The first-generation MAOIs—isocarboxazid, phenelzine, and tranylcypromine—have few direct effects on reuptake or receptor blockade. Instead, they inhibit MAO in various organs, exerting greater effects on monoamine oxidase A (MAO-A)—for which norepinephrine and 5-HT are primary substrates—than on MAO-B, which acts primarily on other amines (e.g., phenylethylamine) and dopamine. Also, MAO-A is found in the gut mucosa and is responsible for degrading various amines that can act as false neurotransmitters and produce hypertensive crises (see later in this section). Isocarboxazid, phenelzine, and tranylcypromine are so-called irreversible inhibitors. When the enzyme is inhibited by these agents, protein regeneration is required before MAO enzymatic activity is restored. Selegiline (Eldepryl), a selective irreversible MAO inhibitor used in the treatment of Parkinson's disease, exerts its effects on MAO-B and is generally thought to have a very low risk of producing hypertensive crises. However, at the low dosages used in treating parkinsonian patients (5–10 mg/day), this drug is a weak antidepressant, and data from Sunderland et al. (1989) suggested that at higher antidepressant dosages, the drug affects both MAO-A and MAO-B and thus does not protect against hypertensive crises. More information on selegiline is provided in the section "Selective and Reversible Monoamine Oxidase Inhibitors" later in this chapter.

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Figure 3–9. Chemical structures of monoamine oxidase inhibitors (MAOIs).
Table Reference Number
Table 3–12. Monoamine oxidase inhibitors (MAOIs): names, formulations and strengths, and dosages
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Note. FDA = U.S. Food and Drug Administration; MDD = major depressive disorder; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Monoamine oxidase inhibitors (MAOIs): overview


Third-line agents for

 MDD (FDA approved for resistant depression)

 Social anxiety

 Panic disorder

Second-line agents for Parkinson's disease (selegiline has FDA approval)

Side effects

Weight gain


Sexual dysfunction

Dry mouth



Safety in overdose

Can be lethal in overdose. Hypertensive crisis, stroke, and myocardial infarction have been reported. Manage with lavage, emesis induction, and close management of blood pressure and airway.

Dosage and administration

Phenelzine: start at 15 mg bid or tid and increase by 15 mg per week to target dosage of 60–90 mg/day.

Tranylcypromine: start at 10 mg bid or tid and increase by 10 mg per week to target dosage of 40–60 mg/day.

Isocarboxazid: start at 10 mg bid and increase dosage, if the drug is tolerated, by 10 mg every 2–4 days to 40 mg/day by end of first week. Maximum recommended dosage is 60 mg/day, administered in divided doses.

Selegiline transdermal system (Emsam): start with 6-mg patch daily for 4 weeks and then increase to 9-mg patch for 2 weeks, and then 12-mg patch as needed. No dietary restrictions at 6 mg/day.


Flulike symptoms, hallucinations, hypomania, and dysphoria reported with sudden discontinuation. Taper dose by 25% per week.

Drug interactions

Foods containing high levels of tyramine (contraindicated) (see Table 3–14Table 3–14): hypertensive crisis

-Blockers: hypotension, bradycardia

Oral hypoglycemics: hypoglycemic effects

Bupropion (contraindicated): hypertensive crisis, seizure

Carbamazepine (contraindicated): hypertensive crisis

Meperidine (contraindicated): serotonin syndrome

Nefazodone: possible serotonin syndrome

Sympathomimetics: hypertensive crisis

SSRIs (contraindicated): serotonin syndrome

TCAs: clomipramine contraindicated

Mirtazapine (contraindicated): hypertensive crisis

SNRIs (contraindicated): serotonin syndrome

Table Reference Number
Table 3–13. Common or troublesome side effects of monoamine oxidase inhibitors (MAOIs)
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Table 3–14. Foods to be avoided with monoamine oxidase inhibitors (MAOIs)


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