Monoamine Oxidase Inhibitors (MAOI): Significant Drug-Drug/Drug-Food Interactions with MAOIs

Significant Drug-Drug/Drug-Food Interactions with MAOIs

MAOIs can be involved in several significant drug-drug and drug-food interactions, and these interactions are one of the reasons that many clinicians are reluctant to use these agents. However, these potential interactions are well-known and well-characterized. Knowledge of these interactions by clinicians and education of patients about these interactions can help avoid their occurrence.

Pharmacokinetic Interactions

Irreversible MAOIs have minimal effect on the metabolism and pharmacokinetics of most other drugs. Tranylcypromine has few clinically significant effects on cytochrome P450 (CYP) enzymes; it is a potent competitive inhibitor of CYP2A6 and potentially inhibits the metabolism of substrates for this enzyme (ifosfamide, cyclophosphamide, tamoxifen, nicotine, and propofol). However, CYP2A6 is of minor importance to the overall metabolism of these compounds with the exception of nicotine. Tranylcypromine may elevate nicotine plasma levels and may reduce smoking in treated patients. Phenelzine is a weak inhibitor of CYP2C19 and CYP3A4, but there are no reported significant interactions with drugs that are substrates for these enzymes. Monitoring is warranted however since phenelzine’s effect on these enzymes is irreversible (as it is with MAO), and cumulative effects may occur (14).

Moclobemide may potentially affect the metabolism and pharmacokinetics of other drugs. It is an inhibitor of CYP2C19 and, to a lesser extent, CYP2D6 and CYP1A2. At least theoretically, moclobemide may increase plasma concentrations and clinical effects drugs that are substrates for these enzymes. Moclobemide’s strength as an inhibitor of these enzymes has not been well-characterized. There is little clinical or study data to suggest that these interactions actually occur; however one small study did find that moclobemide increased plasma concentrations of trimipramine. Cimetidine significantly decreases moclobeimide clearance. Patients receiving cimetidine should have their moclobemide dosage reduced by 50% (30).

Some “triptans” (5HT_1B/1D agonists used in the treatment of migraine) are significantly metabolized by MAO-A – specifically: Almotriptan (50% renally excreted unchanged and approximately 25% metabolized by MAO-A), rizatriptan, sumatriptan, and zolimitriptan. Co-administration of almotriptan with moclobemide (150 mg twice daily for 8 days) resulted in a 27% decrease in almotriptan clearance and a 6% increase in Cmax. These changes are not believed to dictate a need for change in almotriptan dosage in the presence of MAOIs (38,39). Administration of rizatriptan, sumatriptan, and zolmitriptan with MAO-A inhibitors is considered contraindicated in the prescribing information. Most of the research on these interactions has been conducted with moclobemide, but one would expect any MAO-A inhibitor to cause similar interactions. Moclobemide increased the AUC and Cmax of both rizatriptan and its primary metabolite by 1.4- to 5.3-fold; it increased sumatriptan AUC by 80%; and it increased exposure to zolmitriptan’s active metabolite by 300% (40-44). Eletriptan, frovatriptan, and naratriptan are not MAO-A substrates and can be used safely with MAOIs (see comments below regarding serotonin syndrome).

Transdermal selegiline’s FDA labeling states that carbamazepine increases plasma levels of selegiline and that this effect increases the risk of serious hypertensive reactions; the labeling also states that carbamazepine is contraindicated in combination with MAOIs (19). An apparently unpublished pharmacokinetic study in patients receiving 400 mg/day of carbamazepine found 2-fold increases in plasma selegiline concentrations after a single 6 mg/24 hr dose of transdermal selegiline. There apparently was variability of this effect among subjects (45). Presumably, the warning about serious hypertensive reactions stems from concerns about an increased risk of interaction with food or other drugs at higher selegiline concentrations. The actual clinical significance of this interaction with carbamazepine is unknown (45).

