This page describes pharmacological agents that may have legal restrictions, side effects, and drug interactions in your jurisdiction. Information is for educational research only — consult a clinician before considering any compound.

High-risk compound

Surface here is educational only; do not use without medical supervision. Our editorial verdict is SKIP-FOR-NOW — current cost / risk / redundancy puts it below the line.

Browse

Nardil

Well Researched

Phenelzine | the original irreversible non-selective MAOI (MAO-A + MAO-B + GABA-T) | hydrazine derivative

Aliases (5)

phenelzine · phenelzine sulfate · the original MAOI · PLZ · β-phenethylhydrazine

TYPICAL DOSE

45-90 mg/day PO divided BID-TID

Initiation 15 mg TID = 45 mg/day; titrate to 60-75-90 mg/day over 4-6 weeks

ROUTE

Oral (tablet)

Oral tablet, divided BID-TID

CYCLE

Daily continuous; 2-4 week taper to discontinue…

Daily continuous chronic use; 2-4 week taper to discontinue

STORAGE

Room temperature; original container

Overview

What is Nardil?

Nardil (phenelzine) is the original FDA-approved (1961) irreversible non-selective monoamine oxidase inhibitor — the prototype of the MAOI class. A hydrazine derivative that suicide-inhibits both MAO-A and MAO-B, with a unique secondary mechanism (GABA transaminase inhibition) that distinguishes it from tranylcypromine (Parnate). FDA-approved for atypical depression and major depression with anxiety; off-label first-line MAOI for treatment-resistant social anxiety disorder per Liebowitz 1992 RCT. Same tyramine-driven hypertensive crisis liability as Parnate. Hydrazine moiety covalently sequesters vitamin B6 (pyridoxine), producing a deficiency syndrome that requires routine B6 supplementation. Rare hydrazine hepatotoxicity (parallel to isoniazid). Distinct from selegiline (selective MAO-B at low oral doses, no tyramine cliff) — phenelzine has no tier that escapes the non-selective profile.

Key Benefits

Strongest evidence base of any MAOI for social anxiety disorder (Liebowitz 1992); A-tier for atypical depression (Quitkin Columbia series); B-tier for panic disorder, treatment-resistant PTSD, bulimia. The GABA-T inhibition mechanism gives anxiolytic + sedating profile (vs. Parnate's stimulant character) — preferred for agitated/anxious depression, panic, SAD over Parnate's preference for anergic/atypical-with-fatigue presentations.

Mechanism of Action

Irreversibly inactivates both MAO-A (serotonin/NE/tyramine) and MAO-B (dopamine/PEA/benzylamine) by suicide-inhibition of the FAD cofactor. Secondary GABA transaminase (GABA-T/ABAT) inhibition raises whole-brain GABA 30-90% (uniquely among irreversible MAOIs — distinguishes phenelzine from Parnate; underlies the sedating + anxiolytic profile). Tertiary mechanism: hydrazine moiety covalently binds pyridoxal 5'-phosphate (active B6), sequestering the cofactor and causing the signature B6 deficiency syndrome (paresthesias, edema, myoclonic jerks). Recovery of MAO activity requires de-novo enzyme synthesis (~2-3 weeks washout).

Pharmacokinetics

PeakHalf-life

Approximate curve — visual aid only, not data-precise PK

Research Indications

Most Effective

Primary mechanism — irreversible non-selective MAO inhibition

Phenelzine is a β-phenethylhydrazine — phenelzine's distinguishing chemical feature is the hydrazine (-NHNH₂) moiety attached to a phenet…

Effective

Secondary mechanism — GABA transaminase (GABA-T) inhibition (unique among MAOIs)

This is the key mechanism distinguishing phenelzine from tranylcypromine. Phenelzine and its primary metabolite phenylethylidenehydrazine…

Investigational

Tertiary mechanism — pyridoxine (B6) sequestration

The hydrazine moiety reacts with the aldehyde group of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, forming a hydrazone a…

Investigational

Pharmacokinetics

- Tmax: 2-4 hours - Half-life of parent compound: ~12 hours (elimination of phenelzine itself) - Effective biological half-life of MAO in…

Investigational

Hydrazine vs. amphetamine derivative — the chemotype split

This is the central organizing fact of the irreversible MAOI class: - Hydrazine derivatives: Phenelzine (Nardil), isocarboxazid (Marplan)…

Peptide Interactions

Pyridoxine (B6) 50-100 mg/day.

Synergistic

ESSENTIAL prophylactic — reverses the deficiency syndrome.

Lithium augmentation

Synergistic

for treatment-resistant cases. Standard depression-augmentation strategy. Lithium 600-900 mg/day.

Trazodone for insomnia.

Synergistic

Low-dose trazodone (50-100 mg HS) is one of the few hypnotics safely combinable with MAOIs (technically a serotonin antagonist + reuptake inhibitor — SARI — …

CBT for SAD.

Synergistic

Combined treatment > monotherapy in SAD. Phenelzine + exposure therapy is the canonical treatment-resistant SAD protocol.

All other MAOIs.

