP2A6	CYP2B6, CYP3A4, CYP2A6	CYP2B6, CYP3A4, CYP2A6

Section 4: Clinical Pharmacology and Therapeutic Indications

Selegiline's unique pharmacological properties have led to its approval and investigation for a range of neurological and psychiatric disorders. Its clinical applications are highly dependent on the chosen formulation and dose, which determine its primary site of action and degree of MAO isoenzyme selectivity.

4.1 Approved Indication: Parkinson's Disease

Selegiline is well-established in the management of Parkinson's disease (PD). It is approved by the FDA as an adjunctive therapy to levodopa/carbidopa for patients experiencing motor fluctuations.[15] In this setting, Selegiline's inhibition of MAO-B prolongs the synaptic availability of dopamine derived from levodopa, thereby extending the duration of "on" time (periods of good motor control) and reducing the severity of "off" periods (when symptoms return).[14] This can often allow for a reduction in the total daily dose of levodopa, which may in turn mitigate some of levodopa's long-term motor complications, such as dyskinesia.[8]

Selegiline is also used as an initial monotherapy in early-stage PD, particularly when motor symptoms are mild.[3] Early clinical trials, such as the landmark DATATOP study, provided evidence that initiating treatment with Selegiline could significantly delay the need for starting levodopa therapy by approximately 9 to 18 months.[8] This was initially interpreted as evidence of a disease-modifying or neuroprotective effect. While the debate over whether Selegiline truly slows the underlying neurodegenerative process continues, its symptomatic benefit in early PD is well-recognized.[3] The formulations approved for this indication are the conventional oral tablets/capsules (Eldepryl) and the orally disintegrating tablets (Zelapar).

4.2 Approved Indication: Major Depressive Disorder

The use of Selegiline for major depressive disorder (MDD) is exclusively approved for the transdermal system, marketed as Emsam.[8] While oral Selegiline has been used off-label for depression, it is not formally approved for this indication due to the safety concerns associated with the high doses required to achieve non-selective MAO inhibition.[8]

The development of the Emsam patch was a pivotal innovation that "rescued" the therapeutic potential of an MAOI for depression by engineering a solution to its primary safety liability. The transdermal route of administration allows Selegiline to be absorbed directly into the systemic circulation, bypassing the gastrointestinal tract and the liver during its first pass.[8] This is critically important because it avoids significant inhibition of intestinal and hepatic MAO-A, the enzyme responsible for metabolizing dietary tyramine. As a result, the lowest approved dose of the patch (6 mg/24 hours) can be used without the strict dietary tyramine restrictions that are mandatory for all oral MAOIs.[10] This greatly improves the safety and practicality of using an MAOI for depression. At higher doses (9 mg/24 hours and 12 mg/24 hours), enough Selegiline is absorbed to partially inhibit gut MAO-A, and dietary restrictions become necessary.[10] The efficacy of Emsam for MDD is considered modest and comparable to that of other antidepressant classes, and it is often reserved for patients who have not responded adequately to other treatments.[8]

4.3 Investigational and Off-Label Applications

Selegiline's ability to modulate central monoamine pathways has made it a subject of continuous research for a wide spectrum of CNS disorders. The diverse investigational portfolio is not random but represents a logical exploration of a drug with a central mechanism relevant to numerous conditions involving dysregulation of dopamine, norepinephrine, and serotonin.

• Attention-Deficit/Hyperactivity Disorder (ADHD): Selegiline is used off-label for the treatment of ADHD.[3] The therapeutic rationale is based on its ability to increase dopaminergic and noradrenergic tone in the prefrontal cortex, a mechanism shared with established ADHD stimulant medications.
• Substance Use Disorders: The role of dopamine in the brain's reward circuitry has prompted investigation into Selegiline for addiction. Completed Phase 2 clinical trials have explored its efficacy for treating nicotine dependence (tobacco use disorder) and marijuana dependence.[25] The goal in these studies is to modulate the dopamine system to reduce craving and withdrawal symptoms.
• Dementia and Cognitive Enhancement: Selegiline has been used for the palliative treatment of cognitive symptoms in mild to moderate Alzheimer's disease.[6] There has also been interest in its potential as a nootropic or "smart drug" and as an anti-aging agent, stemming from its potential neuroprotective properties and monoamine-enhancing effects, though the evidence supporting these uses is considered controversial and uncertain.[8]
• Other Potential Uses: Clinical research has also explored Selegiline for a variety of other conditions, including social anxiety disorder, erectile dysfunction, and psychosis, though it is not approved for these uses.[8]

Section 5: Formulations, Dosage, and Administration

Selegiline is available in three distinct formulations, each with specific indications, dosing regimens, and administration instructions. The choice of formulation is a critical clinical decision that directly impacts the drug's pharmacokinetic profile, efficacy, and safety liabilities.