Pharmacodynamic Interactions: Hypertensive Crisis

Interaction with Tyramine-Containing Food (“Cheese” Effect)

Ordinarily, dietary TYR is catabolized by intestinal MAO during absorption and by hepatic MAO during initial circulation through the liver (first pass metabolism); therefore, dietary TYR normally doesn’t reach the general circulation in significant concentrations. In patients taking orally administered MAOIs, first pass metabolism is significantly decreased, and TYR reaches the systemic circulation in significant concentrations.

Studies to determine tolerable doses of TYR are often performed by administering encapsulated pure TYR to fasting patients and identifying the dose required to elevate systolic blood pressure by 30 mm Hg (Tyr30). Under those conditions, TYR is more bioavailable and is rapidly absorbed. Food that contains TYR usually also contains other trace amines (e.g., phenylethylamine, octopamine, tryptamine) which exert negative inotropic effects and lessen the pressor response to TYR (46). In unmedicated patients, Tyr30 is 800 – 2000 mg in food. If pure TYR in capsules is administered to unmedicated patients, Tyr30 is only 200 – 800 mg (47). In patients treated with an irreversible MAOI (including oral selegiline at doses of 20 mg/day or more and possibly transdermal selegiline at doses above 6mg/24 hours), Tyr30 would be approximately 20 – 100 mg in food (14,46). The use of a 30 mm Hg elevation in systolic blood pressure is somewhat arbitrary; such an elevation may not represent a dangerous or even symptomatic increase.

After MAOIs came into use as antidepressants, cases of hypertensive crisis, a few resulting in subarachnoid hemorrhage and death, were reported. These reactions were found to be related to ingestion of foods with a high TYR content; often these foods were noted to be aged cheeses (e.g., Stiltons). This finding resulted in these reactions being labeled “cheese reactions” or the “cheese effect” and led to the development of TYR-restricted diets for patients taking MAOIs. Since the late 1960’s very few cases of this reaction have been reported. Patients having a TYR reaction will experience or exhibit palpitations, tachycardia or bradycardia, chest tightness, elevated temperature, and pallor. Systolic blood pressures above approximately 180 mm Hg may be associated with severe headaches, although headache is not a reliable indicator of elevated blood pressure. These effects will begin 30 to 60 minutes following ingestion of food high in TYR and may persist for 1 – 4 hours (2,46-48).

Hypertensive reactions result from the release of NE stored in noradrenergic neurons by TYR. Inhibition of MAO also prevents the metabolism of NE released by TYR. TYR itself also increases blood pressure through positive inotropic activity and by increasing cardiac output through increasing ejection fraction (14).

Different MAOIs appear to have different potencies with respect to their effect on dietary TYR; tranylcypromine appears to be the most potent (i.e., lower doses of dietary TYR are required to elevate blood pressure). It is estimated that most patients on tranylcypromine could ingest 100 mg of dietary TYR without developing a dangerous blood pressure elevation (probably much more than 30 mm Hg elevation in systolic pressure) (14); for other irreversible MAOIs, somewhat larger amounts of TYR would likely be tolerated.

In order to prevent the occurrence of hypertensive reactions to dietary TYR in patients taking MAOIs, TYR-restricted diets were developed. Many of these diets were developed in the early to mid- 1960s and have persisted to the present. TYR is not ordinarily present in fresh animal or plant proteins; its presence is increased by decay (bacterial enzymes convert tyrosine in proteins into TYR) and/or fermentation. Present-day food processing and handling techniques have resulted in significant reductions in the TYR content of foods. In addition, chemical assays for TYR have improved since the late 1990s. As a result, information about food TYR content developed or published prior to 2000 is likely to be inaccurate (7,46-48). Thorough reviews of the food science/nutrition literature regarding the actual TYR content of foods (48,49) found that foods containing potentially dangerous amounts of TYR in reasonably sized servings are quite uncommon. As mentioned above, most patients on irreversible MAOIs would not exhibit an excessive or dangerous blood pressure increase until they ingest more than 100 mg of dietary TYR. Therefore, most published “MAOI Diets” (50,51) are based on outdated information and are unnecessarily restrictive. Tables 2 and 3 identify foods and beverages that should be avoided or only ingested in small servings by patients taking MAOIs. Note that very few foods or beverages must be prohibited. Since the pressor reaction to TYR is related to the dose of TYR ingested, some experts also recommend that patients be educated to ingest small amounts of potentially risky foods on a trial basis (52).

