Monoamine Oxidase Inhibitor (MAOI) Toxicity

Updated: Feb 27, 2020
  • Author: Eddie Garcia, MD; Chief Editor: Michael A Miller, MD  more...
  • Print

Practice Essentials

Monoamine oxidase inhibitors (MAOIs) are a class of antidepressants that have largely fallen out of favor for the treatment of depression. However, their use is on the rise in the treatment of neurodegenerative diseases and they are still used in cases of refractory depression. [1]  In addition, some antibiotics (eg, linezolid [2] are MAOIs. Although MAOI ingestion is rare, MAOI overdoses can potentially cause significant morbidity and mortality. 

MAO has two isoforms: MAO-A and MAO-B. MAO-A is found primarily in the liver, gastrointestinal (GI) tract, and monoaminergic neurons. Circulating monoamines, such as epinephrine, norepinephrine, and dopamine, are largely metabolized by MAO-A in the liver. Ingested monoamines, such as tyramine, are metabolized by MAO-A in the GI tract and liver. [3]  This shields the body from foods with high levels of tyramine, which have to potential to cause adrenergic hyperstimulation. This protective property of MAO-A is critical to the understanding of the most common cause of MAOI toxicity, drug-food interaction. The other isoform, MAO-B, is found primarily in the basal ganglia of the central nervous system and platelets. [4]

First-generation MAOIs, such as phenelzine, isocarboxazid, and tranylcypromine, are nonselective inhibitors. Second- and third-generation MAOIs tend to be specific inhibitors of either MAO-A or MAO-B. Specific MAO-A inhibitors are not commonly used, but have been studied in the treatment of depression. Specific MAO-B inhibitors have been studied in the treatment of both depression and neurodegenerative disorders. They are thought to have a better safety profile, as MAO-A activity in the gut is not inhibited. MAO-B inhibitors include pargyline and selegiline. The selegiline transdermal system has been used to decrease the risk of a dietary tyramine-induced hypertensive crisis associated with these agents. However, the selectivity of even the new MAOIs is dose related. [3]

MAOI toxicity can occur in the following three ways:

  • Drug-food interactions -  the so-called tyramine reaction
  • Overdose
  • Drug-drug interactions

All three mechanisms produce similar symptoms and signs, which stem from an excess of catecholaminergic neurotransmitters (see Pathophysiology). Clinical features include hypertension, tachycardia, tremors, seizures, and hyperthermia. (See Presentation.)

Because of the potential for severe toxicity and the lack of effective antidotes, recognition of the disease, withdrawal of offending agents and aggressive decontamination is very important in patients with MAOI toxicity. Control of hyperthermia and fluid therapy are paramount. (See Treatment.)



Monoamine neurotransmitters (eg, epinephrine, norepinephrine, dopamine, serotonin) are stored in vesicles at the pre-synaptic nerve terminals and released through the plasma membrane into the synaptic cleft. When released into the synaptic space, neurotransmitters are either reabsorbed into the proximal nerve and metabolized by intracellular monoamine oxidase (MAO) or destroyed by catechol-o-methyl transferase (COMT) in the synaptic cleft. 

Monoamine oxidase is responsible for the deactivation of monoamines such as epinephrine, norepinephrine, dopamine, serotonin, and tyramine. When the inhibitory effects of MAOIs are amplified by overdose, drug-drug interactions, or drug-food interactions, the resulting increase of active monoamines is directly responsible for the manifestations of MAOI toxicity.

In a pure MAOI overdose, the ability of the neuron to degrade monoamines is severely diminished. As a result, the storage and release of monoamines is greatly increased. This effect can be potentiated or even enhanced by an additional property of MAOIs: even at therapeutic doses, MAOIs indirectly cause a release of norepinephrine into the synaptic space. Depending on the dose of the exposure, a hyperadrenergic crisis may ensue; 5 mg/kg of a non-selective MAOI can be life-threatening. [3] This occurs uncommonly. Symptoms of intentional overdose may be delayed up to 32 hours post ingestion but generally occur within 24 hours. These patients require prolonged close monitoring to prevent significant morbidity.

