Below is an excerpt of the full MAOI toolkit, available for free download.

References are located at the bottom of the full toolkit PDF.

Dosing and Administration

Recommended MAOI dosing, according to manufacturer labeling is shown in Table 10.

Moclobemide is usually dosed twice daily. However the manufacturer’s labeling states that single daily doses were equally effective to divided daily doses, although there was a significant increase in dizziness and a tendency toward increased nausea, insomnia, and headache with single daily doses (21). Moclobemide exhibits dose- and time-dependent changes in its pharmacokinetics. Oral bioavailability increases with dose size; it also increases with multiple daily doses versus single daily doses. In addition, oral bioavailability increases from 50 -60% at initiation with 150 mg twice daily to almost 100% after 10 – 14 days. This is believed to result from either saturation or autoinhibition of first-pass metabolism (5). Therefore, it is recommended that the initial dose not be increased for at least 2 weeks to allow completion of this process.

Manufacturer-recommended titration for other MAOIs varies (16-19).

  • Isocarboxazid should be initiated at 20 mg/day and increased as tolerated every 2 – 4 days to a target of 40 mg/day by the end of the first week. The dose can then be increased by 20 mg per week to a recommended maximum of 60 mg/day. Should be administered in 2 divided doses.
  • Phenelzine should be initiated at 45 mg/day and increased to 60 mg/day as quickly as tolerated. 90 mg/day, the maximum recommended dose, may be needed. Should be administered in 3 divided doses.
  • Transdermal selegiline should be started at 6 mg/24 hours and, if necessary, increased by 3 mg/24 hours no more often than every 2 weeks to a maximum of 12 mg/24 hours.
  • Tranylcypromine should be started at 30 mg/day and increased, if necessary, by 10 mg/day every 1 – 3 weeks to a maximum dose of 60 mg/day. Should be administered in 2 divided doses.

Some clinicians may titrate phenelzine more gradually by starting at 15 mg/day and increasing by 15 mg/day every 2 – 4 days. This approach may reduce the risk of side effects, although there is little evidence for this.

As phenelzine and, possibly, isocarboxazid are more likely to cause sedation, a larger portion of their daily dose can be given at bedtime; this can be based on individual patient response. Tranylcypromine is more likely to be stimulating; if needed, a smaller portion of its daily dose can be given at bedtime.

Table 10. Recommended MAOI Dosage (16-20)

MAOI Initial Target Maximum Renal/Hepatic Dosing
Isocarboxazid 10 mg BID 40 mg/day
60 mg/day Caution with renal impairment; contraindicated with severe renal impairment. Avoid with hepatic impairment.
Moclobemide 150 mg BID 450 mg/day
(BID – TID; can be given as single daily dose)
600 mg/day No dose adjustment needed with renal impairment. With severe hepatic impairment (cirrhosis), reduce dose to 1/2 or 1/3 of usual
Phenelzine 15 mg TID 60 mg/day
90 mg/day Avoid with severe renal impairment. Avoid with hepatic impairment
Transdermal Selegiline 6 mg/24 hours 6 – 9 mg/24 hours
12 mg/24 hours No dose adjustment needed with mild to moderate renal or hepatic impairment. Not studied with severe renal or hepatic impairment
Tranylcypromine 10 mg TID 30 – 60 mg/day
60 mg/day Use cautiously with renal impairment. Avoid with hepatic impairment.

Considerations When Starting MAOI Treatment

Co-Existing Conditions

Before initiating MAOI therapy, consideration should be given to the patient’s other illnesses and conditions.

  • Overweight/Obesity: Patients who are overweight or obese should be evaluated for the presence of pre-diabetes, diabetes, and dyslipidemia. If these conditions are present, they should be treated, and the patient’s weight and BMI should be monitored during MAOI treatment (88). This approach would be especially important when phenelzine or isocarboxazid are used owing to their increased likelihood of inducing weight gain.
  • Hypertension: Orthostatic hypotension is common as a side effect of MAOIs. Patients may require adjustment of their antihypertensive medications. FDA-approved labeling for isocarboxazid states that it is contraindicated in patients with hypertension (as well as known/suspected cerebrovascular defect, cardiovascular disease, or a history of headache) (17). For orally administered MAOIs some recommend monitoring blood pressure before and 45 – 60 minutes after doses until blood pressure is stable (88). However, since these agents are usually administered 2 – 3 times daily, this monitoring might prove burdensome for outpatients.
  • Elderly: Orthostatic hypotension may increase the risk for falls.
  • Substance Use Disorders: Patients should be screened for a history of substance use disorder or current use of substances. Use of MDMA, cocaine, LSD, psilocybin, mescaline or (meth)amphetamine in combination with MAOIs can put patients at risk for serotonin syndrome or hypertensive reactions. Patients with or at risk for opioid use disorder may also be at risk for exposure to drugs (e.g., methadone) that could precipitate serotonin syndrome. People at risk for substance use disorder are probably not good candidates for treatment with tranylcypromine (see above). Phenelzine, isocarboxazid, moclobemide, and, possibly, transdermal selegiline would be better choices. The l-(meth)amphetamine generated by selegiline metabolism might theoretically be problematic; however, there are no reports of abuse of transdermal selegiline. Patients using transdermal selegiline should be made aware that their urine may show a false positive screening test for amphetamine (7,139).
  • Personality Disorder: Cluster B personality disorders have been pointed out as a possible risk factor for tranylcypromine abuse – especially when substance use disorder also present.