Patients treated with moclobemide are at lower risk for hypertensive responses to TYR; moclobemide is a RIMA which can be displaced from MAO by higher concentrations of TYR and of NE released by TYR. This displacement restores the activity of MAO and allows it to catabolize TYR and released NE. The labeling for moclobemide carries warnings about ingesting high-TYR foods that are similar to those for irreversible MAOIs despite clear evidence in the literature that, with moclobemide doses of up to 900 mg/day, a TYR-restricted diet is not necessary (5,30).

An additional perspective on the significance and risk of TYR-associated pressor responses is provided by Gillman (14,46,47,52). He points out that strenuous physical activities (e.g., marathon running, gym exercise with weights) may cause systolic blood pressure elevations well above the 180 mm Hg usually described as the threshold for onset of symptoms of hypertensive emergencies. He also points out that elevated blood pressure itself is not likely to independently cause subarachnoid hemorrhage; other underlying conditions are likely necessary for this to occur. Gillman also emphasizes that TYR-induced pressor responses in patients taking MAOIs are relatively short-lived (2 – 4 hours). Therefore, the use of treatments that rapidly reduce blood pressure, such as sublingual nifedipine, is unnecessary and potentially may cause more harm than good. He recommends that, if treatment is felt to be necessary, administration of a benzodiazepine carries a lower risk and will help reduce blood pressure gradually and moderately. It has been suggested that patients taking MAOIs could be provided with “small doses” (not specified) of chlorpromazine to use if a symptomatic hypertensive emergency occurs (53). This is based on chlorpromazine’s alpha-adrenergic antagonist properties. There does not appear to be any evidence supporting this approach, and the same concerns about rapidly reducing blood pressure emphasized by Gillman would apply.

Table 2: Tyramine Dietary Considerations

References: 1,48,49,53,157,158

Table 3: Tyramine-Risky vs Mythically Dangerous Foods/Beverages

References: 1,48,49,53,157,158

Interactions with Sympathomimetic Agents

Orally administered sympathomimetics (e.g., pseudoephedrine, ephedrine, phenylephrine, amphetamine, methamphetamine) may cause significant increases in blood pressure when they are administered to patients receiving irreversible MAOIs. Like TYR, indirect-acting agents such as (meth)amphetamine, pseudoephedrine and ephedrine stimulate release of stored NE from neurons. As a result, a significant pressor response may occur. Phenylephrine is a direct-acting stimulant at alpha receptors. It is also a substrate for MAO. Ordinarily, most of a dose of oral phenylephrine is destroyed by MAO in the intestine and liver. In patients receiving MAOIs, this destruction does not occur, and much larger systemic exposure to phenylephrine occurs possibly resulting in a significant pressor response (54,55). Phenylephrine and pseuoephedrine do not appear to cause significant pressor responses when administered to normal subjects receiving transdermal selegiline at 6 mg/24hr (56). There is little information regarding the effect of MAOIs with nasally administered sympathomimetics, but, considering the small doses administered by this route, the probability of a significant interaction seems low. Patients receiving MAOIs should be educated to avoid using over-the-counter oral decongestants.

Unlike (meth)amphetamine, methylphenidate does not appear to cause severe hypertension when combined with MAOIs. Both amphetamine and methylphenidate have been successfully and safely used in combination with MAOIs to augment the antidepressant effects, treat MAOI side effects such as hypotension, and to treat comorbid conditions such as ADHD (57,58). When this has been done, starting doses of stimulants were small and doses were increased gradually with close monitoring of blood pressure. Use of this type of combination therapy still carries risks and should probably be left for those with extensive experience using MAOIs.

