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Serious Risks with MAO Inhibitors

This article details the causes, symptoms & management of 2 serious risks with MAOIs: serotonin syndrome and increased blood pressure due to tyramine ingestion.

Serotonin Syndrome

Tyramine-Induced Hypertension

 

Both serotonin syndrome and hypertensive crises are almost always avoidable. Patients potentially displaying signs or symptoms of either, should seek immediate medical attention or call 911. A comprehensive, but not complete, list of of medications and foods to avoid due to a risk of developing serotonin syndrome and/or hypertensive crisis when combined with a MAOI can be found below. Of note, some of the medications below may be combined with a MAOI but should only be done under the guidance of a medical provider aware of the risks. Safer alternatives listed below should only be explored under the guidance of a medical provider.

Medications to AVOID:

  • Supplements
    • Neurotransmitter Precursors – L-Dopa, L-Tyrosine, L-Tryptophan, 5-HTP. These supplements are occasionally used to augment antidepressants by increasing production of neurotransmitters. [10, 11] These supplements pose a high risk when combined with MAOIs and should only be used under the supervision of a medical provider. Read our guide on Tryptophan and 5-HTP augmentation here or learn about a case of serotonin syndrome from L-Tryptophan use here. Note that L-tyrosine is sometimes found in energy drinks and other energy-boosting supplements.
    • St. John’s Wort – Occasionally used to treat depression and anxiety. Believed to have numerous mechanisms of action including increasing the number of serotonin receptors and inhibiting reuptake of serotonin, norepinephrine, and dopamine. [12]
    • Ergotamine – Sometimes used to treat migraines by constricting blood vessels in the brain. Also binds to and activates some serotonin receptors (5-HT1A, 5-HT1B, 5-HT1D) [13, 14]
    • Ginseng – A supplement used by many for a variety of purposes including fatigue, depression, inflammation, and erectile dysfunction
  • Mental Health Medications
    • SSRIs – Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil, Pexeva), Sertraline (Zoloft), Vilazodone (Viibryd), Vortioxetine (Trintellix)
    • SNRIs – Desvenlafaxine (Pristiq, Khedezla), Duloxetine (Cymbalta, Irenka), Levomilnacipran (Fetzima), Milnacipran (Savella), Venlafaxine (Effexor)
    • TCAs & TeCAs – Amitriptyline (Elavil), Amoxapine (Asendin), Clomipramine (Anafranil), Desipramine (Norpramin), Doxepin, Imipramine (Tofranil), Nortriptyline (Pamelor), Protriptyline (Vivactil), Trimipramine (Surmontil)
    • Antipsychotics – Geodon (Ziprasidone) & Caplyta (Lumateperone). Other antipsychotics pose minimal risk.
    • Other Medications – Buspar (Buspirone), Wellbutrin (Bupropion), other MAOIs
  • Stimulants Amphetamines, Amphetamine Derivatives
    • Adipex-P (Phentermine) – Weight loss medication
    • Fenfluramine – Appetite suppressant and an uncommon anti-seizure medication
    • Redux (Dexfenfluramine) – Weight loss medication
    • Amphetamine/Dextroamphetamine/Levoamphetamine (Adderall, Vyvanse, Dexedrine) – Can have significant serotonin activity and increase blood pressure, particularly at higher doses
    • Methylphenidate (Ritalin, Focalin, Concerta) – Can raise blood pressure
    • Alternatives for Weight Loss: Metformin (caution for risk of hypoglycemia exacerbated by MAOIs), Semaglutide (caution for risk of hypoglycemia exacerbated by MAOIs), and Orlistat (may cause vitamin deficiencies and poor absorption of some medications).
    • Alternatives for ADHD:  Non-Stimulants (Clonidine, Atomoxetine, Guaifenesin)
  • Upper Respiratory Infection or “Cold” Medications
    • Dextromethorphan  – A cough suppressant
    • Brompheniramine & Chlorpheniramine – Antihistamines
    • Pseudoephedrine & Ephedrine – Nasal decongestants
    • Of note, Oxymetazoline is safe to take with a MAOI and increasing replacing Pseudoephedrine and Ephedrine in cold medications
    • Alternatives: Flonase (for nasal congestion), Benzonatate (for cough), and Benadryl (for allergies).
  • Pain/Opioids Medications
    • Anesthetic Drugs – These medications are generally safe but discussed in greater detail here
    • Some Opioids (Levorphanol, Meperidine, Methadone, Pentazocine or Talwin NX, Tapentadol or Nucynta, Tramadol) – Meperidine is also used for shivering in the post-operative setting and Methadone is commonly used for opioid dependence
    • Local Anesthetics with Epinephrine – While small amounts (e.g., typical amounts used in dental offices) are typically okay, larger amounts may cause blood pressure to rise. A safer alternative is to ask for local anesthetic (e.g., lidocaine) without epinephrine.
    • Cyclobenzaprine (Flexeril) – A muscle relaxant
    • Alternatives: For non-narcotic pain control, Tylenol and NSAIDs including Toradol may be effective. For narcotic pain control, opioids except those listed above may be effective.
  • Blood Pressure Medications
    • Hydralazine
    • Methyldopa
    • Midodrine
    • Reserpine
  • Migraine Abortive Medications – Some triptans are only degraded by MAO and thus cannot be taken with MAOIs:
    • Rizatriptan (Maxalt)
    • Sumatriptan (Imitrex)
    • Zolmitriptan (Zomig)
    • Alternatives: Triptans with alternative degradation pathways that may be used with a MAOI including Eletriptan (Relpax), Frovatriptan (Frova), Naratriptan (Amerge) & Almotriptan (Axert).
  • Antibiotics/Antifungals
    • Zyvox (Linezolid) – An antibiotic typically only used in the inpatient setting
    • Isoniazid – An antibiotic
    • Diflucan (Fluconazole) & Cipro (Ciprofloxacin) – Commonly prescribe outpatient antimicrobial agents; however, many similar effective and safe antimicrobial agents exists that can be used instead
    • Alternatives: Numerous antibiotics and antifungals can be used instead for most types of infections.
  • Recreational or Illicit Drugs – MDMA, LSD, Cocaine, Methamphetamine, Amphetamine, Ayahuasca, and more
  • Other Medications
    • Tegretol (Carbamazepine) – An anti seizure medication with ill-defined effects on serotonin activity
    • Antabuse (Disulfiram) – Used for alcohol dependence
    • ProvayBlue (Methylene Blue) – A drug used to treat methemoglobinemia, a life-threatening condition
    • Methergine (Methylergonovine) – Typically only used in the postpartum setting to control uterine bleeding
    • Other Medications with MAOI properties such as Pargyline and Rasagiline

