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.