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Side Effects with MAO Inhibitors

This article discusses common and rare side effects with MAO inhibitor use and ways to effectively treat them.​

Note: This section does not address two major risks with MAO inhibitors: hypertensive crisis from tyramine ingestion and serotonin syndrome. Both are addressed in the article, “Serious Risks with MAO Inhibitors.”

Insomnia Side Effect & Treatments

Other Side Effects & Management Strategies

The types of side effects a patient may experience with MAO inhibitor use are difficult to predict. However, several of the most common side effects are listed below. Most of these side effects only present for a few days to weeks before disappearing but some may experience these side effects longer-term. Fortunately, most of these side effects can be effectively managed. While we have listed common non-pharmacological, over-the-counter, and prescription treatments for these side effects below, you should always check with your provider first.

Frequency of side effects based on our anecdotal experience

⚠⚠⚠

⚠⚠

⚠

Somewhat Common

Somewhat Uncommon

Rare

Insomnia (Difficulty Falling Asleep and/or Staying Asleep)

⚠⚠⚠ Parnate & Nardil

⚠⚠ Selegiline

⚠ Marplan

  • Overview:
    • Most common side effect
    • Most commonly presents trouble falling asleep, but some have trouble staying asleep
  • Presentation
    • Typically presents early in treatment and may present as early as the first night after taking a MAOI
    • Typically resolves or improves substantially after 1-3 months on a therapeutic dose
  • Cause
    • Mechanism by which MAOIs cause insomnia is not well understood [1]
  • Treatment (non-pharmacologic)
    • Practicing good sleep hygiene as noted by the Sleep Foundation
    • Taking a MAOI in the early morning or as far away from bedtime as possible helps most patients but some patients find taking a MAOI closer to bedtime helps
    • Common first-line treatment: Doxepin 10 mg, Trazodone 50-100 mg, or Remeron 7.5-15 mg
    • Common second-line treatment: Seroquel (Quetiapine) 25-100 mg or Zyprexa (Olanzapine) 2.5-10 mg
    • See below for more information on sleep aids

 

Melatonin Receptor Agonists

  • Melatonin (0.3-10 mg) – May cause mild drop in blood pressure with a MAO inhibitor and, independently, can cause unusual dreams. [2] Should be taken sublingual. However, because a sublingual formulation is not readily available, it may be purchased as oral disintegrating tablets (ODTs) which are frequently called “fast dissolve” or “quick dissolve” on amazon. This ODT formulation can be placed under the tongue to allow for sublingual absorption. Some patients find lower doses of melatonin to be more effective and thus high and low doses of melatonin should be tested. Of note, supplements are not regulated by Food & Drug Administration (FDA) and instances of contamination of melatonin-containing products with serotonin have been noted. Therefore, there is a risk of serotonin syndrome, however, this risk is minimal.
  • Ramelteon or Rozerem (8mg) – Ramelteon binds to the melatonin receptor and generally works better than melatonin but has not been studied extensively for use in patients on MAO inhibitors. [3] Ramelteon has a weak affinity for serotonin (5-HT2B) receptors but has been used in combination with MAO inhibitors by us safely and without signs of serotonin syndrome. [4] A risk of serotonin syndrome still remains but is believed to be relatively minimal when Ramelteon is combined with a MAOI. Read more about our use of Ramelteon as a sleep aid in patients on MAO inhibitors here. Ramelteon may be a good sleep aid for patients who have at least a partial benefit from melatonin. Unfortunately, insurance companies frequently do not cover Ramelteon.