5.1 Available Formulations

• Conventional Oral Capsules and Tablets (e.g., Eldepryl): These are supplied as 5 mg tablets or capsules containing selegiline hydrochloride.[18] This formulation is administered orally and undergoes significant first-pass metabolism.
• Orally Disintegrating Tablets (ODT) (Zelapar): This formulation is supplied as 1.25 mg tablets containing selegiline hydrochloride.[12] It is designed to dissolve rapidly on the tongue without the need for water. This allows for a portion of the drug to be absorbed through the buccal mucosa, reducing first-pass metabolism and the formation of amphetamine metabolites compared to conventional tablets.[18]
• Transdermal System (Patch) (Emsam): This is an extended-release patch designed for once-daily application. It is available in three strengths that deliver 6 mg, 9 mg, or 12 mg of selegiline over a 24-hour period.[23] This system provides continuous drug delivery and bypasses the gastrointestinal tract entirely.

5.2 Dosing Regimens by Indication

The dosing of Selegiline is highly specific to the indication and the formulation being used. Exceeding the recommended doses, particularly for the oral formulations, increases the risk of non-selective MAO inhibition and its associated dangers.

For Parkinson's Disease (Adjunctive Therapy):

• Conventional Oral (Eldepryl): The standard dosage is 5 mg taken twice daily, with breakfast and lunch. The total daily dose should not exceed 10 mg.[18] Taking doses later in the day is generally avoided to minimize the risk of insomnia.
• Orally Disintegrating Tablet (Zelapar): Treatment is initiated at a dose of 1.25 mg once daily, taken in the morning before breakfast. This dose is maintained for at least six weeks. If the clinical response is insufficient, the dose may be increased to 2.5 mg once daily. The maximum recommended daily dose is 2.5 mg.[12] The lower maximum dose for this formulation reflects its higher bioavailability compared to conventional tablets and is intended to maintain its selectivity for MAO-B.

For Major Depressive Disorder:

• Transdermal System (Emsam): Treatment is initiated with the 6 mg/24 hours patch applied once daily. If a greater clinical response is needed, the dose can be increased in increments of 3 mg/24 hours (to 9 mg/24 hours, then to 12 mg/24 hours) at intervals of no less than two weeks. The maximum recommended dose is 12 mg/24 hours.[10]

5.3 Special Populations

Dosage adjustments may be necessary for patients with hepatic or renal impairment, and these recommendations differ between formulations due to their unique pharmacokinetic pathways. This difference highlights how formulation science can de-risk a drug for use in patients with common comorbidities.

• Hepatic Impairment:
• Zelapar (ODT): For patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9), the daily dose should be reduced to 1.25 mg. It is not recommended for use in patients with severe hepatic impairment (Child-Pugh score >9).[12]
• Emsam (Patch): No dosage adjustment is required for patients with mild or moderate hepatic impairment.[16] This suggests that first-pass metabolism is a less critical clearance pathway for the transdermal formulation, making it a potentially safer option in this population.
• Renal Impairment:
• Zelapar (ODT): No dosage adjustment is needed for mild to moderate renal impairment (Creatinine Clearance [CrCl] 30-89 mL/min). However, its use is not recommended in patients with severe renal impairment or end-stage renal disease (CrCl <30 mL/min).[12]
• Emsam (Patch): No dosage adjustment is required for patients with mild, moderate, or severe renal impairment.[16]
• Geriatric Use: For elderly patients (65 years and older) being treated for depression, the recommended dose of Emsam is 6 mg per 24 hours.[10] Elderly patients may be more susceptible to certain adverse effects, such as orthostatic hypotension.[30]

Table 5.1: Approved Selegiline Formulations, Dosages, and Administration Guidelines

Formulation (Brand Name)	Indication	Starting Dose	Titration Schedule	Maximum Dose	Administration Instructions	Special Population Adjustments
Oral Capsule/Tablet (Eldepryl)	Parkinson's Disease	5 mg twice daily	N/A	10 mg/day	Take with breakfast and lunch.	No specific recommendations provided.
Orally Disintegrating Tablet (Zelapar)	Parkinson's Disease	1.25 mg once daily	After ≥6 weeks, may increase to 2.5 mg/day.	2.5 mg/day	Dissolve on tongue before breakfast. No food/drink 5 min before/after.	Hepatic: Reduce to 1.25 mg/day (mild-mod); Not recommended (severe). Renal: Not recommended (severe).
Transdermal System (Emsam)	Major Depressive Disorder	6 mg/24 hours once daily	Increase by 3 mg/24h at ≥2 week intervals.	12 mg/24 hours	Apply patch to dry, intact skin (upper torso, thigh, arm). Rotate sites daily.	No adjustment needed for mild-mod hepatic or mild-sev renal impairment.

