Most monoamine oxidase (MAO) inhibitors are used primarily for severe depression resistant to other antidepressant drugs, but are also used to treat phobias and anxiety disorders. First-generation MAO inhibitors include isocarboxazid, phenelzine, and tranylcypromine. Newer-generation MAO inhibitors with lower toxicity include selegiline, rasagiline and safinamide, used in the treatment of Parkinson's disease and off-label for Alzheimer's disease and attention deficit disorder, and moclobemide, a less toxic antidepressant that is available in many countries, but not in the United States. Other MAO inhibitors are marketed outside the United States to treat depression, anxiety disorders, Parkinson's disease, and bacterial infections. Serious toxicity from MAO inhibitors occurs with overdose or owing to interactions with certain other drugs or foods (Table II-39).

Drugs of other classes may have MAO-inhibiting activity, including procarbazine, linezolid, the recreational drugs paramethoxyamphetamine (PMA) and methylenedioxymethamphetamine (MDMA, “ecstasy”), and methylene blue. The popular herbal product used for depression, St. John's wort (Hypericum perforatum), appears to act in part as an MAO inhibitor and has been implicated in interactions with medications such as selective serotonin reuptake inhibitors (SSRIs). A number of other plant products containing tryptamines, harmines, and hydroxyindole have also been shown to have MAO-inhibiting activity, including such popular herbals as resveratrol piperine (found in pepper), ginkgo biloba, ginseng, and berberine.

MAO inhibitors inactivate MAO, an enzyme responsible for degradation of biogenic amines within CNS neurons. The enzyme has two major subtypes, MAO-A and MAO-B. MAO-A is also found in the liver and intestinal wall, where it metabolizes tyramine and therefore limits its entry into the systemic circulation.

1. Toxicity results from the release of excessive neuronal stores of vasoactive amines, inhibition of metabolism of biogenic amines (catecholamines and serotonin), or absorption of large amounts of dietary tyramine (which in turn releases catecholamines from neurons).
   1. Selegiline and other selective MAO-B inhibitors do not usually require a restrictive diet. (MAO-B selectivity for selegiline is lost at doses >20 mg/d; thus, overdose with selegiline resembles that of the older MAO inhibitors.) Antidepressant treatment with transdermal selegiline is feasible because higher doses of selegiline reach the CNS owing to bypass of hepatic first-pass metabolism. A recent study showed that at low transdermal doses (6 mg/24 h), no dietary restrictions were required, although there is still the potential for drug interactions (see below).
   2. Older MAO inhibitors and selegiline are irreversible inhibitors of the enzyme. Because effects can last up to 2 weeks, concomitant or delayed drug and food interactions are common and potentially fatal with the first-generation drugs. However, moclobemide is a reversible competitive MAO-A inhibitor. As a result, it does not require food restrictions, has much less potential for drug interactions, and is much safer in overdose than are the older MAO inhibitors.
2. Toxic reactions to MAO inhibitors can be classified into four distinct types: food interactions, interactions with certain drugs, serotonin syndrome, and acute overdose.
   1. Food interactions. Tyramine is a dietary monoamine that is degraded by gastrointestinal MAO-A. MAO inhibition allows excessive absorption of tyramine, which acts indirectly to release norepinephrine, causing a hyperadrenergic syndrome. Patients taking therapeutic oral doses of MAO-B-specific agents (eg, selegiline) or the reversible inhibitor moclobemide (up to 900 mg/d) are not susceptible to this interaction and can eat a nonrestrictive diet.
   2. Interactions with indirectly acting monoamine drugs. MAO inhibits degradation of presynaptic norepinephrine, so that increased amounts are stored in the nerve endings. Drugs that act indirectly to release norepinephrine, such as pseudoephedrine, phenylpropanolamine and phenylephrine, can cause marked hypertension and tachycardia in people taking MAO inhibitors. Selegiline is not likely to cause this reaction because MAO-B has a much greater effect on brain dopamine than on norepinephrine levels.
   3. Serotonin syndrome. Severe muscle hyperactivity, clonus, and hyperthermia may occur when patients receiving MAO inhibitors use even therapeutic doses of drugs such as meperidine, tramadol, dextromethorphan, tricyclic antidepressants, SSRIs, venlafaxine, lithium, buspirone, methylene blue, tryptophan, or MDMA (“ecstasy”). It appears to involve elevation of CNS serotonin levels via multiple mechanisms.
   4. Acute overdose involving any MAO inhibitor is very serious and can be fatal. Selectivity for MAO-B is lost in selegiline overdose. In addition, selegiline is metabolized to L-amphetamine, which can contribute to hyperadrenergic symptoms in overdose.
3. Note: Because of irreversible MAO inhibition, adverse drug interactions may occur for up to 2 weeks after discontinuation of older MAO inhibitors. Interactions may also occur when MAO inhibitors are started within 2-3 weeks after stopping fluoxetine, owing to the long half-life of fluoxetine.