Antihistamines

  • Diphenhydramine or Benadryl (25-50 mg) – Over-the-counter and generally safe option. [7, 8] Can cause anticholinergic side effects (dizziness, urinary retention, blurred vision, and constipation) and thus should be used with care at higher doses, in the elderly, and in men with BPH or enlarged prostates. Diphenhydramine can cause anticholinergic side effects (e.g., dizziness, blurred vision, constipation, urinary retention, dry mouth).
  • Doxylamine or Unisom (25 mg) – An over-the-counter option that is typically much more sedating than Diphenhydramine but has a longer half-life so more likely to cause next-day drowsiness. [7, 8] Can cause anticholinergic side effects (dizziness, urinary retention, blurred vision, and constipation) and thus should be used with care at higher doses, in the elderly, and in men with BPH or enlarged prostates. Doxylamine can cause anticholinergic side effects (e.g., dizziness, blurred vision, constipation, urinary retention, dry mouth).
  • Doxepin (10 mg) – May cause weight gain, however, this is typically when used at high doses (over 100 mg) over long periods. At 10 mg, antihistamine effects are significant while serotonergic effects are minimal, however, there is a risk of serotonin syndrome. Similar to Diphenhydramine and Doxylamine, the role of Doxepin in treatment MAO inhibitor-induced insomnia is not well established but literature supports its use in low doses for the treatment of insomnia [9]
  • Remeron or Mirtazapine (7.5-15 mg) – An effective drug for sleep; however, is also a powerful appetite stimulant and thus may cause weight gain, particularly if given at doses that are insufficient to cause the patient to fall and stay asleep. There is a small risk of serotonin syndrome when combined with a MAOI.
  • Nortriptyline or Pamelor (25-150mg) and Desipramine or Norpramin (25-200mg) – Both tricyclic antidepressants are effective augmenting agents to improve the effectiveness of MAOI. Both have minimal serotonin activity but still pose a small risk of serotonin syndrome. [10] While a common practice to augment MAO inhibitors with these drugs because they have minimal binding affinity for serotonin receptors, this form of augmentation has not been well-studied in the literature. Both drugs are known for promoting sleep secondary to their substantial antihistamine effects. [11] At higher doses, need labs to check levels and potentially an EKG. [12]

Antidepressants/Other

  • Trazodone (50-100 mg) – May increase risk of serotonin syndrome although studies have found up to 100 mg to generally be a safe dose when combined with a MAOI. [5, 6]
  • Gabapentin (100-1200 mg) – While Gabapentin may also help with anxiety, Gabapentin often requires higher doses to have a significant sedative effect. Some patients are highly sensitive to Gabapentin and find 100 mg very sedating while some patients do not obtain sedation even at doses above 1200 mg. Gabapentin may also help with nerve pain but generally only lasts in the body for 8 hours and thus nerve pain management frequently requires dosing three times per day. Because Gabapentin may increase serotonin activity (both in the brain and periphery), it is essential to start doses at 100 mg per a day increase by 100 mg each day until desired effect is achieved.

Alpha adrenergic drug (primarily agonist but also has antagonist properties for some alpha receptors):

  • Clonidine (0.1-0.3 mg) – Clonidine is an effective drug for sedation at low doses but can lower blood pressure and heart rate dramatically. Furthermore, if discontinued after daily use for several weeks, it can cause dangerous levels of hypertensions and thus should be slowly discontinued. Clonidine has significant utility in treating anxiety and PTSD as well.

Second Generation or Atypical Antipsychotic (typically the most effective option):

  • Seroquel or Quetiapine (12.5-200 mg) – Seroquel is a highly sedating atypical antipsychotic. It is infrequently associated with short-term motor or muscle problems that are often treatable to medications such as Benadryl or propranolol. It is also associated with a very low risk of tardive dyskinesia, a permanent side effect that typically involves involuntary twitching of facial muscles. Additional side effects include weight gain, increased risk of developing diabetes, and increased cholesterol. However, these risks can be minimized with low, infrequent doses taken at night and with the use of metformin off-label to suppress appetite.
  • Zyprexa or Olanzapine (2.5-15 mg) – Zyprexa is a highly sedating atypical antipsychotic. It is infrequently associated with short-term motor or muscle problems that are often treatable to medications such as Benadryl or propranolol. It is also associated with a very low risk of tardive dyskinesia, a permanent side effect that typically involves involuntary twitching of facial muscles. Additional side effects include weight gain, increased risk of developing diabetes, and increased cholesterol. However, these risks can be minimized with low, infrequent doses taken at night and with the use of metformin off-label to suppress appetite.

