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Selegiline

L-Deprenyl · Deprenyl · Eldepryl · Zelapar · Emsam

C
Animal replicated
FDA-approvedMAO-B InhibitorPropargylamineSmall Molecule
RouteOralFDA-approved
C
Evidence grade: Animal replicated

Effect demonstrated in multiple animal studies; human data sparse or extrapolated. Grades summarize evidence quality, not whether a compound is appropriate, legal, or risk-free.

At a glance
What it is
L-Deprenyl — MAO-B Inhibitor — Dopamine Optimizer — Neuroprotective — FDA Approved — MAO-B Inhibitor, Propargylamine, Small Molecule.
Why people use it
Used primarily for cognitive support and longevity and anti-aging.
What the evidence supports
Rasagiline (Azilect) is the second-generation selective irreversible MAO-B inhibitor, developed specifically to overcome selegiline's limitations. Understanding the comparison clarifies when selegiline remains the preferred choice.
Key risks
Key risks: Meperidine (pethidine/Demerol) is absolutely contraindicated with selegiline at any dose. This combination can produce a fatal serotonin syndrome through mechanisms that include MAO-B inhibition even at low doses — the precise mechanism is not fully established but may involve meperidine's serotonin reuptake inhibiting properties combined with reduced serotonin degradation. This is not a low-dose exemption: meperidine + selegiline at any dose = hard contraindication. Anyone having elective surgery where opioids will be used should inform the anesthesiologist about selegiline use and request alternative opioids (morphine, oxycodone, hydromorphone are acceptable). Tramadol is also a concern — it has serotonergic properties and should be used with caution..
If you only read one thing

Selegiline is simultaneously a 50-year-old well-characterized pharmaceutical with FDA-approval, decades of clinical safety data, and a precise mechanistic understanding — and a compound whose longevity and nootropic applications are based on rat data and mechanistic inference that has never been fully validated in human controlled trials. The Parkinson's indication is Grade A evidence. The longevity application is Grade C (rat data). The neuroprotective claim is genuinely contested — DATATOP showed symptomatic benefit, not structural neuroprotection, a distinction that took years to fully appreciate. At low community doses (1-5 mg every 2-3 days), the compound has an excellent safety profile, no meaningful tyramine risk, and effects that are mechanistically coherent. At the standard Parkinson's clinical dose (10 mg/day), the amphetamine metabolites become more relevant and the risk profile changes somewhat. Understanding the dose-dependent selectivity is the most important pharmacological concept for safe community use.

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Route / form

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Evidence fit
Route-specific

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Route caveat
Screen contraindications

Hard-stop risk to review first: Meperidine (pethidine/Demerol) is absolutely contraindicated with selegiline at any dose. This combination can produce a fatal serotonin…

Protocol anchor
Full dosing section

Open the full report at the dosing chapter for protocol rows, cycle context, and administration notes.

Typical dose snapshot
See route notes
Evidence varies by use case
Evidence reality check
Evidence snapshot
Rasagiline (Azilect) is the second-generation selective irreversible MAO-B inhibitor, developed specifically to overcome selegiline's limitations. Understanding the comparison clarifies when selegiline remains the preferred choice.
From the chapter quick-reference block.
Risk posture
1 hard stop
Absolute contraindications should dominate the decision.
Indication map
Supported / plausible / speculative / avoid
Avoid
Meperidine (pethidine/Demerol) is absolutely contraindicated with selegiline at any dose. This combination can produce a fatal serotonin syndrome through mechanisms that include MAO-B inhibition even at low doses — the precise mechanism is not fully established but may involve meperidine's serotonin reuptake inhibiting properties combined with reduced serotonin degradation. This is not a low-dose exemption: meperidine + selegiline at any dose = hard contraindication. Anyone having elective surgery where opioids will be used should inform the anesthesiologist about selegiline use and request alternative opioids (morphine, oxycodone, hydromorphone are acceptable). Tramadol is also a concern — it has serotonergic properties and should be used with caution.
See section 8.4.
Categories
Cognition & MoodLongevity & Anti-agingMitochondrial & Energy
Properties
✓ FDA-approvedNot injectable
  • ⛔ Meperidine (pethidine/Demerol) is absolutely contraindicated with selegiline at any dose. This combination can produce a fatal serotonin syndrome through mechanisms that include MAO-B inhibition even at low doses — the precise mechanism is not fully established but may involve meperidine's serotonin reuptake inhibiting properties combined with reduced serotonin degradation. This is not a low-dose exemption: meperidine + selegiline at any dose = hard contraindication. Anyone having elective surgery where opioids will be used should inform the anesthesiologist about selegiline use and request alternative opioids (morphine, oxycodone, hydromorphone are acceptable). Tramadol is also a concern — it has serotonergic properties and should be used with caution. — See section 8.4.
Evidence
CAnimal replicated
The Core Mechanism
Selegiline irreversibly inhibits MAO-B — the predominant monoamine oxidase isoform in the brain (accounting for ~80% of brain MAO). MAO-B catabolizes dopamine, phenylethylamine (PEA), and other catecholamines. Inhibiting MAO-B: preserves striatal and cortical dopamine (reducing its oxidative metabolism); increases PEA levels in the brain (PEA itself has mood-elevating and cognitive-enhancing effects and stimulates dopamine and norepinephrine release); reduces hydrogen peroxide production from dopamine oxidation (the antioxidant/neuroprotective mechanism); upregulates BDNF and other neurotrophic factors. DOSE-DEPENDENT SELECTIVITY: below ~10 mg/day oral, selegiline is highly MAO-B selective; above this threshold, MAO-A inhibition begins, producing dietary tyramine risk ('cheese reaction') and serotonergic drug interaction risk.
The Longevity Data
Joseph Knoll's 1988 landmark study: rats treated with deprenyl (selegiline) at 0.25 mg/kg lived significantly longer than saline-treated controls — the first demonstration that a MAO-B inhibitor extended maximum lifespan in rats. Corroborated in multiple subsequent studies including Drosophila lifespan extension. The proposed mechanism: enhanced dopaminergic and catecholaminergic neuron activity (the 'enhancer effect' theory); neuroprotection via reduced oxidative stress; anti-apoptotic mechanisms; possible tumor-suppressing effects (reduced fibromyxosarcoma incidence in Knoll's later studies). Community use for longevity is anchored to this rat data.
The DATATOP Clarification
DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) trial 1989: selegiline appeared to slow Parkinson's disease progression, delaying the need for levodopa by approximately 9 months. This was initially interpreted as neuroprotection. Subsequent analysis revealed: the benefit was symptomatic (selegiline's dopamine-preserving effect masked the natural disease progression signal) rather than true structural neuroprotection. This is the most important clinical context: selegiline does not reverse or halt neurodegeneration in Parkinson's disease — it reduces symptom severity by preserving the dopamine that remains. True neuroprotection has not been demonstrated in humans for selegiline.
The Amphetamine Metabolites
Selegiline is metabolized to L-amphetamine (20-60% urinary recovery) and L-methamphetamine (9-30%). The critical distinction: these are the L-enantiomers (levorotatory), not the D-enantiomers that characterize d-amphetamine/d-methamphetamine with their potent CNS stimulant properties. L-methamphetamine is a weak sympathomimetic with primarily peripheral (nasal decongestant) activity and minimal CNS stimulation. L-amphetamine has modest CNS activity but substantially less than d-amphetamine. At low community doses (1-5 mg), the amphetamine metabolite burden is clinically insignificant. At standard Parkinson's doses (10 mg/day), some mild stimulant effects may be noted. The metabolites are NOT the same as illicit methamphetamine.
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