Monoamine Oxidase Inhibitor (MAOI) Toxicity

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.

Pharmacokinetics

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]

Foods

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:

• Dextromethorphan
• Selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, paroxetine)
• Sertraline
• All serotoninergic agents

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]

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 .

The patient history is of vital importance to the diagnosis of monoamine oxidase inhibitor (MAOI) toxicity. Because many of the signs and symptoms are nonspecific, a careful history of all prescription medications, over-the-counter drugs, supplements, and dietary items must be obtained. Additionally, because the effects of many MAOIs (including all of the ones available in the United States) are irreversible and restoration of MAO activity takes 2-3 weeks,[3] , a history of past medications should be obtained as well.

The most common MAOIs are phenelzine, tranylcypromine, isocarboxazid, and selegiline. Reversible inhibitors of MAO are available in Europe (eg, brofaromine, cimoxatone, clorgyline, lazabemide, moclobemide). Other common agents that have MAOI-like activity and have been reported to cause serotonin syndrome include St. John's wort, methylene blue, and linezolid.[12, 13, 14, 15, 23]

In many cases, a significant latent period occurs between exposure and the maximal of clinical effects. Early mild symptoms include irritability, anxiety, flushing, sweating, and headache. As the episode continues, a patient may complain of fever, agitation, diplopia, and restlessness. If the toxicity progresses further, severe symptoms include seizures, confusion, hallucinations, altered mental status, and coma.

As with any ingestion, the possibility of self-harm exists and a detailed psychiatric history should be taken as well.

Patients with MAOI overdoses or interactions present with excessive catecholamine stimulation toxidromes. Late in the course, the patient may become hypotensive and comatose. Clinical manifestations can be classified into mild, moderate, and severe.

A peculiar nystagmus has been reported in cases of overdose. Rapid jerking movement of the eyes as if watching a tennis or ping pong match—termed "ping pong gaze"[24, 25] or opsoclonus—has been reported in severe MAOI intoxication.

Mild signs include agitation, diaphoresis, tachycardia, and mild temperature elevation. Signs of moderate toxicity include altered mental status, tachypnea, vomiting, dysrhythmias, hyperthermia, and hypertension, which can be critically severe and precipitate rhabdomyolysis, myocardial infarction, intracranial hemorrhage, renal failure, and other hypertensive emergency complications.

Severe signs include the following:

• Severe hyperthermia (> 106° F)
• Seizures
• CNS depression
• Coma
• Cardiorespiratory depression
• Muscle rigidity
• Myoclonus

Standard laboratory tests for poisoned patients are indicated if the patient has significant symptoms. Such tests may include the following:

• Rapid bedside glucose determination
• Arterial blood gas determination - Indicated if a compromise in oxygenation or ventilation is suspected
• Lactate level - May be useful in phases 2 and 3 of an acute overdose to help determine end-organ perfusion
• Determination of serum electrolyte, calcium, and magnesium levels - Calculation of the anion gap possibly helpful in screening for co-ingestions (see the Anion Gap calculator)
• Serum acetaminophen level and salicylate level - Indicated in intentional overdoses
• Screening for serum levels of alcohol (ethanol, methanol, isopropyl alcohol) - Indicated if alcohol ingestion is clinically suspected
• Urine pregnancy test - Indicated in all women of childbearing age
• Urinalysis and urine pH determination - May be useful in the setting of rhabdomyolysis
• Urine drug screening - Comprehensive drug screening and screening for commonly abused drugs is possibly helpful in assessing co-ingestions

Quantitative levels of monoamine oxidase inhibitors are not readily available and, therefore, are not clinically useful. Consider workup for hypertensive emergencies if any signs or symptoms are present.

Chest radiography is indicated if aspiration is a concern. Perform postintubation chest radiography to evaluate the position of the endotracheal tube in relation to the carina if respiratory support is needed.

As with most toxic ingestions, the cornerstone of management of monoamine oxidase inhibitor (MAOI) toxicity is continuous monitoring, decontamination when clinically indicated, and meticulous supportive care. Patients with MAOI overdoses should be admitted to the hospital primarily because of the prolonged latent stage. All patients with suspected MAOI ingestion require 24 hours of intensive care unit (ICU) care or frequent monitoring in an inpatient facility. Any child with evidence of MAOI toxicity should be stabilized and transferred to a tertiary pediatric center.