SSRI = Selective Serotonin Reuptake Inhibitor | SNRI = Serotonin Norepinephrine Reuptake Inhibitor | TCA = Tricyclic Antidepressant | TeCA = Tetracyclic Antidepressant

Medications to take with CAUTION:

Medications that should be used with some caution for reasons independent to serotonin syndrome, although may generally be permitted:

  • Asthma Medication – Some asthma medication may raised the blood pressure of patients on MAO inhibitors and blood pressure checks with each addition or change in dose is warranted
  • Diabetes Medications – MAOIs may increase the risk of hypoglycemia and thus close monitoring of glucose levels which should be done with the addition or dosing change of any diabetes medication have added value

Medications that are generally SAFE:

Safe medications that can generally be taken with MAOIs, although you should still inform your provider:

  • Caffeine – A mild, reversible MAO inhibitor. [15] However to our knowledge, caffeine has never been reported to precipitate serotonin syndrome when used in conjunction with a MAO inhibitor. There is a case report of a patient on a MAO inhibitor and drinking 10-12 cups of coffee per day who experienced severe hypertension that promptly resolved with discontinuation of coffee intake. [16]
  • Birth Control Pills (minipill or progestin only as well as combined estrogen-progestin pills)
  • Buspar (Buspirone) – an anti-anxiety medication that binds to serotonin receptors and partially activates them, however, has a minimal affect on serotonin transmission
  • Lamictal (Lamotrigine) – a mood stabilizer with minimal serotonin activity and a weak inhibitor of MAO
  • Epipen – Although MAOIs increase catecholamine synthesis and storage and Epipens cause the release of these catecholamines, the use of Epipen in an emergent setting should not be deferred or withheld because the patient is taking a MAO inhibitor
Tyramine Food Chart
Some of the foods that can cause a reaction.

Serotonin Syndrome

Overview

While serotonin syndrome almost certainly will not occur solely from MAOI monotherapy,  it may occur if MAOIs are combined with other medications or supplements. The following is an incomplete list of common drugs that, when taken by a patient on a MAO inhibitor, may precipitate serotonin syndrome. [8, 9] Most of these medications are not strictly prohibited in patients taking MAO inhibitors but, if given, should be done under the close supervision of an experienced medical provider.

Presentation of Serotonin Syndrome

A thorough list of symptoms present with serotonin syndrome is listed below. However, because a lot of these symptoms are non-specific (e.g., insomnia and anxiety) and thus not clear indications that serotonin syndrome may be occurring, several diagnostic criteria exist such as the Hunter Serotonin Toxicity Criteria.

We often encourage our patients to be especially mindful of three signs that are often unique to serotonin syndrome and typically occur in mild-to-moderate serotonin syndrome:

  • Tremors,
  • Clonus, and/or
  • Increased Blood Pressure (in the absence of explained, severe anxiety or recent consumption of tyramine).