Section 6: Safety Profile, Tolerability, and Risk Management

Selegiline is an effective medication but is associated with a complex and significant safety profile that requires careful patient selection, monitoring, and counseling. Its adverse effects can be understood through three distinct mechanistic categories: on-target dopaminergic effects related to its use in Parkinson's disease; off-target or dose-dependent MAO-A effects that emerge at higher doses or with specific drug interactions; and formulation-dependent effects unique to the delivery system.

6.1 Black Box Warning: Suicidal Thoughts and Behaviors

The U.S. FDA has mandated a boxed warning for Selegiline, specifically for the Emsam transdermal system, consistent with the class-wide warning for all antidepressant medications.[10] The warning highlights an increased risk of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults (ages 18-24).[10]

Due to this risk, as well as the potential for hypertensive crisis, Emsam is contraindicated in patients younger than 12 years of age.[10] All patients, regardless of age, who are started on Selegiline for depression should be closely monitored for clinical worsening, the emergence of suicidal ideation, or unusual changes in behavior such as agitation, irritability, or panic attacks.[31] This monitoring should be most intensive during the initial few months of therapy and following any dose adjustments. The context for this warning is particularly important for Selegiline, as the Emsam patch is often reserved for patients with treatment-resistant depression, a population with an intrinsically higher baseline risk of suicide.[24] This situation demands an elevated standard of care and vigilant, proactive monitoring from clinicians.

6.2 Adverse Drug Reactions

The adverse effect profile of Selegiline is extensive and varies with the indication and formulation.

Common Adverse Reactions (across formulations):

• Central Nervous System: Dizziness, insomnia, and headache are frequently reported.[8]
• Autonomic: Orthostatic hypotension (a drop in blood pressure upon standing, leading to lightheadedness or fainting) is common, especially during treatment initiation and dose titration.[15] Dry mouth is also a frequent complaint.[8]
• Gastrointestinal: Nausea and constipation are common.[12]

Dopaminergic-Related Adverse Reactions (primarily in Parkinson's disease):

These effects are an extension of Selegiline's primary pharmacology and result from excessive dopaminergic stimulation.

• Dyskinesia: Selegiline can cause new onset or worsening of pre-existing involuntary movements. This can often be managed by reducing the dose of concomitant levodopa.[12]
• Psychiatric Effects: Hallucinations (visual or auditory), confusion, agitation, and psychotic-like behavior can occur.[12]
• Impulse Control Disorders: There have been reports of patients developing intense and uncontrollable urges, such as pathological gambling, increased sexual urges, or compulsive shopping.[12]

Formulation-Specific Adverse Reactions:

• Zelapar (ODT): Because the tablet dissolves in the mouth, it can cause local irritation, including mouth sores, ulcers, pain, and difficulty swallowing.[12]
• Emsam (Patch): Application site reactions are the most common adverse event, occurring in a significant percentage of patients. These reactions include redness, itching, rash, and swelling at the site of patch application.[8]

Serious Adverse Reactions:

• Serotonin Syndrome: A potentially life-threatening condition resulting from excessive serotonergic activity.[8]
• Hypertensive Crisis: A rapid and severe increase in blood pressure, typically triggered by interactions.[8]
• Sudden Onset of Sleep: Patients have reported falling asleep without warning while engaged in daily activities, including driving.[30]
• Withdrawal Effects: Abrupt discontinuation of Selegiline can lead to a syndrome of hyperpyrexia (high fever) and confusion, resembling neuroleptic malignant syndrome.[12]

6.3 Contraindications

The use of Selegiline is absolutely contraindicated in several situations due to the risk of severe or fatal reactions.

• Concomitant Medications:
• Other MAOIs: Co-administration with any other MAO inhibitor (e.g., phenelzine, linezolid) is contraindicated due to the risk of additive inhibition and hypertensive crisis.[18]
• Opioids: Use with meperidine, tramadol, methadone, and propoxyphene is contraindicated because of the high risk of fatal serotonin syndrome.[10]
• Serotonergic Drugs: Concomitant use with SSRIs, SNRIs, most tricyclic antidepressants, St. John's wort, and the cough suppressant dextromethorphan is contraindicated.[10] Strict washout periods of 2 to 5 weeks are required when switching between Selegiline and these agents.
• Other Drugs: Use with the muscle relaxant cyclobenzaprine and the anticonvulsant carbamazepine is also contraindicated.[18]
• Patient Conditions:
• Known hypersensitivity to Selegiline or any component of the formulation.[18]
• Pheochromocytoma (a catecholamine-secreting tumor), which is a contraindication for the Emsam patch.[10]

6.4 Warnings and Precautions

In addition to the boxed warning and contraindications, several other important warnings require clinical attention.