Transitioning From Other Antidepressants

When a patient is switched from another antidepressant to an MAOI, the standard recommendation has been that the prior medication should be discontinued for 2 weeks (5 weeks for fluoxetine and 3 weeks for vortioxetine) before the MAOI is started. This is especially important for serotonergic antidepressants (see Table 6); it is not clear that other antidepressants present a large risk of interaction if they are not completely discontinued before the MAOI is started. This time period may be unnecessarily long for most antidepressants with shorter half-lives. Waiting for 4 – 5 half-lives of the discontinued drug (or any active metabolites) should be sufficient; this usually amounts to five to seven days (2).

In patients who don’t adequately respond to or tolerate their first therapeutic trial of a MAOI, a trial of a second MAOI may be considered. In this situation, FDA labeling recommends that a 7 – 14 day washout of the first MAOI occur before the second is initiated (16-19). There are case reports describing adverse events such as acute central nervous system toxicity, hypertensive crisis, stroke and death following switches between MAOIs with no or short washout periods (140-144). It has been suggested that switches from another MAOI to tranylcypromine may carry a greater risk of adverse outcome; this is possibly based on tranylcypromine’s amphetamine-like actions (140). There are also, however, a number of case reports describing rapid switches and even cross-titration between phenelzine and tranylcypromine (in either direction) without significant adverse effects (140,145). At least one expert suggests that, if a rapid switch is necessary on clinical grounds (e.g., severe depression that would otherwise require lengthy hospitalization or marked, intolerable side effects to the first MAOI), rapid switching is likely to be safe and should be considered (146).

Patient Education

Education of patients about MAOIs should begin during the process of deciding whether or not to use one of these medications. Patients should be given enough information to make an informed decision about electing to take an MAOI. Education should be reinforced at the point of initiation of the MAOI. The education provided should be specific to the MAOI to be used; since there are differences between these agents, a “generic” education approach is not likely to be helpful. The following education points should be helpful.

  • Dosing: For oral agents, discuss starting doses, number of times per day, and titration schedule. For transdermal selegiline, discuss proper application and need for site rotation.
  • Onset of Antidepressant Action: As with any antidepressant, patients should be informed that 2 – 4 weeks may pass before symptoms of depression start to improve.
  • Possible side effects:
    • Sedation: May occur with all MAOIs. Often lessens with time. Less likely with tranylcypromine, moclobemide, and transdermal selegiline. Daytime sedation with tranylcypromine may occur if the medicine is causing nighttime insomnia.
    • Activation/Insomnia: Most likely with tranylcypromine.
    • Weight gain/loss: Should be discussed. For patients who have gained weight during an episode of atypical depression, a discussion of possible weight loss may be appropriate. Possible weight gain should be discussed with patients taking phenelzine and, possibly, isocarboxazid.
    • Dizziness/Orthostatic hypotension: Patients should be informed of this possibility and cautioned to be aware of the possibility of falls. Patients should be encouraged to monitor their blood pressure – sitting and 2 standing readings are recommended.
    • Post-Dose Hypertensive Reaction: Patients should be informed about this phenomenon and encouraged to report symptomatic blood pressure elevations (sudden-onset, severe headache most commonly associated). Patients should be encouraged to monitor their blood pressure.
    • Sexual dysfunction: Discussing the possibility of “changes in sexual function” is appropriate. Especially important to discuss for patients taking phenelzine.
    • Vitamin B6 Deficiency: Should be discussed with patients taking phenelzine and isocarboxazid. They should be told that symptoms of numbness/tingling, muscle twitches, noise sensitivity, and possibly edema may result from vitamin B6 depletion and that these symptoms can be treated with replacement of the vitamin.
    • Hepatotoxicity: Patients taking phenelzine should be told that it very rarely may cause liver damage and that they should be aware of symptoms such as appetite loss, weakness, loss of energy, and, especially, jaundice.
  • Withdrawal Effects: Patients taking phenelzine, tranylcypromine, and possibly isocarboxazid should be informed of the importance of not running out of their medicine or discontinuing their medicine abruptly. These patients should be told that sudden discontinuation may result in a rapid return of depressive symptoms, nightmares, headaches, feelings of intense cold, confusion, and disturbances in thinking.
  • Dietary Restrictions: Patients should be educated regarding the role of dietary TYR in hypertensive reactions to MAOIs. Overly restrictive diets may interfere with patient adherence. Tables 2 and 3 can be shared with patients. It can be emphasized to patients that hypertensive reactions are related to the ingested dose of TYR, and that they should consider eating small “test” amounts of potentially risky foods. It should be emphasized that reasonable portion sizes are important. They should also be informed of the symptoms that may accompany a reaction: onset of severe headache, pounding heart, chest tightness, and pallor 30 – 60 minutes after eating high-TYR food. They can be reassured that, in most cases, these symptoms will last only 1 – 4 hours and are not likely to cause damage. Patients should be informed that, if blood pressures persist above 180/120 mm Hg for longer than 2 – 4 hours after ingestion of TYR-containing foods, they should seek care from a health professional.
  • Interactions with Other Drugs: In general, patients taking MAOIs should be taught that they should not take any new over-the-counter or prescription medication until they have consulted with their pharmacist, physician, or other prescriber. The risks of hypertensive reactions to decongestants (as well as [meth]amphetamine in patients at risk for use of these substances) should be explained to patients. They should be told that they symptoms they might experience would be the same as those that might occur with TYR-containing foods, but that the risk of a serious reaction is probably greater. Patients should be told that over-the-counter cough and cold preparations are potentially dangerous because they contain decongestants and that they are also potentially dangerous because they may contain dextromethorphan and/or certain antihistamines. The potential risk of serotonin syndrome from use of recreational drugs such as MDMA, LSD, psilocybin, and mescaline should also be explained. The symptoms of serotonin syndrome should be described (gastrointestinal upset, jitters, changes in thinking, tremor, muscle twitching, muscle spasm, elevated temperature), and the patient should be encouraged to seek medical attention if they begin to experience these symptoms after taking a new medication.