First-generation MAO inhibitors have a low therapeutic index; acute ingestion of 2-3 mg or more of tranylcypromine, isocarboxazid, or phenelzine per kilogram should be considered potentially life-threatening. In contrast, overdoses of up to 13 times the daily starting dose of moclobemide alone (~28 mg/kg) typically result in mild or no symptoms. (However, overdose of moclobemide at lower doses, if taken along with SSRIs, can result in life-threatening toxicity.)

Symptoms may be delayed by 6-24 hours after acute overdose but occur rapidly after ingestion of interacting drugs or foods in a patient on chronic MAO inhibitor therapy. Because of irreversible inactivation of MAO, toxic effects (and the potential for drug or food interactions) may persist for several days when first-generation drugs are involved.

1. Drug or food interactions typically cause tachycardia, hypertension, anxiety, flushing, diaphoresis, and headache. Hypertensive crisis can lead to ischemia and end-organ damage such as intracranial hemorrhage, myocardial infarction, or renal failure.
2. With the serotonin syndrome, an altered mental status with both neuromuscular and autonomic instability, such as hyperthermia, tremor, myoclonic jerking, hyperreflexia, and shivering, may develop. Lower extremity clonus occurs often and ocular clonus is sometimes reported. Patients are usually agitated, diaphoretic, and/or delirious. Severe hyperthermia can lead to acute cardiovascular collapse and multiple-organ failure.
3. Acute overdose can cause a clinical syndrome characterized by elements of both adrenergic hyperactivity and excessive serotonin activity, including severe hypertension, delirium, hyperthermia, dysrhythmias, seizures, rhabdomyolysis, obtundation, hypotension and cardiovascular collapse with multisystem failure. One case documented drug-induced myocarditis with shock and severely depressed ventricular function. Other findings may include mydriasis, nystagmus, hallucinations, and tachypnea.
4. Hypotension, particularly when the patient is in an upright position (orthostatic hypotension), is seen with therapeutic dosing and also may occur with overdose.

Is based on clinical features of sympathomimetic drug intoxication with a history of MAO inhibitor use, particularly in combination with drugs or foods known to interact. Suspect serotonin syndrome in patients with altered mental status and signs of autonomic and neuromuscular instability, especially clonus.

1. Specific levels. Drug levels are not generally available. Most agents are not detectable on comprehensive urine toxicology screening. Selegiline is metabolized to L-amphetamine, which may be detected on some urine toxicology screening tests.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, creatine kinase (CK), cardiac troponin, 12-lead ECG, and ECG monitoring. If intracranial hemorrhage is suspected, perform a CT head scan.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
   2. Treat hypertension, coma, seizures, and hyperthermia if they occur.
      1. Use titratable intravenous antihypertensives such as nitroprusside and phentolamine because of the potential for rapid changes in hemodynamics.
      2. If hypotension occurs, it may reflect depletion of neuronal catecholamine stores, and in this case the directly acting agent norepinephrine is preferred over the indirectly acting drug dopamine.
   3. Continuously monitor temperature, other vital signs, and ECG for a minimum of 6 hours in asymptomatic patients and admit all symptomatic patients for continuous monitoring for 24 hours.
2. Specific drugs and antidotes
   1. Because the hypertension is catecholamine-mediated, alpha-adrenergic blockers (eg, phentolamine) or combined alpha- and beta-adrenergic blockers (eg, labetalol) are particularly useful. Note: Use of nonselective beta blockers without a vasodilator may cause paradoxical worsening of hypertension owing to unopposed alpha-adrenergic effects.
   2. Serotonin syndrome should be treated with supportive care, sedation, and cooling. Anecdotal case reports suggest benefit with cyproheptadine, 12 mg orally (PO) initially followed by 4 mg every hour for 3-4 doses. Chlorpromazine 25-50 mg IV has also been used.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37,). Consider gastric lavage if the patient presents early after a very large ingestion of a first-generation drug or selegiline.
4. Enhanced elimination. Dialysis and hemoperfusion are not effective. Repeat-dose activated charcoal has not been studied.