Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). These enzymes metabolize monoamine neurotransmitters and related amines, including serotonin, norepinephrine, dopamine, epinephrine, tyramine, and several trace amines.
MAOIs include several pharmacologically distinct groups. The classic antidepressant MAOIs (phenelzine, tranylcypromine, and isocarboxazid) are irreversible, non-selective inhibitors of both MAO-A and MAO-B and are used primarily in major depressive disorder, including treatment-resistant depression. Other MAOIs include reversible inhibitors of MAO-A (RIMAs), such as moclobemide, and selective MAO-B inhibitors, such as selegiline, rasagiline, and safinamide, which are used mainly in Parkinson's disease or, in the case of transdermal selegiline, depression.
MAOI selectivity can vary by dose, route, formulation, and systemic exposure. For example, selegiline is relatively selective for MAO-B at lower doses used in Parkinson's disease, but at higher antidepressant doses also inhibits MAO-A and can function clinically as a non-selective MAOI.
The use of classic MAOIs declined for many years, following earlier reports of serious interactions with tyramine-containing foods and some sympathomimetic or serotonergic drugs. Nevertheless, modern reviews and prescribing guides state that classic MAOIs remain a highly effective treatment option for depression, and can be used safely when standard dietary and medication interaction precautions are followed. The dietary risk is considered much lower than in the early decades of MAOI use, as modern food production, hygiene standards, refrigeration, and starter culture methods have greatly reduced tyramine exposure in ordinary diets. The possibility of serious tyramine related hypertensive reactions is therefore described as substantially reduced under modern dietary standards and guidance, although not completely eliminated.
Medical uses
Depression Classic irreversible MAOIs are used in the treatment of major depressive disorder, especially treatment-resistant depression. Modern guidance recommends considering phenelzine, tranylcypromine, or isocarboxazid after insufficient response to other antidepressant treatments, including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), mirtazapine, bupropion, tricyclic antidepressants (TCAs), or augmentation strategies. The same guidance states that classic MAOIs are typically considered before electroconvulsive therapy when rapid response is not required, although ECT may be preferred when urgent response is necessary, such as in imminent suicide risk, inanition, or catatonia.
MAOIs have long been associated with efficacy in atypical depression, but modern expert guidance also emphasizes their use in severe treatment-resistant depression more broadly, including melancholic or endogenous depression. Phenelzine may be particularly useful when anxiety or panic symptoms predate or accompany depression, while tranylcypromine may be considered when psychomotor retardation or melancholic features are prominent. Isocarboxazid has fewer comparative data, but modern guidance describes it as an effective alternative, including when phenelzine or tranylcypromine are not well tolerated, and as a possible first option where available; its generally favorable tolerability profile may be relevant when sedation, somnolence, weight gain, edema, or other adverse effects limit treatment with another classic MAOI. Expert guidance cautions against treating these distinctions as absolute.
MAOIs may also be effective in some cases of bipolar depression, although antidepressant treatment in bipolar disorder requires specific caution because of the risk of mood switching and the need for mood-stabilizing treatment.
Anxiety-related and other psychiatric disorders MAOIs have been studied or used in several anxiety-related disorders, including panic disorder with agoraphobia, social anxiety disorder, and mixed anxiety and depressive states. Modern prescribing guidance also notes potential usefulness in treatment-resistant anxiety disorders.
Other studied or reported uses include bulimia nervosa, post-traumatic stress disorder, borderline personality disorder, and obsessive–compulsive disorder (OCD). Evidence for some of these indications is limited, and in several cases consists mainly of older trials, small studies, or uncontrolled reports.
Parkinson's disease and other uses Selective MAO-B inhibitors, including selegiline, rasagiline, and safinamide, are used in the treatment of Parkinson's disease, where inhibition of dopamine metabolism can increase dopaminergic activity. Non-selective MAOIs and MAO-B inhibitors have also been investigated in other neurological contexts, including neuroprotection and migraine prevention, but these uses vary by drug and indication.
Pargyline is a non-selective MAOI that was previously used as an antihypertensive agent to treat hypertension.
Adverse effects
Common adverse effects The adverse effect profile of MAOIs varies by drug, dose, and selectivity. Common adverse effects of classic irreversible MAOIs can include orthostatic hypotension, sleep disturbance, sedation or somnolence, insomnia, dry mouth, sexual dysfunction, urinary retention, constipation, edema, weight change, agitation, and paresthesias.
Orthostatic hypotension is a predictable dose-related effect of classic MAOIs. It often appears after dose increases, may peak after about 10 to 14 days, and often improves over the following weeks. Blood pressure measurements while sitting or lying and standing can help distinguish this effect from baseline variation or transient post-dose increases.
The pattern differs among classic MAOIs. Phenelzine is more often associated with weight gain, edema, somnolence, sexual dysfunction, pyridoxine deficiency, and rare hepatotoxicity, while tranylcypromine is less associated with weight gain and hepatotoxicity but may produce more insomnia and transient post-dose blood pressure increases. Isocarboxazid is generally described as better tolerated than phenelzine, although higher doses can produce anticholinergic-type adverse effects, insomnia, subjective weakness, edema, carbohydrate cravings, and rare hepatotoxicity.