Other Considerations

Drug Shortages

Drug shortages of MAOIs may occur; these agents are not widely used, and few companies manufacture or market them. Historically, shortages of isocarboxazid seem to have been common. Shortages may also vary depending on the country in which the patient lives

There is little if any information available to recommend strategies in the event that a patient’s MAOI becomes unavailable. Allowing a patient to run out of their MAOI carries a risk of potentially serious withdrawal symptoms and possible rapid, return of severe depression. In shortage situations, a cross-titration to another MAOI may be a possible solution if the shortage can be identified early enough (140); however, there may not be an equivalent antidepressant response to the new MAOI. Pharmacists involved in the management of patients taking MAOIs can help anticipate and recommend management strategies by monitoring shortages of the MAOIs they are using.

Anesthesia: Surgery, Local Anesthesia

There has been debate about the safety of MAOI use during surgical anesthesia. There are no evidence-based guidelines regarding this issue, and there has not been agreement among experts about the necessity for discontinuation of MAOIs before elective surgery. The European Society of Anaesthesiology recommends discontinuation of irreversible MAOIs before surgery (147), and some textbooks also recommend discontinuing MAOIs prior to surgery (2). This recommendation apparently stems from the potential for drug interactions with sympathomimetic pressor agents and opioids (147). There have also been concerns that, when spinal anesthesia is used in a patient taking a MAOI, there may be “combined hypotensive effects” (88).

These recommendations raise concerns, because the MAOI (although not moclobemide) would need to be discontinued for approximately two weeks before surgery to allow re-synthesis of functional MAO. Patients would be placed at risk for return of depressive symptoms as well as significant withdrawal symptoms; slow tapering of the MAOI would expose the patient to several weeks of possibly sub-therapeutic doses. An observational retrospective cohort study from the Netherlands compared cardiovascular outcomes (tachycardia or bradycardia and hypotension or hypertension) and the possible occurrence of serotonin syndrome in 42 patients who underwent 51 elective surgeries while taking either tranylcypromine or moclobemide versus 149 matched surgical patients not taking MAOIs. Most (84%) of patients received general anesthesia (some of these patients also received regional anesthesia); the others received regional anesthesia only: epidural or spinal anesthesia or nerve blocks. Intraoperative hypotension was significantly less common in patients taking tranylcypromine compared to those not taking MAOIs. Rates of tachycardia, bradycardia, or hypertension in patients taking either moclobemide or tranylcypromine were not significantly different in the two groups. Interestingly, the use of sympathomimetic drugs (ephedrine or phenylephrine) was quite common: 46% of tranylcypromine patients; 48% of moclobemide patients; and 65% & 56% of matched patients not taking MAOIs. In MAOI users who were treated with ephedrine versus phenylephrine there was no difference in rates of intraoperative hypertension. No cases of serotonin syndrome occurred, although one patient who was given meperidine in the recovery room became agitated. The authors concluded that there is little justification for discontinuation of MAOIs before surgery – especially in light of the risk of compromised psychiatric status (147). A case report and extensive review of the literature describing regional and general anesthesia in patients taking MAOIs, pointed out that the majority of reported cases did not result in negative outcomes. Reported cases of poor outcome involved patients with cardiac comorbidity and administration of fentanyl. The authors concluded that “…general or regional anesthesia for non-cardiac surgery without discontinuation of MAO inhibitor treatment may be a safe intervention after careful evaluation of an individual’s perioperative and psychiatric risk” (148).