Prehospital care for MAOI toxicity may include the following:

• Stabilization of vital signs - Intravenous fluids
• Treatment of seizure activity - Benzodiazepines
• Attention to airway maintenance
• Attention to temperature control

Give careful attention to airway management. Endotracheal intubation is required in any patient with a decreasing level of consciousness or signs of impending respiratory failure.

Because of the potential for severe toxicity and lack of antidotes, aggressive decontamination is important. Consider activated charcoal decontamination in any patient who presents within 1 hour after the ingestion. However, decontamination with activated charcoal should be performed with caution and with attention to the possibility of airway compromise. Gastric lavage is reserved for patients with life-threatening overdoses (2-3 mg/kg) who present within 1 hour of the ingestion. Before proceeding with any decontamination, secure the patient's airway. 

Because of the pharmacokinetics of MAOIs, extracorporeal removal, such as with hemodialysis or repeat doses of activated charcoal, is likely less effective to reduce MAOI levels.

Frequent measurements of temperature is recommended. If the patient is hyperthermic, decreasing the temperature rapidly (within 20-30 min) is imperative. Antipyretics and use of a cooling blanket are generally inadequate.

The best methods for cooling patients include increasing evaporative losses by wetting their skin with warm water and maintaining airflow over them with fans. Removing the patient's clothing and exposing the patient to room air may help. In extreme cases (temperature greater than 106ºF [41.1ºC], rigidity, altered mental status), packing the individual in ice or in a bath of ice water may prove lifesaving.[26]

Fluid therapy is of paramount importance. Patients may be significantly dehydrated from hyperthermia.

Treating the associated hypertension is usually not necessary and may actually be dangerous, because it may exacerbate the eventual hypotensive phase. If antihypertensive therapy is deemed necessary, use of a short-acting antihypertensive agent, such as nitroprusside, nitroglycerin, or phentolamine, is advisable. Avoid beta-blockers because they leave unopposed alpha stimulation.

Intravenous benzodiazepines are useful for agitation and seizure control. They also may help control the hypertension.

Hospital admission is recommended in a patient with a tyramine reaction if symptoms do not resolve within 6 hours of onset or if the episode was an intentional MAOI overdose. Maintain vigilance regarding recrudescence of fever and ongoing fluid requirements.

Consult the regional poison control center or a local medical toxicologist (certified through the American Board of Medical Toxicology and/or the American Board of Emergency Medicine) to obtain additional information and patient care recommendations. Critical care management may be required for cardiovascular complications.

Pharmacologic therapy in patients with monoamine oxidase inhibitor (MAOI) toxicity is principally directed toward decontamination and reversal of the cardiac and central nervous system (CNS) effects of these drugs. Pharmaceutical agents should be used after the patient is adequately hydrated. Choose medications that have a short half-life and are easily titratable because of the rapid changes in cardiovascular status that may occur from a drug-food interaction, drug-drug interaction, or overdose involving an MAOI.

Class Summary

Useful for limiting systemic burden of the ingested substance, especially if administered within 1-4 h of ingestion.

Activated charcoal (Liqui-Char)

Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

For maximum effect, administer within 30 min of ingesting poison.

Alternate use of cathartic and monitor for active bowel sounds.

Class Summary

Used to lower blood pressure during hypertensive crisis.

Nitroprusside (Nitropress)

Produces vasodilation and increases inotropic activity of the heart. At higher doses, may exacerbate myocardial ischemia by increasing the heart rate.

Nitroglycerin IV (Deponit, Nitrostat)

Relaxes vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production, resulting in a decreased blood pressure.

May administer bolus of 12.5-25 mcg before continuous infusion.

Initial infusion rate of 10-20 mcg/min may be increased 5-10 mcg/min, q5-10 min until desired clinical or hemodynamic response is achieved.

Infusion rates of 500 mcg/min have occasionally been required.

Class Summary

Useful to control agitation and for treatment of drug-induced seizures.

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life.

By increasing the action of GABA, a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Midazolam (Versed)

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.

Class Summary

Used as a third-line treatment for MAOI-induced serotonin toxicity after the interventions listed above. [3]

Cyproheptadine

Cyproheptadine is a first-generation antihistamine with antiserotonergic and anticholinergic properities. Its effectiveness in patients with a serotonergic crisis due to MAOI-toxicity has not been proven, but could be useful as an adjunctive treatment to hydration and benzodiazepines. It is dosed at 12 mg orally with 2 mg orally every two hours as needed for symptomatic control.