 Dizziness When Standing Up Quickly (Orthostatic Hypotension)

⚠⚠⚠ Nardil

⚠⚠ Parnate

⚠ Marplan & Selegiline

 

  • Overview:
    • Very common but typically not bothersome and short-lived
    • Can be severe with some patients on Nardil requiring aggressive treatments
    • May be exacerbated by a lower baseline blood pressure as MAOIs can lower baseline blood pressure as well
  • Presentation:
    • Typically presents at lower doses and disappears at higher doses or with time (up to 1-3 weeks on a given dose)
    • Almost always, this symptom improves significantly within a few days to a month at a given dose in our experience.
  • Cause:
    • While the cause of orthostasis or orthostatic hypotension is not well-known, it has been speculated that this effect may be due to the MAO inhibitors’ reduction of activity of norepinephrine, a chemical messenger involved in the regulation of blood pressure, at the postsynaptic receptors. (For those interested, it has also been speculated that it may be due to the drug’s accumulation of noradrenaline in the brain resulting in stimulation of inhibitory alpha-adrenoreceptors in the brainstem, thereby producing reduced sympathetic tone and decreased peripheral vascular resistance.) [19]
  • Treatment:
    • Minimizing or stopping medications that can further lower blood pressure such as Propranolol and Clonidine
    • Moving and squeezing one’s legs before standing up slowly. In the morning, before getting out of bed, one should hang their feet off the side of the bed for a few minutes before standing.
    • Drinking lots of fluids rich in electrolytes (particularly sodium, potassium, and magnesium), such as sports drinks or electrolyte mixes or powders added to water. This assumes contraindications to heavy fluid and electrolyte intake such as heart failure or severe kidney disease is not present. Salt tabs may be helpful as well in the absence of autonomic dysregulation but should only be used under strict provider guidance as rapid changes in the body’s sodium level can cause permanent neurological damage. Additionally, salt tabs should be taken with adequate hydration and potassium supplementation. 
    • A slower titration schedule to increase doses may be used as dizziness typically disappears within 1-3 weeks or tablets can be cut with a pill cutter to accommodate smaller increases in dose.
    • Splitting the daily dose of MAOI (e.g., taking half in the morning and half 2-3 hours later) instead of taking it all at once is often helpful as dizziness is frequently worse 1-2 hours after taking a MAOI
    • In rare cases where orthostatic hypotension is too debilitating and more conservative measures detailed are insufficient, Fludrocortisone (Florinef) with potassium supplementation may be used and tapered over weeks to months. Other options include norepinephrine reuptake inhibitors with minimal serotonin activity such as Desipramine, Nortriptyline, and Bupropion XL (150 mg once, twice, or three times per day), however, these pose additional risks such as significant anticholinergic effects or a small risk of serotonin syndrome. You can read about how to dose Desipramine and Nortriptyline on patients taking MAO inhibitors here. Stimulants such as dextroamphetamine time release with a starting dose of 5 mg twice daily is frequently effective at raising blood pressure as well. Midodrine, while effective, is generally not advised given the risk of a hypertensive crisis when combined with a MAOI.

Fatigue

⚠⚠⚠ Nardil

⚠⚠ Parnate, Marplan, Selegiline (often at lower doses with resolution at higher doses)

 

  • Overview:
    • Common but typically treatable and short-lived side effect
    • Can be caused or exacerbated by low blood pressure, a side effect of MAOIs
  • Presentation:
    • Often presents early in treatment
    • Fatigue from Parnate, Marplan, and Selegiline frequently resolves or improves substantially with higher doses while fatigue with Nardil typically worsens with higher doses
    • Fatigue with any of the four MAOIs improves with time but can takes weeks to months for some patients
  • Cause:
    • While fatigue is a common side effect among all antidepressants , not just MAOIs, the exact cause is not known but believed to be through modulation of neurotransmitter activity such as serotonin and norepinephrine [20]
  • Treatment:
    • Splitting the daily dose of MAOI (e.g., taking half of the daily dose in the morning and half 2-3 hours later or taking 1/3 of the daily dose in the morning, taking another 1/3 of the daily dose 2-3 hours later, and taking the final 1/3 of the daily dose another 2-3 hours ) instead of taking it all at once
    • Caffeine – has a small risk of increasing blood pressure at high doses and very small risk of serotonin syndrome as caffeine is a weak, reversible MAOI. [21]
    • Bupropion (Wellbutrin)
    • Modafinil (Provigil)
    • Stimulants. However, all stimulants pose a risk of increased blood pressure when combined with a MAOI and amphetamine-stimulants pose a small risk of serotonin syndrome at higher doses

Weight Gain/Loss

⚠⚠⚠ Nardil (associated with weight gain)