RIMAs such as moclobemide are less likely to interact with indirect-acting sympathomimetics (59); however, a small, randomized, placebo-controlled crossover study showed that the pressor effect of 100 mg of ephedrine (50 mg doses 4 hours apart) was increased about threefold in patients on moclobemide. Symptoms such as palpitations and headache were more common with combined therapy versus placebo (60). Moclobemide interacts only minimally with oral phenylephrine (61).

Pharmacodynamic Interactions with Wake-Promoting Agents

FDA labeling for modafinil and armodafinil states that caution should be used if they are administered with MAOIs (62,63). This warning appears to be based primarily on theoretical concerns. However, there are 2 published case reports of adverse events associated with use of these agents in patients taking tranylcypromine. The first case involved a patient with major depression who was stable on tranylcypromine 80 mg/day. Modafinil, 200 mg/day, was initiated to improve wakefulness after an increase in workload. Three days later, the patient presented with confusion, severe choreiform movements, lip smacking, tongue protrusion, and neck opisthotonus. Hyperthermia (38° C) developed 24 hours after presentation. Tranylcypromine and modafinil were discontinued, and the patient was treated with cyproheptadine for suspected serotonin syndrome. Symptoms resolved within 48 hours. The authors noted that modafinil has been shown to have dopaminergic effects in some studies and that orofacial and limb dyskinesias have been reported as an adverse effect. They also pointed out that there is evidence that modafinil increases cortical 5HT by enhancing its release. They hypothesized that their patient’s symptoms resulted from tranylcypromine’s augmentation of modafinil’s dopaminergic (dyskinesias) and serotonergic (hyperthermia and confusion) effects (64). The second case involved a patient with bipolar disorder who was taking tranylcypromine 40 mg/day and brexpiprazole 0.5 mg/day. The patient had also been taking armodafinil 250 mg/day for 2 months. On the morning of her reaction, her tranylcypromine had been changed from 20 mg twice daily to 40 mg once daily in the morning. Less than an hour after taking tranylcypromine and armodafinil, the patient presented to the emergency department complaining of the “worst headache of my life”. The headache was holocephalic and progressed from 3/10 severity to 10/10 severity over approximately one hour. It was accompanied by nausea, blurred vision, altered alertness, and neck stiffness; the patient’s blood pressure was 186/120. A CT scan did not show acute hemorrhage; MRI and venography were normal. Psychiatric medications were withheld. The patient was treated with morphine, and her blood pressure and headache pain gradually decreased over 24 hours. Symptoms resolved after 2 days. These authors also pointed out that armodafinil increases central catecholamine and 5HT activity. They noted that the time course of their patient’s symptoms correlated with the pharmacokinetics of the medications (65). Subsequently, it was pointed out that this second case may have been more likely the result of spontaneous acute hypertensive crisis related to tranylcypromine alone and possibly a result of the administration of a larger single dose (66). This seems a more reasonable interpretation, since the patient had been taking armodafinil with tranylcypromine for 2 months without problems. MAOIs may cause spontaneous acute hypertensive reactions (67).

Modafinil has been combined with phenelzine and tranylcypromine to relieve excessive daytime sleepiness in one patient with narcolepsy (200 mg/day) and one patient with dysthymia (100 mg/day); the excessive sleepiness was not believed to be a side effect of the MAOI. No adverse side effects were noted in these cases (68,69).

FDA labeling for solriamfetol states that its use with MAOIs or for 14 days after discontinuation of a MAOI is contraindicated (70). As there are no reported cases in the literature of adverse effects from this combination, this contraindication appears to be based on theoretical considerations. Solriamfetol inhibits DA and NE reuptake; it does not inhibit 5HT reuptake. Theoretically, if it were combined with an MAOI, there might be a risk of hypertensive response or excess dopaminergic activity.

Pitolisant, a recently-approved wake-promoting agent for adults with narcolepsy, is a selective histamine 3 receptor antagonist/inverse agonist. It does not appear to have effects on monoamine neurotransmission, nor is it metabolized by MAO. Therefore, it is unlikely that pitolisant would adversely interact with MAOIs. FDA labeling for pitolisant does not carry warnings or precautions regarding its use with MAOIs (71).