• Hypertension: Patients should be monitored for new or exacerbated hypertension. The risk is increased by concomitant use of sympathomimetic drugs (e.g., pseudoephedrine in cold remedies) and, at higher doses, by the ingestion of tyramine-containing foods.[10]
• Activation of Mania/Hypomania: Like other antidepressants, Selegiline should be used with caution in patients with a history of bipolar disorder, as it may trigger a manic or hypomanic episode.[10]
• External Heat (Emsam Patch): A critical warning specific to the transdermal formulation is to avoid exposing the application site to direct heat sources, such as heating pads, saunas, hot tubs, or prolonged direct sunlight.[10] Heat can increase the rate and extent of Selegiline absorption from the patch, potentially leading to dangerously elevated serum levels and toxicity.

Section 7: Clinically Significant Interactions

Selegiline's interaction profile is extensive and complex, representing one of the greatest challenges in its clinical use. The potential for severe, life-threatening reactions necessitates thorough medication reconciliation and patient education. The risk of interactions is not static but is a dynamic liability that increases with the dose, as the drug transitions from a selective MAO-B inhibitor to a non-selective MAO inhibitor.

7.1 Drug-Food Interactions: The Tyramine-Induced Hypertensive Crisis

The most famous interaction associated with MAOIs is the tyramine-induced hypertensive crisis, often called the "cheese reaction."

• Mechanism: Tyramine is an amino acid found in high concentrations in aged, fermented, pickled, or spoiled foods. Under normal conditions, it is metabolized and inactivated by MAO-A in the intestinal wall and liver. When MAO-A is inhibited by a drug like Selegiline (at non-selective doses), ingested tyramine is absorbed systemically. It then acts as an indirect sympathomimetic agent, displacing large quantities of norepinephrine from sympathetic nerve terminals. This massive norepinephrine surge causes a rapid, severe, and potentially fatal increase in blood pressure.[8]
• Risk Stratification and Dietary Counseling: The risk of this interaction with Selegiline is entirely dependent on the dose and formulation, requiring a tiered approach to patient counseling.
• Low-Dose Oral Formulations (for Parkinson's Disease): At recommended doses (≤10 mg/day for Eldepryl, ≤2.5 mg/day for Zelapar), Selegiline is largely selective for MAO-B, and MAO-A activity in the gut remains mostly intact. Therefore, the risk is low, and strict dietary restrictions are not typically required.[20] However, hypertensive reactions have been reported even at these doses, so caution is still advised.[12]
• Emsam 6 mg/24 hours Patch: This low-dose transdermal formulation delivers Selegiline systemically without significantly inhibiting gut MAO-A. Consequently, no dietary tyramine restrictions are required.[10]
• Emsam 9 mg/24 hours and 12 mg/24 hours Patches: At these higher doses, enough Selegiline is absorbed to cause partial inhibition of intestinal MAO-A. Therefore, patients using these strengths must avoid foods and beverages high in tyramine.[10] This restriction should begin on the first day of using a higher-dose patch and continue for two weeks after reducing the dose or discontinuing the medication.
• High-Tyramine Foods to Avoid: Patients on restricted diets should be provided with a list of foods to avoid, including but not limited to: aged cheeses (cheddar, blue cheese, brie), cured or fermented meats (salami, pepperoni), pickled herring, sauerkraut, soy sauce, tofu, fava beans, tap beer, and red wine.[14]

7.2 Drug-Drug Interactions

Drug-drug interactions with Selegiline are numerous and can be broadly categorized as pharmacodynamic (additive effects on neurotransmitter systems) or pharmacokinetic (alterations in drug metabolism). Interaction databases list over 500 potential drug interactions, with more than 100 classified as major.[40]

Pharmacodynamic Interactions:

• Serotonergic Agents: This is the most dangerous class of drug-drug interactions. Co-administration of Selegiline with SSRIs (e.g., fluoxetine, sertraline), SNRIs (e.g., venlafaxine, duloxetine), tricyclic antidepressants, triptans, most opioids (especially meperidine, tramadol, methadone), and dextromethorphan can lead to serotonin syndrome. This is a medical emergency caused by excessive serotonin levels, characterized by a triad of mental status changes (agitation, confusion), autonomic hyperactivity (fever, tachycardia, sweating), and neuromuscular abnormalities (tremor, rigidity, myoclonus). This combination is contraindicated.[10] Because Selegiline's inhibition of MAO is irreversible, its effects persist long after the drug is cleared. This necessitates a mandatory washout period of at least 2 weeks after stopping Selegiline before starting a serotonergic agent. When stopping fluoxetine, which has a very long half-life, a washout of at least 5 weeks is required before starting Selegiline.[10]
• Sympathomimetic Agents: Drugs like pseudoephedrine, phenylephrine, ephedrine, and amphetamines can potentiate the pressor effects of norepinephrine, and when combined with an MAOI, can trigger a hypertensive crisis. Patients should be warned to avoid over-the-counter cold and weight-loss preparations containing these agents.[10]
• Dopaminergic Antagonists: Antipsychotic medications (e.g., haloperidol, risperidone) and other dopamine blockers like metoclopramide can directly oppose the therapeutic action of Selegiline in Parkinson's disease, leading to reduced efficacy.[12]