⚠ Parnate, Selegiline, & Marplan (from our extensive experience, these MAOIs are more likely to cause weight loss than weight gain; however, very limited literature suggests Marplan causes weight gain)

 

  • Overview:
    • While weight gain is associated with Nardil, weight gain is less common with Parnate, although substantial weight gain is experienced by some patients at very high doses. [22-24]
  • Presentation:
    • Most commonly, patients stay weight neutral or may gain or lose 5-10 lbs initially without further weight changes
    • Changes in weight are associated with higher doses
    • Although not well-reported in the literature, patients taking MAOIs often have cravings for sweets and junk food but may still lose weight due to appetite suppression in our experience.
  • Cause:
    • Weight gain occurs primarily through an increase in appetite which is likely related to increase serotonin activity. However, if the maoi causes significant fatigue to the point where one is not as physically active, weight gain can be through a decreased metabolic rate.
    • Weight loss primarily occurs through appetite suppression, likely secondary to increased norepinephrine activity but can also be due to increased physical activity from a remission of depression and anxiety or from increased energy levels, a common effect of Parnate
  • Treatments To Help Lose Weight:
    • A healthy diet with adequate fiber and avoiding low volume and high-calorie foods as well as regular exercise.
    • Avoid or minimize augmenting agents that can contribute to weight gain (e.g., second-generation antipsychotics) if possible.
    • Metformin
    • Wellbutrin (Bupropion XL)

    • Semaglutide [25-27]

    • Stimulants , particularly in cases involving binge eating
    • Contrave (Bupropion and Naltrexone)
    • Low-dose Topamax (e.g., 50 mg) may be effective for treating food cravings
  • Treatments To Help Increase Weight:
    • For patients who may require an appetite stimulant to gain weight, Remeron (Mirtazapine) or Zyprexa (Olanzapine) can help and treat insomnia.

Headache

⚠ Parnate

 

  • Overview:
    • A common side effect of all oral medications and is often associated with 
    • All oral medications, including MAOIs, pose a risk of headache. Among MAOIs, headache is most commonly associated with Parnate.
  • Presentation:
    • Typically presents shortly after taking the MAOI
    • Can worsen with increasing the dose but typically resolves or improves substantially over a few days to a few weeks
  • Cause:
    • Commonly caused by Paradoxical Hypertension
    • Severe headaches that do not respond to over-the-counter treatments mentioned above may be indicative of very high blood pressure
  • Treatment:
    • Lowering the dose and increasing the dose more slowly
    • Ibuprofen or Advil or Motrin. This may not be appropriate for patients with irritation of the stomach, stomach or intestinal ulcers, or bleeding disorders or diseases
    • Drinking lots of water. This may not be appropriate for patients with medical conditions that necessitate fluid restriction such as heart failure or severe kidney disease
    • Tylenol or Acetaminophen
    • Propranolol, especially if the cause of headaches is Paradoxical Hypertension

Swelling (Typically of Feet & Ankles)

⚠ Nardil

 

  • Overview:
    • Swelling is a relatively uncommon side effect of MAOIs and typically only occurs in some patients taking Nardil
    • It is very rare for swelling to spread beyond the feet and ankles or be significant enough to change shoe sizes [32]
  • Presentation:
    • Swelling of feet and ankles may start early in treatment but is often not noticed for weeks to months
  • Cause:
    • Swelling is due to water retention, however, the cause of water retention is not well understood
    • Swelling as a direct side effect of Nardil is primarily a cosmetic issue rather than one that requires medical treatments (e.g., a diuretic or water pill)
    • In rare cases, swelling from Nardil is indirectly due to vitamin B6 deficiency or heart or liver damage which are very rare
  • Treatment:
    • Evaluation of liver and heart function, particularly if significant risk factors (e.g., chronic hypertension, history of heart disease, history of alcohol or other drug use) are present. If low suspicion, blood tests (BNP and liver function tests) may be sufficient.
    • Compression stockings or socks
    • Elevating feet at night with a pillow
    • Vitamin B6 supplementation (100-200 mg per day) may help as well as low vitamin B6 levels lead to diminished dopamine activity at the kidney resulting in greater excretion of salts and retention of water. Nardil and Marplan may also cause vitamin B6 deficiency. [33, 34]
    • Although they may be considered, diuretics (e.g., hydrochlorothiazide 12.5-100 mg) are rarely helpful and may require potassium supplementation. Swelling rarely improves with time but resolves with discontinuation of Nardil.