MAOI toxicity can be seen when an MAOI is combined with any drug that increases the synthesis, release, or effect of monoamines or decreases the metabolism or reuptake of monoamines. For a detailed list, see Etiology.

Delayed presentations of MAOI toxicity are common, ranging from several hours to 24 hours for maximal toxicity, but symptoms can also be seen within minutes. Though MAOIs interact unfavorably with many medications, fatalities are rare with supportive care. [3]

The most common MAOI toxicity results from interaction with tyramine-containing foods. When MAO found in the gut and liver (type A) is inhibited, ingested tyramine indirectly causes an amplification of adrenergic activity. It is usually rapid in onset, occurring within 15-90 minutes after ingestion. Most symptoms resolve in 6 hours. Fatalities are rare, but have been reported due to complications from hypertensive emergencies. See Etiology for a detailed list of tyramine-containing foods.

Serotonin syndrome

The combination of an MAOI with a drug that increases serotonin levels can result in serotonin syndrome, a disease entitiy similar to an adrenergic crisis from MAOI toxicity. It is characterized by mental status changes, neuromuscular dysfunction, and autonomic instability. Serotonin syndrome is thought to be secondary to excessive serotonin activity in the spinal cord and brain. Toxicity of serotonergic drugs can be caused by overdosage, interaction with other drugs, and, rarely, therapeutic doses. 

Accidental ingestion by toddlers and illicit drug use in adolescents (methylenedioxymethamphetamine [MDMA], or ecstasy) are important pediatric considerations. In adults, serotonin syndrome typically develops after the addition of a serotonergic agent to a regimen that already includes a serotonin-enhancing drug.


MAOIs are absorbed well orally and peak plasma concentrations are reached within 2-3 hours. These drugs have a relatively large volume of distribution (1-5 L/kg) and are highly protein bound. They are metabolized by oxidation and acetylation in the liver and are excreted in the urine.

The two isoforms of MAO have different affinities for specific neurotransmitters. MAO-A is the primary metabolizer of norepinephrine. Dopamine and tyramine can be metabolized equally by MAO-A and MAO-B. [4]

MAOIs bind irreversibly at their sites of action (moclobemide is an exception). By this binding, they are eliminated from circulation and, since they do not recirculate afterwards, their effects are not determined by their concentration in the blood. As it takes 2-3 weeks for enough new MAO to be synthesized, MAOIs have clinical effects for that amount of time after the last dose has been ingested. Third-generation MAOIs (not available in the United States) are reversible inhibitors and exist in a competitive equilibrium. [5]

MAOIs absorbed through the gastrointestinal tract bind significantly to MAO in the gut mucosa and liver, producing a significant first pass effect. Thus, to produce their clinically desired effect in the central nervous system (CNS), MAOIs must be given in high enough doses to reach centrally-located MAO. A transdermal preparation of a selective MAO-B inhibitor, selegiline, appears to produce antidepressant effects with a significantly reduced risk for dietary-induced toxicity by bypassing the first pass effect of gut and hepatic MAOI effects. [6, 7] At the lowest effective dosage of 6 mg/day, selegiline can be used without dietary modification. [8]



Monoamine oxidase inhibitors (MAOIs) can interact with foods that contain tyramine and with a variety of drugs. Any drug that is serotoninergic or releases catecholamines may precipitate life-threatening events in individuals who are taking MAOIs or have taken MAOIs in the preceding weeks. [3]


Tyramine-containing foods associated with MAOI interactions include the following:

  • Aged cheeses
  • Aged, pickled, or smoked meats (eg, salami) or fish (eg, herring)
  • Yeast extracts
  • Beer (dark more than light; on tap more than bottled because tyramine is adsorbed to glass)
  • Red wine more than white wine
  • Avocado
  • Sauerkraut
  • Ginseng

Drug interactions

Meperidine is probably the most infamous of medications known to produce significant toxicity when administered to an individual taking an MAOI. Meperidine produces a release of serotonin, which can precipitate a potentially fatal outcome.