Pharmacokinetic Interactions:

• CYP450 Inducers: Drugs that induce the CYP enzymes responsible for Selegiline's metabolism (primarily CYP2B6 and CYP3A4), such as carbamazepine, rifampin, and phenytoin, may decrease plasma concentrations of Selegiline and reduce its effectiveness. Concomitant use should be approached with caution.[12]
• CYP450 Inhibitors: While theoretically possible, there is less evidence for clinically significant interactions with inhibitors of Selegiline's metabolism. An in vivo study found that the potent CYP3A4 inhibitor erythromycin did not alter Selegiline's pharmacokinetics, suggesting this pathway may be less critical.[19]

Table 7.1: Major Drug-Drug and Drug-Food Interactions with Selegiline

Interacting Agent/Class	Potential Outcome	Risk Level	Management Recommendation
SSRIs, SNRIs, TCAs, St. John's Wort	Serotonin Syndrome	Contraindicated	Avoid combination. Mandatory washout period of 2-5 weeks required when switching.
Meperidine, Tramadol, Methadone	Serotonin Syndrome (potentially fatal)	Contraindicated	Absolutely avoid combination. Allow ≥14 days between discontinuation of MAOI and initiation of opioid.
Other MAOIs (e.g., Phenelzine)	Hypertensive Crisis	Contraindicated	Avoid combination. Allow ≥14 days between discontinuation of agents.
Sympathomimetics (e.g., Pseudoephedrine)	Hypertensive Crisis	Major	Avoid combination if possible. Monitor blood pressure closely if use is unavoidable.
Tyramine-rich Foods	Hypertensive Crisis	Major (Dose-Dependent)	Dietary restrictions required for Emsam 9 mg & 12 mg. Caution advised for oral doses. No restriction for Emsam 6 mg.
Dopamine Antagonists (Antipsychotics)	Reduced Selegiline Efficacy	Moderate	Monitor for worsening of Parkinson's symptoms. Combination may be necessary but effectiveness is reduced.
Dextromethorphan	Psychosis, Bizarre Behavior, Serotonin Syndrome	Contraindicated	Avoid combination.

Section 8: Overdose and Toxicology

An overdose of Selegiline is a serious medical emergency that can lead to severe and prolonged toxicity. The clinical presentation is not specific to Selegiline but mirrors the toxidrome seen with classic, non-selective MAOIs, as the overdose state eliminates any selectivity for the MAO-B isoenzyme.

8.1 Clinical Presentation of Toxicity

A dangerous feature of Selegiline overdose is the potential for a significant delay in the onset of symptoms, which can be a clinical trap for the unwary. A patient may appear well for up to 6 to 12 hours post-ingestion before rapidly deteriorating.[42] This delay is thought to be due to the time required for the irreversible enzyme inhibition to result in a critical accumulation of monoamine neurotransmitters.

Initial symptoms are often non-specific and may include agitation, irritability, hyperactivity, dizziness, and headache.[15] This can progress rapidly to a severe sympathomimetic and/or serotonergic toxidrome, characterized by:

• Central Nervous System: Severe headache, confusion, hallucinations, agitation, progressing to seizures, and coma.[15]
• Autonomic Instability: Tachycardia, rapid and irregular pulse, severe hypertension or hypotension, sweating, and hyperthermia (high fever).[15]
• Neuromuscular Abnormalities: Muscle rigidity, tremor, hyperreflexia, trismus (lockjaw), and opisthotonos (severe arching of the back).[15]

Severe toxicity can lead to life-threatening complications, including rhabdomyolysis (muscle breakdown), acute renal failure, disseminated intravascular coagulation (DIC), and intracranial hemorrhage secondary to hypertensive crisis.[42] The primary driver of multi-organ failure in severe cases is uncontrolled hyperthermia, making temperature management a critical priority.

8.2 Management of Overdose

There is no specific antidote for Selegiline overdose; management is intensive and supportive, focusing on controlling the life-threatening symptoms of the resulting toxidromes.[43]