When local anesthesia is needed in patients taking MAOIs, it is recommended that anesthetics without vasoconstrictor (epinephrine or levonordefrin) be used to avoid possible changes in blood pressure (2). FDA labeling for local anesthetics containing epinephrine (149) or levonordefrin (150) contain warnings regarding the risk of severe prolonged hypertension if these agents are given with MAOIs. An animal study (151) found that the pressor effects of epinephrine, NE, and levonordefrin were not potentiated by administration of phenelzine. A human study (152) found that the pressor effects of epinephrine and NE were not increased in patients premedicated with either tranylcypromine or phenelzine. Apparently, this lack of interaction is a result of preferential metabolism of peripherally-administered epinephrine, levonordefrin, and, possibly, NE by catechol-O-methyltransferase (153). Therefore, it appears that concerns about vasoconstrictor-containing local anesthetics in patients receiving MAOIs are based on theoretical concerns alone. There don’t appear to be published examples of severe hypertensive reactions to these agents.

Electroconvulsive Therapy (ECT)

There have been concerns about the safety of ECT administration in patients taking MAOIs. These are primarily based on concerns about administration of general anesthesia in these patients. A literature review (154) found over 100 reported cases of ECT administration in patients taking MAOIs. Very few significant complications were reported; there were a small number of isolated respiratory complications. The authors reported four additional patients who had no complications from ECT combined with MAOI therapy. It was recommended that, if a patient has not responded to a MAOI, it could be discontinued before ECT was started, but that no washout period is necessary. In patients with a partial response to a MAOI, it may be desirable to continue the medication during ECT, and, in patients with severe depression, a MAOI may be a safe and effective augmentation agent during maintenance ECT (154).

MAOI Overdose

Drug overdose is always a potential risk in the treatment of depression. Overdose with an irreversible MAOI (especially tranylcypromine, phenelzine , or isocarboxazid) causes severe, life-threatening manifestations. It is estimated that 5mg/kg or more may lead to a potentially fatal outcome. After overdose, patients may be asymptomatic for up to 24 hours. When symptoms develop they occur in a biphasic pattern. There is initial peripheral sympathetic stimulation with hypertension and CNS excitation; later hypotension occurs. Over a period of days there is a potential end result of coma and death. Manifestations seen in MAOI overdose are summarized in Table 11 (155).

Overdoses of oral selegiline are apparently uncommon. A single reported complex case involved ingestion of 195 mg of selegiline, 8,600 mg of carbamazepine, 16,000 mg of sustained-release valproate, 2,250 mg of trazodone, and 70 mg of nitrazepam. There were symptoms suggestive of serotonin syndrome after 5 days of intubation for aspiration pneumonia. After recovery from pneumonia, on day 12, the patient developed visual hallucinations, high blood pressure, and generalized seizures resistant to drug therapy. These symptoms persisted for 6 days. Too few details about the patient’s drug therapy (e.g., continuation of pre-overdose antiepileptic agents) are provided to allow conclusions about the role of selegiline in the reactions (156).

Moclobemide appears to be safe in even extremely large overdoses when it is ingested alone. Doses as high as 20.55 grams were not associated with fatality. Doses of up to 2 grams are only associated with mild gastrointestinal symptoms; 3 – 8 gram doses were associated with CNS depression, agitation, tachycardia, and hypertension. Co-ingestion of serotonergic drugs (clomipramine, citalopram, fluoxetine) and moclobemide in overdoses has resulted in fatal serotonin syndrome (30,59).

Table 11. Clinical Manifestations of MAOI Overdose

Body Temperature Severe hyperthermia (> 106° F)
Neuropsychiatric Agitation, akathisia, hallucinations, headache, seizures, confusion, coma
Neuromuscular Myoclonus, hypertonia, hyperreflexia, muscular rigidity potentially resulting in hyperthermia and rhabdomyolysis
Cardiovascular Early: Hypertension, tachycardia, palpitations
Late: Hypotension, bradycardia, reflex tachycardia
Ischemic ECG changes, peaked T waves
Myonecrosis, myocarditis
Gastrointestinal Nausea, vomiting, diarrhea
Dermatologic Flushing, piloerection, diaphoresis
Ophthalmologic Ocular clonus, mydriasis, nystagmus

Adapted from Manini (155)