In 1984, an MAOI-meperidine interaction changed physician training in the United States. Libby Zion was a young woman admitted to a major hospital with fever, agitation, and jerking motions. There is a great deal of controversy about the historical information, but it is clear that she had been receiving an MAOI. Either this was not known or the interaction risk was not appreciated by the young resident physician who ordered meperidine for the patient's shaking, which resulted in severe hyperpyrexia and her eventual death. This case led to the modern emphasis on shorter work hours for resident physicians and greater supervision by senior physicians. [9]

Tricyclic antidepressants (TCAs) block the inactivation of norepinephrine and serotonin; TCAs taken in combination with MAOIs can lead to excessive catecholamine and serotonin activity, a potentially life-threatening situation. Because of the prolonged action of MAOIs, a 2-4 week washout period must be observed before treatment with TCAs is started.

Tramadol, since it exerts some MAOI-like effects, perhaps some release of serotonin, and some serotonin-reuptake inhibition, has been thought to potentially precipitate toxicity and its use is considered by some to be contraindicated in patients receiving an MAOI. [10]

Linezolid, an antibiotic used to treat certain drug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA), has been determined to be a reversible, nonselective MAOI and has been implicated in acute serotonin syndrome, usually in patients concurrently receiving SSRIs. [2, 11]

Methylene blue has been reported to be associated with serotonin syndrome. [12, 13, 14]  It has been studied as a potent reversible MAO-A inhibitor. [15]  Additionally, analogs of methylene blue may also carry risk of serotonin syndrome. [16]

The psychoactive beverage ayahuasca contains several MAOIs. These are responsible for ayahuasca's psychoactive and hallucinogenic effects on the central nervous system. [17]

Although at one time reported to be a risk factor for serotonin syndrome, triptans are no longer considered a high-risk medication. Since triptans are serotonin agonists at 5-HT1B/D and not 5HT2A, they should have little or no association with serotonin syndrome. [18]

Other drugs that may interact with MAOIs include the following:




The American Association of Poison Control Centers National Poison Data System (AAPCC-NPDS) annual reports show a steady decline in case mentions of MAOI exposure, from 618 in 1990 [19] to 216 in 2018. [20]

Depending on the year, 40%-50% of these cases were single exposures to MAOIs, with the remainder of the cases involving co-exposures. In 2018, there were 91 single exposures to MAOIs reported. Adults accounted for 66 of the cases for which age was reported; 57 exposures were known to be unintentional. [20]

The decline in MAOI toxicity cases presumably reflects the preferential use of other classes of antidepressants. However, MAOIs are currently being studied as potential neuroprotective agents in Alzheimer disease and in the treatment of Parkinson disease. [21, 22] If they prove effective for that purpose, their use—and episodes of toxicity—may well increase.



Patients should recover without sequelae if no adverse reactions occur, such as renal failure, stroke, or refractory hypotension. Severe toxicity is manifested by hyperthermia, seizures, respiratory depression, and CNS depression. Hypotension, cardiovascular collapse, and death may ensue but this is rare with supportive care. In 2018, the AAPCC-NPDS reported 8 MAOI single exposures that resulted in moderate morbidity, 5 cases of major morbidity, and 1 death (from tranylcypromine). [20]


Patient Education

All patients who are starting treatment with a monoamine oxidase inhibitor (MAOI) should receive extensive education regarding the potential for interactions with tyramine-containing foods and with other drugs. Patients should be encouraged to have all of their prescription and nonprescription drugs dispensed from one pharmacy so that an accurate medication profile can be maintained.

For patient education information, see Monoamine Oxidase Inhibitors (MAOIs) for Bipolar Disorder and Child Safety Proofing .