Pharmacodynamic Interactions: Serotonin Syndrome

Serotonin syndrome (serotonin toxicity) is believed to result from excessive stimulation of postsynaptic 5HT_2A and, possibly, 5HT_1A receptors. There is a significant potential for the occurrence of serotonin syndrome when MAOIs are co-administered with drugs that either inhibit the reuptake of 5HT or exert significant serotonergic activity. This interaction can potentially result in fatality. Patients taking RIMAs such as moclobemide may be equally at risk for serotonin syndrome if they are exposed to serotonergic agents (52). Symptoms of serotonin syndrome are described in Table 4 (72-75). The Hunter Serotonin Toxicity Criteria (76) are considered to be the best tool for diagnosis of serotonin syndrome (75); they are described in Table 5. Table 6 contains a list of drugs that are likely to interact with MAOIs to cause serotonin syndrome.

Table 4: Serotonin Toxicity (Serotonin Syndrome) Spectrum (72-74)

Table 5 Hunter Serotonin Toxicity Criteria: Decision Rules (76)

Table 6: Drugs Which May Interact With MAOIs to Cause Serotonin Syndrome

References: 1,2,53,81,86,88,94

The most common pharmacologic mechanism for this interaction is the inhibition of 5HT reuptake. Imipramine and clomipramine are potent inhibitors of 5HT reuptake, and they should be avoided in combination with MAOIs. Other TCAs are less likely to interact and cause serotonin syndrome (52). Cyclobenzaprine is structurally similar to TCAs, and has been found to significantly inhibit 5HT reuptake; it has been involved in several reported cases of serotonin syndrome (77,78). There have been warnings against combining carbamazepine with MAOIs because of carbamazepine’s structural similarity to TCAs (2). FDA labeling for tranylcypromine and isocarboxazid also states that carbamazepine is contraindicated with these drugs; phenelzine’s labeling does not mention carbamazepine (16-18). Apparently this is a theoretical concern regarding risk of serotonin syndrome based on carbamazepine’s structural similarity to TCAs. There are no published reports of an interaction between carbamazepine and MAOIs. There have been isolated single cases of possible serotonin syndrome associated with both carbamazepine and its close relative, oxcarbazepine used in combination with SSRIs (79,80). Therefore, some caution may be warranted.

Several opioids inhibit 5HT reuptake and have been reported to cause serotonin syndrome in combination with MAOIs. Fentanyl and oxycodone are not 5HT reuptake inhibitors; their involvement in numerous cases of serotonin syndrome (many without coadministration of MAOIs) is thought to be related to their stimulation of 5HT_2A receptors (81).

The antihistamines, chlorpheniramine and brompheniramine, are known to be potent inhibitors of 5HT reuptake, and their use should be avoided by patients taking MAOIs. There are few published reports of serotonin syndrome related to these drugs. It is possible that their contribution to cases may not have been recognized (82,83), because they may be included in over-the-counter cold medications that also contain other drugs that may interact with MAOIs (e.g., phenylephrine, dextromethorphan). Patients taking MAOIs should be educated to avoid over-the-counter products containing these antihistamines as well as sympathomimetics and dextromethorphan. An additional concern is the inhibition of CYP2D6 metabolism of dextromethorphan by moclobemide (84). This would likely increase the risk of serotonin syndrome in patients who receive both of these medications.

MDMA and cocaine both act to increase 5HT activity through either reuptake blockade or stimulation of its release (85). LSD, psilocybin, and mescaline act as potent 5HT agonists, and high doses of (meth)amphetamine also cause release of 5HT.(86). Patients taking MAOIs should be screened for risk of use of these substances before the MAOI is prescribed and they should be educated regarding the dangers of use of these substances while they are taking MAOIs. It is also important that patients understand that the effects of irreversible MAOIs persist for 2 – 3 weeks following discontinuation.