Sexual Dysfunction

⚠⚠ Nardil (although typically much less sexual side effects than SSRIs)

⚠ Parnate, Marplan & Selegiline

  • Overview:
    • Similar to other serotonergic medications, MAOIs can cause changes in sexual desire, arousal, erection, and climaxing. [28]
    • While the exact incidence of sexual dysfunction as well as longer term sequelae is likely unreported, we have noticed less sexual dysfunction with MAO inhibitors compared to SSRIs, SNRIs, and tricyclic antidepressants. [29]
    • While SSRIs pose a risk of long-term sexual dysfunction even after being discontinued called Post-SSRI sexual dysfunction, we are not aware of any cases of sexual dysfunction caused by a MAOI that persists after stopping the MAOI
  • Presentation:
    • Typically worsens with increases in doses but resolves or improves substantially within a few months on a stable dose
  • Cause:
    • Sexual dysfunction is likely due to the increase in serotonergic activity, however, the exact mechanisms of sexual dysfunction with MAOIs is unknown
  • Treatment:
    • Bupropion XL [30]
    • Viagra (Sildenafil) or Cialis (Tadalafil). Viagra (Sildenafil) can be used in both men and women. [31] Both erectile dysfunction drugs should only be used after checking blood pressure as both drugs can slightly lower blood pressure.
    • Evaluation of testosterone levels

Urinary Retention

 

⚠ Nardil, Parnate

  • Overview:
    • Relatively uncommon and typically only associated with Nardil and Parnate
    • Males with a history of enlarged prostates (e.g., benign prostatic hyperplasia (BPH) or prostate cancer) or over the age of 50 are at higher risk of urinary retention
  • Presentation:
    • May not be present at lower doses but worsens at higher doses
    • Typically resolves or improves substantially after 1-3 months on a stable dose
  • Cause:
    • Urinary retention from MAOIs is believed to be due to the anticholinergic effects of MAOIs
  • Treatment:
    • Decreasing the dose of MAOI
    • Flomax – a medication that can lower blood pressure which may already be low from a MAOI
    • In very rare cases, patients who are unable to urinate for 6-8 hours should seek emergency medical care

 

Brain Fog

⚠ Nardil

 

  • Overview:
    • Brain fog or difficulty thinking can occur with any antidepressant including MAOIs. Among MAOIs, Nardil is most associated with brain fog although a significant number of our patients have noted that their thought process has become clearer, rather than worse, from Nardil 
  • Cause:
    • The cause of brain fog in some patients is not well known
  • Presentation:
    • Brain fog side effect tends to worsen with increasing doses of MAOI and improves slowly
  • Treatment:
    • Reducing the dose of the MAOI and increasing more slowly
    • Splitting the dose by several hours instead of taking the entire MAOI dose at once
    • Caffeine – has a small risk of increasing blood pressure at high doses and very small risk of serotonin syndrome as caffeine is a weak, reversible MAOI. [21]
    • Bupropion
    • Stimulants

Dry Eyes and Dry Mouth

⚠ Nardil, Parnate

  • Overview:
    • Relatively uncommon side effect and typically only associated with Nardil and Parnate
  • Presentation:
    • Often not present or minimally present at lower MAOI doses and more noticeable as the dose increases
    • Typically resolves or improves substantially in 1-3 months 
  • Cause:
    • Anticholinergic activity of MAOIs and or other medications used in conjunction with MAOIs
  • Treatment:
    • Avoiding or minimizing other medications that can cause anticholinergic side effects, including over-the-counter medications like Benadryl
    • Artificial tears
    • Sipping on water throughout the day
    • Sucking on a sugarless lozenges or gum. Note that the presence of sugar substitutes such as sorbitol may cause loose and frequent stools.
    • Avoid or minimize caffeine, alcohol, and tobacco use
    • Avoid mouthwashes that contain alcohol
    • Using a humidifier at night
    • In severe cases of dry mouth, can use over-the-counter saliva substitutes

 

Nausea, Stomach Upset, Constipation, and Diarrhea

⚠ Parnate, Nardil, Marplan & Selegiline

 