• Initial Management and Decontamination: Immediate medical attention is required. Consultation with a regional poison control center is highly recommended.[15] Gastric decontamination with activated charcoal (e.g., 50 grams) may be considered if the patient presents within 1 to 2 hours of a significant ingestion and is able to protect their airway. It is contraindicated in patients with a declining level of consciousness due to the risk of aspiration.[42]
• Supportive Care: The cornerstones of treatment are airway management, circulatory support, and continuous monitoring of vital signs, temperature, and mental status in an intensive care setting.[43] Intravenous fluids are essential for hydration and to support blood pressure.
• Specific Pharmacological Interventions:
• Agitation and Seizures: Intravenous benzodiazepines (e.g., lorazepam, diazepam) are the first-line treatment and should be administered liberally to control agitation and terminate seizure activity.[42]
• Hypertensive Crisis: Severe hypertension should be managed with short-acting, titratable intravenous antihypertensives, such as labetalol or nicardipine. Vasodilators like nitroprusside may also be used.[43]
• Hyperthermia: This is a critical, life-threatening complication that must be managed aggressively. Treatment includes external cooling methods (e.g., ice packs, cooling blankets) and, in severe cases (temperature >39.5°C), requires immediate intubation, neuromuscular paralysis with a non-depolarizing agent, and mechanical ventilation to halt endogenous heat production from muscle rigidity.[42]
• Serotonin Syndrome: In addition to benzodiazepines and cooling, the serotonin antagonist cyproheptadine may be administered orally or via a nasogastric tube (e.g., 12 mg initial dose) to help mitigate serotonergic effects.[43]
• Disposition: Due to the delayed onset and prolonged duration of toxicity (which can last for days), all patients with a suspected significant Selegiline overdose require admission for a prolonged period of observation (at least 12 to 24 hours), even if they are initially asymptomatic.[42]

Section 9: Regulatory History and Market Overview

The trajectory of Selegiline from its discovery to its current place in therapy is a compelling narrative of scientific refinement, regulatory challenges, and the transformative power of pharmaceutical formulation science.

9.1 Developmental Timeline

• Discovery and Early Research (1960s): Selegiline originated from research conducted in the early 1960s at the Chinoin Pharmaceutical Company in Hungary by József Knoll, Zoltan Ecseri, and colleagues.[8] It was initially studied as part of a class of MAOIs being investigated for antidepressant properties. The initial compound was deprenyl, the racemic mixture of the levo- and dextro-enantiomers.[8] Subsequent research led to the isolation and purification of the levorotatory enantiomer, selegiline, which was found to possess selective MAO-B inhibitory properties.[8]
• First Medical Approvals for Parkinson's Disease (1970s-1980s): Selegiline was first introduced for medical use in Hungary in 1977 for the treatment of Parkinson's disease.[8] It gained approval in the United Kingdom in 1982 and was subsequently approved by the U.S. FDA in 1989 under the brand name Eldepryl for use as an adjunct to levodopa/carbidopa.[8]
• Formulation Innovations and New Approvals (2000s): The 2000s saw the introduction of two new formulations that significantly expanded Selegiline's clinical utility.
• Emsam (Transdermal System): The Emsam patch was first approved by the FDA on February 27, 2006, for the treatment of major depressive disorder.[44] This was a landmark approval, as it provided a novel delivery system that successfully mitigated the primary safety concern (tyramine interaction) of using an MAOI for depression, thereby revitalizing a largely abandoned class of antidepressants.
• Zelapar (Orally Disintegrating Tablet): Zelapar was approved by the FDA on June 14, 2006, as an adjunctive treatment for Parkinson's disease.[45] Its regulatory journey was notably complex. The New Drug Application (NDA), originally submitted in 2002, received two "Approvable" letters from the FDA (in 2003 and 2005) before final approval.[19] The delays were due to the FDA's requests for more comprehensive data on the drug's metabolism (identification of CYP450 enzymes), its safety in patients with hepatic and renal impairment, its potential for enzyme induction, and labeling clarifications. This process serves as a case study in the rigorous scientific standards of modern drug regulation, where a deep understanding of a drug's pharmacokinetic profile is a prerequisite for approval.[19]

9.2 Market Landscape

• Branded Products: The three key branded formulations of Selegiline in the United States are Eldepryl (oral capsule, originally by Somerset), Zelapar (orally disintegrating tablet, by Valeant/Bausch), and Emsam (transdermal system, by Somerset).[1]
• Generic Availability: Conventional oral 5 mg tablets and capsules of selegiline hydrochloride are widely available from numerous generic manufacturers, including Apotex, Lannett, and others.[46] As of the latest available information, generic versions of the more complex Zelapar ODT and Emsam transdermal patch formulations were not available, granting them a period of market exclusivity.[8]
• Market Drivers: The continued use and market for Selegiline are driven by several factors. The rising prevalence of Parkinson's disease and depression in an aging global population ensures a sustained need for effective therapies.[46] Selegiline's therapeutic advantages, particularly the improved safety profile of its selective MAO-B inhibition and the innovative transdermal delivery system, make it a favorable option compared to older, non-selective MAOIs. Ongoing research into its potential neuroprotective effects and off-label uses for other neuropsychiatric conditions could further expand its market in the future.[46]

Section 10: Conclusion

Selegiline stands as a remarkable example of a versatile and enduring therapeutic agent whose clinical identity has been shaped and redefined over decades of research and development. Its journey from a non-selective MAOI precursor to a targeted neurological agent and, finally, to a modern antidepressant encapsulates a broader evolution in pharmacological understanding and drug delivery technology. The core of Selegiline's clinical profile lies in its dose-dependent duality: it is a selective MAO-B inhibitor at low doses for Parkinson's disease and a non-selective MAO-A/B inhibitor at higher doses for depression. This dichotomy is both the source of its therapeutic breadth and the root of its complex safety and interaction profile.

