Selegiline

Selegiline

Selegiline (also called deprenyl) is a selective MAO-B inhibitor, originally approved for Parkinson's disease, that's been used off-label for decades as a low-dose tool for cognitive resilience, mood, libido, and brain aging. It works by slowing the enzyme that breaks down dopamine in the brain, so the dopamine you produce sticks around longer and signals more. The practical effect at low doses is steadier focus, motivation, and drive, with a slow build rather than a stimulant kick.
Most people taking it outside a Parkinson's context use it at 1-5 mg a few times a week, aiming for the brain-aging and cognitive end of the dose-response curve rather than the antidepressant end. At those low doses it's selective for MAO-B, doesn't interact with tyramine in food, and has a clean tolerability profile. The catch is that it's a real MAO inhibitor with real drug interactions, so it sits in a different category from a typical nootropic and needs to be respected as such.

Deep-dive

Selegiline irreversibly inhibits monoamine oxidase B (MAO-B), the enzyme that breaks down dopamine and phenylethylamine in the brain. MAO-B activity rises with age and is particularly concentrated in glial cells. By blocking it, selegiline lets endogenous dopamine accumulate and signal for longer, and reduces the hydrogen peroxide and reactive oxygen species generated as dopamine is metabolised. That second effect is part of why it's been studied as a neuroprotective compound rather than just a symptomatic one.
It's selective for MAO-B at low doses. The FDA label puts the selectivity threshold around 10 mg/day for swallowed selegiline, with tyramine sensitivity beginning to appear around 5 mg of the orally disintegrating form. Above those thresholds it begins inhibiting MAO-A as well, which is what you want for an antidepressant effect but also what brings the food and drug interactions of classical MAOIs back on the table. Most people using selegiline as a nootropic or longevity tool stay well below this, in the 1-5 mg range a few times a week.
Catecholaminergic activity enhancement. Beyond MAO-B inhibition, selegiline has a separate, weirder property that the original Hungarian researcher Joseph Knoll spent decades on. At very low doses, far below those needed to inhibit MAO-B, selegiline acts as a catecholaminergic activity enhancer, potentiating the release of dopamine and noradrenaline in response to neuronal stimulation. This is a separate mechanism from MAO-B inhibition and doesn't follow the same dose curve. It's part of why some people report effects from sub-milligram doses that don't fit a pure MAO-B story.
Neurotrophic factors. Selegiline upregulates BDNF and to a lesser extent GDNF and NGF in dopaminergic regions. In SH-SY5Y cells, selegiline at concentrations of 10⁻⁷ to 10⁻⁹ M significantly increased BDNF expression, and animal models show induction of nerve growth factor and GDNF in nigrostriatal pathways. It also activates anti-apoptotic Bcl-2 family proteins. These mechanisms are why selegiline keeps showing up in neuroprotection literature beyond Parkinson's, in models of methamphetamine neurotoxicity, ischaemic stroke, and amyloid-induced cognitive impairment.
Longevity data. This is the part of selegiline's story that gets the most attention and warrants the most caution. Knoll's 1988 rat study treated 24-month-old male rats with 0.25 mg/kg three times a week and found average lifespan extended from 147 weeks to 192 weeks, with the longest-lived deprenyl rat dying at 226 weeks against a previously known maximum of 182 weeks for the species. This was the first claimed extension of maximum lifespan for any species by any drug. Subsequent rat studies have been mixed, with some showing 15-44% mean lifespan extension and others showing no effect on maximum lifespan. The size of Knoll's effect has never been cleanly replicated. In dogs, selegiline has been shown to improve cognitive function in age-related canine cognitive dysfunction. In humans, no controlled study has demonstrated lifespan extension. The Parkinson's DATATOP trial, the largest long-term human selegiline dataset, found no mortality benefit and at one point raised mortality concerns that were later argued to be artefacts of trial design. The honest read is: striking effects in some rodent studies, plausible mechanism, no human evidence either way.
Cognition and mood. In a synergistic cognition study, low-dose selegiline combined with donepezil rescued cognitive impairment in amyloid-injected mice via cholinergic and dopaminergic pathways. Selegiline alone improved performance on Y-maze and conditioned fear learning tasks. The selegiline transdermal patch (Emsam) is FDA-approved for major depressive disorder at 6-12 mg/24 hours, where it delivers therapeutic CNS levels without significantly inhibiting gut MAO-A. Trials show response rates of 33-40% versus 22-30% on placebo, comparable to other antidepressants but with notably less weight gain and sexual dysfunction.
Women. Most of the selegiline longevity work was done in male rats and most of the human data comes from Parkinson's trials, which skew male. The pharmacokinetic differences are significant. A British Journal of Clinical Pharmacology study found that women on oral contraceptives had selegiline AUC and Cmax 10-20 times higher than women not on oral contraceptives at the same dose, across doses from 5 to 40 mg. The mechanism is ethinylestradiol's inhibition of CYP3A4 and other CYP enzymes that metabolise selegiline. Practically: a woman on combined oral contraceptives taking 5 mg of selegiline may end up with brain levels equivalent to 50-100 mg in a non-OC user, which puts her well past the MAO-B selective threshold and into territory where tyramine restrictions and full MAOI precautions become relevant. HRT containing oestradiol and progestins has a similar but smaller effect. Women not on hormonal contraceptives or HRT process selegiline similarly to men. There's no women-specific contraindication beyond this interaction and the standard advice to avoid in pregnancy and breastfeeding (pregnancy category C, with rat developmental concerns at high transdermal doses).
Older adults. This is the population selegiline was originally designed for and where the rationale is strongest. MAO-B activity rises with age, dopamine declines, and the neuroprotective and pro-neurotrophic effects have the most theoretical room to work. Older adults are also more sensitive to orthostatic hypotension and insomnia, the two main side effects, so dose conservatively and monitor blood pressure standing and lying.