  • Overview:
    • Although relatively uncommon, all oral medications (including MAOIs) can cause gastrointestinal symptoms
  • Presentation:
    • Typically presents early on, often on the first day
    • Tends to resolve or substantially improve with time but adjustments detailed below may be needed
  • Cause:
    • Like all oral medications, MAOIs have the potential to irritate the stomach lining of some patients and as a result cause nausea or discomfort [35]
    • Constipation is typically caused by anticholinergic activity and/or increase norepinephrine activity with MAOIs and is more commonly associated with Nardil and Parnate than the other two MAOIs
    • Diarrhea may be the result of increased serotonin activity
    • Constipation is believed to be caused by the anticholinergic activity of MAOIs and/or increased norepinephrine activity from MAOIs
  • Treatment for Nausea and Stomach Upset:
    • Taking the maoi with food
    • Splitting the daily dose over 2 or more meals
  • Treatments for Constipation:
    • Increased physical activity to stimulate movements of the bowel
    • Increase fiber intake
    • Colace (Docusate)
    • Milk of Magnesia or Magnesium Citrate
  • Treatments for Diarrhea:
    • Mirtazapine (3.75 – 7.5 mg), which is a potent 5-HT2 and a weak 5-HT3 serotonin receptor blocker, although this drug is frequently sedating and can increase appetite.

Very Rare Side Effects

  • Liver Failure – Liver failure with MAOI use is very rare. It has been most commonly reported with Nardil. Due to cross-sensitivities with MAO inhibitors, patients who experience liver injury from one MAO inhibitor are at increased risk of experiencing liver injury with other MAO inhibitors. [36] Additionally, of the MAO inhibitors, Nardil is most likely to cause liver injury and liver injury typically occurs 1 to 3 months after starting treatment. [37] While signs and symptoms of minor liver injury are rarely present, severe liver injury may present with yellowing of the skin and/or the white regions of the eyes, unusual rashes, edema or swelling of the extremities or abdomen, and abdominal pain. Baseline liver function tests or enzymes (LFTs) may be measured if probable pre-existing liver damage exists (e.g., significant alcohol use, use of IV drugs or non-sterile needles, and frequent and unprotected sexual encounters). If liver enzymes are elevated (indicative of liver injury), this is usually mild and goes away on its own without requiring any dose adjustments. Routine measurement of LFTs after starting a MAOI is not recommended as LFTs are frequently elevated in low levels for a transient period of time. However, detection of elevated LFTs typically necessitates repeat checks of LFTs until they have returned to normal limits.
  • Hand Tremor and Dropping Objects – This has only occurred once with Nardil while we are aware of this case, it has not been reported in the literature. Once this individual stopped Nardil, the hand tremor immediately resolved. Patients who have a hand tremor while on a MAOI may be experiencing serotonin syndrome.
  • Pseudocholinesterase Inhibition – Nardil may lower levels of this enzyme thereby causing prolonged paralysis in patients receiving anesthesia, such as from electroconvulsive therapy (ECT). [38]
  • Bruising – In rare cases, Parnate, particularly when combined with Methylphenidate, may cause thrombocytopenia or low platelet count. There have been cases of thrombocytopenia independent of Methylphenidate use and cases of increased bruising with normal clotting lab values (platelets, INR, PTT) as well. [39, 40] It may be beneficial to obtain a CBC in patients who are expected to combine Parnate with Methylphenidate. In a case where our patient experienced thrombocytopenia at Parnate doses in excess of 100 mg per day, the referring hematologist advised that the patient’s dose of Parnate be reduced and a repeat CBC be ordered.
  • Heart Issues – Although rare, MAO Inhibitors (particular Nardil) may cause heart problems. Heart failure is rare but commonly manifest as increased swelling of the feet and ankles or edema which is also a common and benign symptom of Nardil. Benign and dangerous arrhythmias may also occur in patients on MAO inhibitors, but these are extraordinarily rare. The most common dangerous arrhythmia is Torsades de Pointes which can occur in individuals with QTc (a heart interval) prolongation. MAOIs are less likely than most other antidepressants to cause QTc prolongation and patients with prolonged QTc or with a predisposition for prolonged QTc typically have a family history of sudden cardiac death.

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