Ziprasidone is the only antipsychotic known to cause serotonin syndrome when combined with MAOIs. It is known to possess significant 5HT reuptake inhibition. There has been one well-documented case of serotonin syndrome involving ziprasidone used in combination with tranylcypromine (87). Lumateperone is also known to possess significant 5HT reuptake inhibition, and may have the potential to cause serotonin syndrome if used in combination with a MAOI (88).

When patients are switched from a serotonergic antidepressant to an MAOI, the initial antidepressant should be tapered and then discontinued for five half-lives before the MAOI is initiated. Five to seven days is usually sufficient. This time frame allows for complete elimination of the serotonergic antidepressant (2). However, if an MAOI is to replace fluoxetine, it is necessary to wait five weeks after discontinuation of fluoxetine owing to the long half-life of fluoxetine’s active metabolite. If an MAOI is to replace vortioxetine, it is necessary to wait 3 weeks after discontinuation of vortioxetine (2,89). When patients are switched from an irreversible MAOI to a serotonergic antidepressant, the MAOI should be tapered and discontinued for 2 weeks before initiating the new medication. This time frame is necessary to allow synthesis of adequate amounts of functional MAO (2). If moclobemide is to be replaced by a serotonergic antidepressant, it is only necessary to discontinue moclobemide for 1 – 2 days owing to its short half-life (30).

A small number of poorly documented cases reported possible serotonin syndrome related to the combined use of “triptan” anti-migraine medications and SSRI/SNRI antidepressants. These reports resulted in FDA-mandated warnings in package inserts for these medications advising against their use in combination with serotonergic antidepressants including MAOIs. Triptans are agonists at 5HT_1B-1F receptors; they do not stimulate 5HT_2A or 5HT_1A receptors. The American Headache Society and several other authors have reviewed the evidence for this interaction and concluded that the risk of serotonin syndrome with triptans is unproven and likely to be extremely uncommon, if it actually occurs. While some caution and patient education are warranted, the available evidence does not support limiting the use of triptans with SSRIs or SNRIs. The same conclusion is probably warranted regarding use of triptans (other than rizatriptan, sumatriptan, and zolimitriptan) with MAOIs (90-93).

The labeling for fenfluramine states that it is contraindicated in patients who are treated with MAOIs. Fenfluramine stimulates the release of 5HT, and, therefore, at least theoretically, could cause serotonin syndrome if used with a MAOI (94). There do not appear to be any published case reports of this interaction. Nevertheless, this combination is probably best avoided.

Pharmacodynamic Interactions With Other Antidepressants

Tricyclic Antidepressants

FDA-approved labeling for TCAs indicates that their concomitant use with MAOIs is contraindicated. TCAs that are potent 5HT reuptake inhibitors (clomipramine and imipramine) should not be combined with MAOIs because of a significant risk of serotonin syndrome. However, other TCAs such as amitriptyline can be used safely with MAOIs, and the combination may be helpful for cases of treatment-resistant depression (47,95-99). Because TCAs inhibit NE reuptake, there has been concern that the combination could result in hypertensive crises. This reaction, however, has not proven to be a problem. It has also been pointed out that TCAs that inhibit NE reuptake also inhibit the uptake of TYR into neurons. Therefore, combined treatment with MAOIs and that type of TCA would protect patients from pressor reactions to ingested TYR (47,97). It is recommended that TCAs not be added to established MAOI treatment. If a combination of a TCA and MAOI is to be used, there should be an appropriate washout period from the previous antidepressant (5 half-lives for non-MAOIs and moclobemide or 2 – 3 weeks for irreversible MAOIs). The two drugs should then be started at the same time, or within 1 – 2 days of each other, at low doses and titrated slowly with careful monitoring (2,97,99).

To avoid any potential problems, when patients are switched from a TCA to an MAOI, the TCA should be tapered and then discontinued for five half-lives before the MAOI is initiated. Five to seven days is usually sufficient to allow complete elimination of the TCA. When patients are switched from a MAOI to a TCA, the MAOI should be tapered and discontinued for at least two weeks before the TCA is initiated. This time frame is necessary to allow synthesis of adequate amounts of functional MAO (2). If moclobemide is to be replaced by a TCA, it is only necessary to discontinue moclobemide for 1 – 2 days owing to its short half-life (30).