The development of the Zelapar orally disintegrating tablet and, most significantly, the Emsam transdermal system, highlights the profound impact of formulation science. These innovations were not mere conveniences but were strategic solutions to specific pharmacological problems—namely, reducing the formation of stimulant metabolites and mitigating the risk of the tyramine-induced hypertensive crisis. The Emsam patch, in particular, successfully engineered a way to deliver an effective antidepressant dose while largely sparing the gastrointestinal MAO-A enzyme, thereby "rescuing" a valuable therapeutic mechanism from the safety limitations that had relegated older MAOIs to therapies of last resort.

Ultimately, Selegiline is a powerful but demanding medication. Its effective and safe use requires a nuanced understanding of its formulation-specific pharmacokinetics, its dose-dependent mechanism of action, and its extensive potential for severe drug and food interactions. For the well-informed clinician, it offers a valuable tool for managing two of the most challenging chronic conditions in modern medicine: Parkinson's disease and major depressive disorder. Its history serves as a testament to the principle that innovation in medicine is not only about the discovery of new molecules but also about the intelligent and sophisticated refinement of existing ones to maximize their therapeutic benefit while minimizing their inherent risks.

Works cited

1. Selegiline | C13H17N | CID 26757 - PubChem, accessed August 27, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Selegiline
2. Selegiline | CAS 14611-51-9 - LGC Standards, accessed August 27, 2025, https://www.lgcstandards.com/MX/en/p/MM0216.13
3. Selegiline | 14611-51-9 - ChemicalBook, accessed August 27, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2137450.htm
4. CAS No : 14611-51-9 | Product Name : Selegiline - API Standards - Pharmaffiliates, accessed August 27, 2025, https://pharmaffiliates.com/en/14611-51-9-selegiline-api-standards-pa191760000.html
5. Selegiline API Manufacturers | Suppliers | Drug Master Files (DMF) - PharmaCompass.com, accessed August 27, 2025, https://www.pharmacompass.com/manufacturers-suppliers-exporters/selegiline
6. Selegiline: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 27, 2025, https://go.drugbank.com/drugs/DB01037
7. R(-)-Selegiline 1.0mg/mL methanol, ampule 1mL, certified reference material, Cerilliant 14611-51-9 - Sigma-Aldrich, accessed August 27, 2025, https://www.sigmaaldrich.com/US/en/product/cerillian/s003
8. Selegiline - Wikipedia, accessed August 27, 2025, https://en.wikipedia.org/wiki/Selegiline
9. Eldepryl, Zelapar (selegiline) dosing, indications, interactions, adverse effects, and more, accessed August 27, 2025, https://reference.medscape.com/drug/eldepryl-zelapar-selegiline-343052
10. EMSAM® (selegiline transdermal system) - accessdata.fda.gov, accessed August 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021336s005s010,021708s000lbl.pdf
11. Selegiline - brand name list from Drugs.com, accessed August 27, 2025, https://www.drugs.com/ingredient/selegiline.html
12. ZELAPAR® (selegiline hydrochloride) orally disintegrating tablets - accessdata.fda.gov, accessed August 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021479s010lbl.pdf
13. Transdermal selegiline for the treatment of major depressive disorder - PMC, accessed August 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2656289/
14. MAO-B inhibitors (rasagiline, selegiline, safinamide) | Parkinson's UK, accessed August 27, 2025, https://www.parkinsons.org.uk/information-and-support/mao-b-inhibitors-rasagiline-selegiline-safinamide
15. Selegiline: MedlinePlus Drug Information, accessed August 27, 2025, https://medlineplus.gov/druginfo/meds/a697046.html
16. EMSAM (SELEGILINE TRANSDERMAL SYSTEM) CONTINUOUS DELIVERY FOR ONCE-DAILY APPLICATION Rx only Suicidality and Antidepressant Drug - accessdata.fda.gov, accessed August 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021336s002lbl.pdf
17. A Closer Look at Selegiline for Parkinson's Symptom Management, accessed August 27, 2025, https://davisphinneyfoundation.org/blog/selegiline-for-parkinsons-symptom-management/
18. Selegiline Monograph for Professionals - Drugs.com, accessed August 27, 2025, https://www.drugs.com/monograph/selegiline.html
19. Action Memo for NDA 21-479, for the use of Zelapar (selegiline orally disintegrating tablets) in patients with Parkinson - accessdata.fda.gov, accessed August 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021479s000_MedR_P1.pdf