Tyramine and hypertensive reactions
People taking classic irreversible, non-selective MAOIs generally need to limit foods and beverages containing substantial amounts of tyramine. Tyramine is formed by microbial decarboxylation of tyrosine and may be present in high amounts in some foods that are fermented, matured, aged, or spoiled. Because inhibition of MAO reduces the breakdown of dietary tyramine in the gastrointestinal tract and liver, excessive tyramine intake can raise blood pressure through peripheral norepinephrine release; this blood pressure raising effect is often called a pressor response. In serious cases, it can cause hypertensive urgency or emergency.
Higher risk foods include some aged cheeses, some artisan beers using natural yeasts, some fermented meats, and fermented products such as soy sauce, miso, tempeh, sauerkraut, Marmite, and kimchi. Dietary tyramine exposure is substantially lower than during the early period of MAOI use, largely because of changes in food production, hygiene standards, refrigeration, and starter culture methods. Modern guidance therefore describes the risk of a serious blood pressure increase as limited when dietary and medication precautions are followed, although it cannot be fully ruled out.
Historical estimates from the early decades of MAOI use reported hypertensive reactions in a small minority of treated patients. One review cited early tranylcypromine era estimates of hypertensive crisis around 0.5% and death around 0.001%, before modern tyramine restricted diets and before the lower tyramine levels associated with contemporary food production. Later safety reviews describe fatal tyramine related reactions as extremely rare, with no deaths from MAOI induced hypertension reported in the medical literature for several decades.
Blood pressure elevation after excessive tyramine intake is usually self-limiting and typically reaches its maximum within about 2 hours. Modern guidance discourages rapid blood pressure reduction outside appropriate medical supervision, because overtreatment can cause hypotensive overshoot; sublingual nifedipine is specifically discouraged.
Dietary risk differs among MAOI subclasses. RIMAs such as moclobemide are reversible MAO-A inhibitors and generally have lower tyramine related dietary risk than classic irreversible non-selective MAOIs. Low-dose selective MAO-B inhibitors also have lower tyramine related dietary risk. However, these distinctions depend on the specific drug, dose, route, and formulation, and higher doses or formulations that also inhibit MAO-A may require dietary precautions.
Withdrawal Abrupt or rapid discontinuation of MAOIs can cause withdrawal symptoms, which may include anxiety, agitation, insomnia or drowsiness, hallucinations, delirium, paranoia, and mania or hypomania. As with many antidepressants, gradual dose reduction is generally used to reduce the risk and severity of withdrawal symptoms.
After stopping an irreversible MAOI, MAO activity returns only as new enzyme is synthesized or repaired, so dietary and medication precautions generally continue for a period after discontinuation. Washout periods are especially important when switching between an MAOI and drugs with significant serotonin reuptake inhibition or serotonin-releasing activity.
Drug interactions
Mechanism based interactions MAOI interactions are best assessed by mechanism rather than by broad drug class. The highest-risk interactions include drugs that substantially increase serotonin, especially those with significant serotonin reuptake inhibition or serotonin-releasing activity. Examples generally avoided for this reason include SSRIs, SNRIs, clomipramine, imipramine, chlorpheniramine, brompheniramine, MDMA, meperidine, tramadol, methadone, tapentadol, dextromethorphan, dextropropoxyphene, pentazocine, and levorphanol. The main risk is serotonin toxicity, a dose-related condition that can include tremor, hyperreflexia, clonus, agitation, autonomic instability, and, in severe cases, life-threatening toxicity.
Other combinations are avoided because of different mechanisms or limited safety data. Modern MAOI prescribing guidance lists pancuronium, cocaine, methyldopa, reserpine, St John's wort, ayahuasca, and drugs that also have clinically relevant MAOI activity, such as methylene blue and linezolid, as combinations to avoid with classic MAOIs. Methylene blue and linezolid are not serotonin reuptake inhibitors; they are usually avoided with classic MAOIs because they also have MAOI activity, safety data are limited, and there is usually little clinical reason to combine multiple MAOIs. The main serotonin-toxicity concern is when their MAOI activity overlaps with drugs that substantially increase serotonin, such as serotonin reuptake inhibitors or serotonin-releasing agents.
Some drugs can markedly increase catecholamine signaling or blood pressure. Medium- or high-dose amphetamines and fenfluramine are avoided because of serotonin-releasing activity. Low-dose amphetamines, ephedrine, and pseudoephedrine are treated as strong relative contraindications rather than absolute contraindications; if used by experienced clinicians, reduced dosing, slow titration, and blood pressure monitoring are required. Direct adrenergic agents such as epinephrine, norepinephrine, phenylephrine, isoproterenol, and dobutamine are not absolute contraindications, but their blood pressure raising effects may be potentiated, so reduced initial dosing and careful titration are advised.