Avoid

Tranylcypromine, isocarboxazid, selegiline (any dose), rasagiline, safinamide, linezolid, methylene blue. Redundant + dangerous.

All SSRIs.

Avoid

Sertraline, fluoxetine (especially — long t½ → 5 week washout needed), paroxetine, citalopram, escitalopram, fluvoxamine. Serotonin syndrome.

All SNRIs.

Avoid

Venlafaxine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran. Serotonin syndrome.

All TCAs.

Avoid

Imipramine, amitriptyline, clomipramine especially, nortriptyline. Some old psychopharmacology specialists do combine TCA + MAOI in deeply refractory cases —…

Bupropion.

Avoid

NDRI; raises NE → hypertensive risk on MAOI.

Tramadol.

Avoid

Serotonin syndrome.

Meperidine (Demerol), methadone, fentanyl-class.

Avoid

Serotonin syndrome / fatal interactions. Tell ER/anesthesiology immediately if taking phenelzine.

Dextromethorphan (DXM).

Avoid

Cough syrups containing DXM must be avoided. Use guaifenesin-only or codeine-only alternatives.

Quality Indicators

✓

Pharmacy-dispensed Rx, intact packaging

Prescription tablets in original sealed packaging from a licensed pharmacy. FDA-approved drug, well-established generic supply chain.

✓

Sugar-coated 15 mg tablet

Standard formulation. Tablets are sugar-coated to mask the bitter phenelzine sulfate taste.

Generic vs. Pfizer brand

Generic phenelzine is bioequivalent and dramatically cheaper ($30-100/mo vs. $400-800/mo brand). Switch carefully if needed and track for any subjective response change.

✗

Counterfeit risk on international/gray-market sources

Less common gray market for phenelzine than for selegiline/modafinil — most legitimate users go through US Rx specialty psychiatry. Counterfeit MAOIs are particularly dangerous given the interaction matrix.

What to Expect

Week 1
Tolerability and dose-response.
Week 2-4
Early effect window.
Week 4-8
Peak benefit assessment.
Week 8+
Cycle decision point.

Side Effects & Safety 14

Side Effects

1Orthostatic hypotension. Especially first 2-4 weeks. Dizziness on standing. Counsel: rise slowly, hydrate well, monitor BP. Concrete fall/syncope risk in older adults; less severe but still relevant in younger users.
2Weight gain. 5-15 lbs over months is typical. Mechanism: GABA-T inhibition appetite effects + atypical-depression hyperphagia resolution + monoaminergic appetite changes.
3Sexual dysfunction. Anorgasmia is common (>30% in some series); ED, decreased libido. Often persists across the treatment course.
4Sedation / fatigue. Especially first weeks; some persistent.
5Insomnia or vivid dreams (paradoxically — minority report).
6Dry mouth, constipation. Anticholinergic-like effects despite no direct anticholinergic action.
7Edema (peripheral, especially feet/ankles). Worsens with B6 deficiency.
8B6 deficiency syndrome. Paresthesias (numbness/tingling in hands), edema, myoclonic jerks at sleep onset, irritability. Reversed by adding pyridoxine 50-100 mg/day, which is why prophylactic supplementation is now standard.
9Headache. First weeks especially.
10Tremor. Mild postural tremor.
11Sweating.
12Mild tachycardia (vs. orthostatic hypotension — both can coexist).
13Anxiety / agitation (paradoxical — minority).
14Hyponatremia (SIADH-like; less common than with SSRIs but reported).

When to Stop

Hypertensive crisis from tyramine ingestion (the cheese reaction). THE defining MAOI safety event. Identical mechanism to Parnate. Symptoms: severe occipital headache, sweating, neck stiffness, palpitations, nausea, BP spike (often >200/120). Real ER event. Triggered by:
Aged cheeses (cheddar, blue, parmesan, brie, camembert, gouda, gruyère)
Aged/cured meats (salami, pepperoni, prosciutto, dry sausage, soppressata, salt-cured fish)
Fermented soy (soy sauce in quantity, miso, aged tofu, tempeh)
Fermented vegetables (sauerkraut, kimchi)
Tap/draft beer + red wine (especially Chianti)
Fava beans (broad beans)
Marmite, Vegemite
Overripe / spoiled food of any kind
Smoked fish
Serotonin syndrome. From co-administration with serotonergic drugs (SSRIs, SNRIs, TCAs, tramadol, DXM, MDMA, triptans, meperidine, methadone, fentanyl-class, St. John's Wort, 5-HTP, L-tryptophan high-dose, linezolid, methylene blue). Symptoms: agitation, hyperthermia, clonus, autonomic instability, tremor, diaphoresis. Can be fatal. 2-week washout in either direction is mandatory.
Hepatotoxicity (hydrazine-mediated). Rare but real. The hydrazine moiety is structurally implicated in idiosyncratic hepatic injury (parallel to isoniazid, the antimycobacterial that produces a similar hepatotoxicity profile). Pattern: hepatocellular injury, sometimes cholestatic. Onset typically 1-6 months. Rate ~1 in 10,000 — 1 in 50,000. Liver enzyme monitoring (ALT/AST baseline + periodic) is standard. NAT2 slow-acetylator polymorphism may confer higher risk — see Pharmacogenomics. This is an ADDITIONAL risk vs. Parnate, which lacks the hydrazine moiety.
Hypomania / mania induction. Class effect for antidepressants; relevant in bipolar-spectrum patients (screen family + personal history).
Suicidal ideation black-box warning. FDA class warning for all antidepressants in <25yo. The user (20yo) is in the at-risk age window.
Withdrawal syndrome. Abrupt discontinuation produces hyperarousal, agitation, insomnia, sometimes psychotic features. Always taper.
First 2-4 weeks: orthostatic hypotension, GI upset, sedation acclimation
First 6 weeks: B6 deficiency symptom emergence (if not supplementing prophylactically)
First 1-6 months: hepatotoxicity surveillance
Ongoing: tyramine vigilance throughout treatment + 2 weeks post-discontinuation