Dosage:

  • Cognitive and longevity use: 1-5 mg orally, 2-5 days per week. Most people land at 1-2.5 mg taken in the morning. This stays clearly within the MAO-B selective range, avoids tyramine restrictions, and matches the dosing range Knoll worked in for his anti-aging research
  • Start low and titrate slow: Begin at 1 mg every other day for 2 weeks. Selegiline is irreversible, so steady-state effects build over time. Increases of more than 1-2 mg every 2-3 weeks are not recommended. The metabolites include amphetamine and methamphetamine derivatives that can disturb sleep and cause overstimulation if you escalate too fast
  • Timing: Take in the morning. The active metabolites have stimulant properties and can interfere with sleep if taken later. Empty stomach or with a light meal is fine. Avoid tyramine-heavy meals (aged cheeses, cured meats, fermented foods, draft beer) close to dosing if you're on the higher end of the range or if you're a woman on oral contraceptives, where effective exposure can be 10-20x higher
  • Forms: Oral tablets and capsules (5 mg) are the standard prescription form sold as Eldepryl and generics. Orally disintegrating tablets (Zelapar, 1.25 mg) bypass first-pass metabolism and produce higher CNS levels at lower doses. The transdermal patch (Emsam, 6/9/12 mg per 24h) is for depression and bypasses gut MAO-A. For low-dose nootropic use, standard oral 5 mg tablets quartered or a liquid dilution work fine
  • Women on hormonal contraceptives or oral HRT: Halve or quarter the dose. The CYP3A4 inhibition from ethinylestradiol can raise selegiline exposure 10-20 fold. A 1 mg dose for an OC user behaves more like a 10-20 mg dose, which puts you past MAO-B selectivity and into territory requiring tyramine restrictions
  • Older adults: Start at 1 mg twice weekly, monitor standing blood pressure for orthostatic drops. The cognitive and neuroprotective rationale is strongest in this population but so is sensitivity to side effects
  • Cycling: Because selegiline is an irreversible inhibitor, MAO-B enzyme function only returns as new enzyme is synthesised, which takes around 2 weeks after stopping. Continuous low-dose use is the standard approach. Some users cycle 5 days on, 2 days off, but there's no specific evidence this is better
  • Antidepressant dosing is different. If you're using selegiline for depression rather than cognitive support, the relevant doses are 6-12 mg/24h transdermal or 20-30 mg oral, both of which lose MAO-B selectivity and require classical MAOI precautions including tyramine restrictions and a strict drug interaction list. This is not a self-managed dose range

Here's what you can expect:

At 1-2.5 mg taken consistently for 2-4 weeks, most people notice steadier motivation, easier task initiation, slightly better mood floor, and sometimes a mild libido lift. It's not a stimulant, the effect builds rather than hits. Compared to caffeine or modafinil, the texture is closer to feeling like you have more drive than usual rather than feeling pushed.
Some people get nothing at sub-2 mg doses and need 5 mg to feel any subjective effect. Others are sensitive to the amphetamine metabolites and find 1 mg keeps them up at night. There's significant individual variability, much of it driven by baseline dopamine tone and CYP3A4 activity.
For cognitive performance specifically, expect modest gains in tasks involving sustained attention, working memory, and motivation, rather than a jump in raw processing speed. The neuroprotective and longevity benefits, if they exist in humans, are slow and not subjectively felt.
If you're using it for libido, the literature on the original deprenyl rat studies and clinical reports in older men suggests this is one of the more reliable subjective effects. Knoll's rats had striking restoration of sexual activity at the same dose used for lifespan extension.

Side effects & risks:

  • Insomnia and overstimulation are the most common dose-limiting side effects. Selegiline is metabolised to L-amphetamine and L-methamphetamine, which can disturb sleep, raise heart rate, and cause anxiety or jitteriness. Take in the morning, start low, and don't stack with other stimulants
  • Headache, nausea, dizziness, dry mouth are common, usually mild, and tend to settle within the first few weeks
  • Tyramine interaction (cheese effect) is the classic MAOI hazard. At low doses (under 5-10 mg/day oral), MAO-B selectivity protects you from tyramine reactions. Above that threshold, or in women on oral contraceptives where effective exposure is 10-20x higher, you need to avoid aged cheeses, cured meats, fermented foods, soy sauce, draft beer, and overripe fruit. Symptoms of a hypertensive crisis include severe occipital headache, palpitations, neck stiffness, sweating, and dilated pupils
  • Serotonin syndrome is a real risk if combined with serotonergic drugs. Hard contraindication with SSRIs, SNRIs, tricyclic antidepressants, MDMA, tramadol, meperidine, dextromethorphan, St John's wort, and other MAOIs. Combination with these has caused fatalities. A 2-week washout (5 weeks for fluoxetine) is required when switching
  • Sympathomimetic interactions including ephedrine, pseudoephedrine, decongestants, and amphetamines can cause hypertensive crisis. Avoid OTC cold medications containing pseudoephedrine
  • L-tyrosine and L-DOPA interactions. L-tyrosine and selegiline combined can theoretically push catecholamines and tyramine metabolism in unwanted directions. Selegiline plus levodopa is the standard Parkinson's combination but increases the risk of dyskinesias and orthostatic hypotension at higher selegiline doses
  • Hepatic and renal impairment. Selegiline is hepatically metabolised. Avoid in severe liver impairment (Child-Pugh >9), reduce dose in moderate impairment, and avoid in severe renal impairment (CrCl <30 mL/min)
  • Pregnancy and breastfeeding. Pregnancy category C. Animal studies show developmental delays at high doses. Selegiline crosses into milk at concentrations 5-15x maternal plasma in animal studies. Avoid unless the indication is unavoidable
  • Long-term human safety data outside Parkinson's is limited. The largest long-term dataset is the DATATOP trial in Parkinson's patients, which followed 800 subjects over 8+ years. There was a mortality signal early on that has been re-analysed multiple times and is now generally considered artefactual, but the controversy underlines that we don't have clean long-term data on healthy users at any dose
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Blood markers

Blood pressure (lying and standing), baseline before starting and rechecked at 4-6 weeks. Selegiline can cause orthostatic drops in older users and supine hypertension at higher doses. A standing BP that drops more than 20 mmHg systolic or 10 mmHg diastolic from supine is a meaningful change worth noting.
Liver enzymes (ALT, AST, GGT), baseline if you have any history of liver issues or are taking other hepatically metabolised compounds. Selegiline is metabolised by CYP2B6 and CYP3A4 and is contraindicated in severe hepatic impairment.
Kidney function (creatinine, eGFR), baseline. Selegiline ODT is not recommended at CrCl <30 mL/min.
For most people using selegiline at 1-5 mg a few times weekly, no specific bloodwork is needed beyond a baseline metabolic panel. The people who need closer monitoring are anyone over 60, anyone on hormonal contraceptives or HRT (where exposure can be 10-20x higher than expected), and anyone using doses approaching 10 mg/day or above where MAO-B selectivity is lost and full MAOI precautions apply.
Prescription drug in most countries. Sold under brand names Eldepryl, Zelapar, and Emsam, with generics widely available.