Bupropion

FDA labeling for bupropion states that its combined use with MAOIs is contraindicated. No details are provided other than animal studies found that the acute toxicity of bupropion was increased by phenelzine (100). Bupropion inhibits neuronal reuptake of DA and, to a lesser extent, NE. Theoretically, its combined use with an MAOI may increase the risk for hypertensive reactions. However, there are no published reports of such an adverse interaction occurring. There are isolated case reports of safe and effective use of the combination (96).

Mirtazapine

FDA labeling for mirtazapine states that its combined use with MAOIs is contraindicated based on the fact that mirtazapine increases serotonergic neurotransmission. The labeling states that this would increase the likelihood of serotonin syndrome with combined therapy (101). There is one published report of possible serotonin syndrome related to use of phenelzine (90 mg/day) with mirtazapine (15 mg/day) (96). There are no published reports of safe and effective use of the combination. It should be noted that mirtazapine is a 5HT₂ antagonist; this effect may decrease the risk of serotonin syndrome.

Trazodone & Nefazodone

FDA labeling for trazodone states that its combined use with MAOIs is contraindicated based on the fact that trazodone inhibits 5HT reuptake and, therefore, may increase the risk of serotonin syndrome with combined administration. The labeling for nefazodone is similar, but not as strongly worded (102,103). There are no published reports of serotonin syndrome related to the combination of nefazodone and a MAOI, nor are there published reports of safe and effective use of nefazodone with MAOIs. One published study identified a series of cases of apparently safe use of trazodone with MAOIs; in most patients trazodone was used at low doses (100 mg/day or less) for the treatment of insomnia; however, several patients were treated with doses of 150 – 400 mg/day. One patient in that series developed possible serotonin syndrome from the combination of trazodone 200 mg/day with phenelzine 75 mg/day (96). It should be noted that both nefazodone and trazodone are 5HT₂ antagonists; this effect may decrease the risk of serotonin syndrome.

Ketamine/Esketamine

Ketamine and esketamine are known to cause increases in blood pressure and heart rate. FDA labeling and REMS for esketamine require blood pressure monitoring prior to and at 40 minutes following administration. There is also a caution that use of esketamine with an MAOI may result in blood pressure increase (104). There is no information in the literature regarding concomitant esketamine and MAOI use. However, there is information regarding the use of ketamine infusions to treat depression in patients receiving MAOIs. In these small series, ketamine at 0.5 – 0.75 mg/kg infused over 40 minutes did not cause significant blood pressure or heart rate increases (105-107).

Prevention and Management of Drug-Drug Interactions

While MAOIs may potentially be involved with significant drug-drug interactions, the most serious of these interactions (hypertensive reactions with sympathomimetics and serotonin syndrome with other serotonergic agents) are well-characterized. When clinicians are knowledgeable about these interactions, they can be avoided or managed. Patient education about potentially serious interactions can also be a valuable tool in their prevention or management. In general, use of sympathomimetic agents, with the possible exception of decongestant nasal sprays, should be avoided; patients should be educated about alternatives such as nasal saline for treatment of congestion associated with upper respiratory infections. Likewise, the use of chlorpheniramine and brompheniramine should be avoided, and alternative antihistamines should be used. Administration of serotonergic agents (Table 6) should be avoided, and patients should be informed of the risk of self-medication with or recreational use of agents such as dextromethorphan, MDMA, LSD, etc. Several potential interactions between MAOIs and other drugs are not well-characterized or well-documented. In situations where combination with these other agents is occurring or being considered, clinicians should evaluate the evidence for risk of an adverse outcome. With that information, a decision about whether to proceed with or continue co-medication can be made with input from and consent by the patient. Table 7 summarizes drug-drug interactions with MAOIs and suggests management and monitoring approaches.

Table 7: Drug-Drug Interactions with MAOIs – Prevention, Management, and Monitoring

^*Not well-documented