References

Liebowitz MR et al. 1992 — Phenelzine vs atenolol in social phobia: a placebo-controlled comparison (Arch Gen Psychiatry; PMID 1550466)

pubmed.ncbi.nlm.nih.gov · 1992

landmark SAD RCT establishing phenelzine as first-line MAOI for social anxiety

Nardil

Overview

What is Nardil?

Key Benefits

Mechanism of Action

Pharmacokinetics

Research Indications

Primary mechanism — irreversible non-selective MAO inhibition

Secondary mechanism — GABA transaminase (GABA-T) inhibition (unique among MAOIs)

Tertiary mechanism — pyridoxine (B6) sequestration

Pharmacokinetics

Hydrazine vs. amphetamine derivative — the chemotype split

Peptide Interactions

Quality Indicators

Pharmacy-dispensed Rx, intact packaging

Sugar-coated 15 mg tablet

Generic vs. Pfizer brand

Counterfeit risk on international/gray-market sources

What to Expect

Side Effects & Safety 14

Side Effects

When to Stop

References

Liebowitz MR et al. 1992 — Phenelzine vs atenolol in social phobia: a placebo-controlled comparison (Arch Gen Psychiatry; PMID 1550466)

Versiani M et al. 1992 — Pharmacotherapy of social phobia: a controlled study with moclobemide and phenelzine (Br J Psychiatry; PMID 1422623)

Quitkin FM et al. 1988 — Phenelzine versus imipramine in the treatment of probable atypical depression (Arch Gen Psychiatry; PMID 3052245)

Quitkin FM et al. 1990 — Atypical depression, panic attacks, and response to imipramine and phenelzine (Arch Gen Psychiatry; PMID 2244798)

Quitkin FM et al. 1993 — Columbia atypical depression. A subgroup of depressives with better response to MAOI than to tricyclic antidepressants or placebo (Br J Psychiatry; PMID 8104214)

McGrath PJ et al. 1993 — Tranylcypromine in atypical depression (J Clin Psychopharmacol; PMID 8101064)

Cipriani A et al. 2018 — Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis (Lancet; PMID 29477251)

Sheehan DV et al. 1980 — Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms (Arch Gen Psychiatry; PMID 7352840)

Frank JB, Kosten TR et al. 1988 — A randomized clinical trial of phenelzine and imipramine for posttraumatic stress disorder (Am J Psychiatry; PMID 3289400)

Walsh BT et al. 1988 — Phenelzine vs placebo in 50 patients with bulimia (Am J Psychiatry; PMID 3052267)

Baker GB et al. 1991 — The effects of phenelzine on rat brain GABA, glutamate, alanine, glutamine, and other amino acids (Eur J Pharmacol; PMID 1959554)

McKenna KF et al. 1991 — Inhibition of GABA-T by phenelzine and PEH (Drug Metabol Drug Interact; PMID 1820065)

McManus DJ et al. 1992 — Effects of phenelzine and PEH on rat brain GABA (Biochem Pharmacol; PMID 1417965)

Paslawski T et al. 1995 — Effects of acute and chronic administration of beta-phenylethylhydrazine on rat brain (Pharmacol Biochem Behav; PMID 7480218)

Heller B et al. 1976 — Effect of phenelzine on pyridoxal phosphate (Biochem Pharmacol; PMID 942895)

Robinson DS, Amsterdam JD 2008 — The selegiline transdermal system in major depressive disorder: a systematic review of safety and tolerability (J Affect Disord; PMID 18083233)

Gillman PK 2018 — A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired old tyramine myths (J Neural Transm; PMID 30143885)

Shulman KI et al. 2013 — Current place of monoamine oxidase inhibitors in the treatment of depression (CNS Drugs; PMID 23625240)

FDA Nardil prescribing information (Pfizer)

Nardil — DailyMed label

Stahl SM, Felker A 2008 — Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants (CNS Spectr; PMID 18900147)

Phenelzine — Wikipedia

Mayo Clinic — Phenelzine oral route

GoodRx — Phenelzine generic pricing

See something off?

Related compounds