20. Selegiline (oral route) - Side effects & dosage - Mayo Clinic, accessed August 27, 2025, https://www.mayoclinic.org/drugs-supplements/selegiline-oral-route/description/drg-20061264
21. Selegiline - PubMed, accessed August 27, 2025, https://pubmed.ncbi.nlm.nih.gov/30252350/
22. Selegiline: a molecule with innovative potential - PMC - PubMed Central, accessed August 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7242272/
23. Selegiline Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 27, 2025, https://www.drugs.com/dosage/selegiline.html
24. Emsam (Selegiline) Patch: Uses, Side Effects, Dosage, & More - Choosing Therapy, accessed August 27, 2025, https://www.choosingtherapy.com/emsam-selegiline/
25. Selegiline Completed Phase 2 Trials for Tobacco Use Disorders Treatment - DrugBank, accessed August 27, 2025, https://go.drugbank.com/drugs/DB01037/clinical_trials?conditions=DBCOND0057920&phase=2&purpose=treatment&status=completed
26. Selegiline Completed Phase 2 Trials for Nicotine Dependence Treatment | DrugBank Online, accessed August 27, 2025, https://go.drugbank.com/drugs/DB01037/clinical_trials?conditions=DBCOND0030647&phase=2&purpose=treatment&status=completed
27. Selegiline Completed Phase 2 Trials for Marijuana Dependence Treatment - DrugBank, accessed August 27, 2025, https://go.drugbank.com/drugs/DB01037/clinical_trials?conditions=DBCOND0030648&phase=2&purpose=treatment&status=completed
28. Erectile Dysfunction Unknown Status Phase 4 Trials for Selegiline (DB01037) - DrugBank, accessed August 27, 2025, https://go.drugbank.com/indications/DBCOND0029956/clinical_trials/DB01037?phase=4&status=unknown_status
29. Emsam (selegiline transdermal) dosing, indications, interactions, adverse effects, and more, accessed August 27, 2025, https://reference.medscape.com/drug/emsam-selegiline-transdermal-342949
30. Selegiline: Parkinson's Uses, Warnings, Side Effects, Dosage - MedicineNet, accessed August 27, 2025, https://www.medicinenet.com/selegiline/article.htm
31. Emsam (selegiline) Patch, accessed August 27, 2025, https://provider.amerigroup.com/docs/gpp/PHARM_ALL_Emsam.pdf?v=202101061820
32. EMSAM (selegiline transdermal system) - accessdata.fda.gov, accessed August 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021336s011lbl.pdf
33. Selegiline Transdermal Patch: MedlinePlus Drug Information, accessed August 27, 2025, https://medlineplus.gov/druginfo/meds/a607003.html
34. Selegiline Side Effects: Common, Severe, Long Term - Drugs.com, accessed August 27, 2025, https://www.drugs.com/sfx/selegiline-side-effects.html
35. www.ncbi.nlm.nih.gov, accessed August 27, 2025, https://www.ncbi.nlm.nih.gov/books/NBK526094/#:~:text=Other%20dangerous%20adverse%20effects%20of,%2C%20dyskinesia%2C%20and%20serotonin%20syndrome.
36. Selegiline Uses, Side Effects & Warnings - Drugs.com, accessed August 27, 2025, https://www.drugs.com/mtm/selegiline.html
37. Selegiline Dissolving Tablets - Cleveland Clinic, accessed August 27, 2025, https://my.clevelandclinic.org/health/drugs/20234-selegiline-dissolving-tablets
38. Selegiline (transdermal route) - Side effects & dosage - Mayo Clinic, accessed August 27, 2025, https://www.mayoclinic.org/drugs-supplements/selegiline-transdermal-route/description/drg-20061256
39. Selegiline and Alcohol/Food Interactions - Drugs.com, accessed August 27, 2025, https://www.drugs.com/food-interactions/selegiline.html
40. Selgene Interactions Checker - Drugs.com, accessed August 27, 2025, https://www.drugs.com/drug-interactions/selegiline,selgene.html
41. Selegiline Interactions Checker - Drugs.com, accessed August 27, 2025, https://www.drugs.com/drug-interactions/selegiline.html
42. MAOI toxicity - LITFL, accessed August 27, 2025, https://litfl.com/maoi-toxicity/
43. How to treat a patient who unintentionally took a 4-day dose of Selegiline (Monoamine Oxidase B inhibitor) and presented with altered mental status? - Dr.Oracle AI, accessed August 27, 2025, https://www.droracle.ai/articles/101892/my-patient-took-unintentionally-4-days-doses-of-seniment-and-selligeline-and-presented-with-change-in-mental-status-how-do-you-treat-that-
44. Emsam (selegiline) FDA Approval History - Drugs.com, accessed August 27, 2025, https://www.drugs.com/history/emsam.html
45. Zelapar (selegiline hydrochloride) FDA Approval History - Drugs.com, accessed August 27, 2025, https://www.drugs.com/history/zelapar.html
46. Generic SELEGILINE HYDROCHLORIDE INN entry, drug patent expiration information and freedom to operate - DrugPatentWatch, accessed August 27, 2025, https://www.drugpatentwatch.com/p/generic-api/SELEGILINE+HYDROCHLORIDE