Serotonin syndrome classically presents with mental status changes, neuromuscular changes, and autonomic system changes. [19, 20]

Presentation of Serotonin Toxicity
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17;352(11):1112-20. doi: 10.1056/NEJMra041867. Erratum in: N Engl J Med. 2007 Jun 7;356(23):2437. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. PMID: 15784664.
  • Mental State Changes
    • Very Mild – Worsening insomnia
    • Mild – Anxiety
    • Moderate – Agitation
    • Severe – Confusion and/or decreased responsiveness
  • Neuromuscular Changes
    • Very Mild – Very brisk reflexes or hyperreflexia
    • Mild – Inducible clonus or involuntary muscle contraction/spasm (e.g., if, while a patient is laying down, face up, and relaxed, another individual suddenly and forcefully pushes the foot up (i.e., opposite movement to pushing down on the gas pedal), and then suddenly and forcefully pushes the foot back to a neutral position (i.e., toes pointed up to the ceiling), patient’s foot may suddenly spasm and move up and down involuntarily for a few seconds)
    • Moderate – Sustained clonus or muscle contraction/spasm, eye clonus or irregular and random eye muscle movements, and/or tremor or shaking
    • Severe – Muscle rigidity and/or failure of the respiratory muscles
  • Autonomic System Changes
    • Very Mild – Diarrhea and/or nausea
    • Mild – Increased heart rate and/or increased blood pressure
    • Moderate – Fever < 38.5 degrees C or < 101.3 degrees F, skin flushing, diffuse sweating, and/or pupil dilation
    • Severe – Fever > 38.5 degrees C or > 101.3 degrees F

 

Management of Serotonin Syndrome

 

Supportive care and monitoring with risk assessment for emergency interventions are the cornerstone of serotonin syndrome management. [21]
 
  • Supportive care
    • Identify and stop the offending drug
    • Monitor and stabilize vital signs (e.g., temperature monitoring, oxygen supplementation, IV fluids)
    • Provide sedation with benzodiazepines to control symptoms of agitation and minor changes in vital signs.  Avoid propranolol which is long-acting, masks an increased heart rate (an important symptom for monitoring serotonin syndrome), and can precipitate low blood pressure.
  • Close monitoring for potential emergent interventions
    • Mild cases can be monitored and only provide with supportive care. Most cases of serotonin syndrome resolve within 72 hours (if not much sooner); however, the time course depends on several factors such as the pharmacokinetics (e.g., half-life) of the non-MAO inhibitor offending drug(s).
    • Cyproheptadine [10]
      • An antihistamine that blocks a serotonin receptor so is commonly given in cases of moderate to severe serotonin syndrome despite a lack of robust evidence supporting its use
      • May cause transient blood pressure drops that is usually responsive to IV fluids
      • Sample dosing regimen: initial dose of 12 mg with an additional 2 mg given every two hours if symptoms continue. Once stable, a maintenance dose of 8 mg every six hours may be used.
      • Use of cyproheptadine is associated with a high likelihood of subsequently developing symptoms of depression for the subsequent 1-3 days
      • In severe cases, paralytic agents, ventilator-assisted breathing, and vasopressors may be necessary
  1.  

Tyramine-Induced Hypertensive Crisis

Overview

 

Hypertensive crisis may occur when individuals taking MAO inhibitors consume significant portions of tyramine-rich foods. Tyramine is an amine derivative of the amino acid tyrosine and is typically found in foods that have spoiled, aged, or matured. Tyramine is typically formed when bacteria on food convert tyrosine to tyramine via a decarboxylase enzyme. Once consumed, tyramine can be degraded by MAO in the gut or absorbed into the body and enter cells via the norepinephrine reuptake receptor. In the cells, tyramine can displace norepinephrine in storage vesicles, causing norepinephrine to be released from the cells where it can bind to alpha- and beta-adrenergic receptors to causes changes in heart rate and an increase in blood pressure. Tyramine consumption under 6 mg is typically considered safe and unlikely to cause a substantial rise in the blood pressure of patients on MAO inhibitors while tyramine doses under 400 mg in patients not on MAO inhibitors is unlikely to cause an increase in blood pressure. [1] Fortunately, avoiding tyramine-rich foods has become significantly easier in the past few decades.

 

Perhaps best summarized by Dr. Ken Gillman, a neuropsychiatrist and world-renowned expert on MAO inhibitors on his website www.psychotropical.com: “In an era when the tyramine content of foods was much higher (1960 to 1964) and MAOI users received no dietary guidance, only 14 deaths were reported among an estimated 1.5 million patients who took MAOIs.” He goes on to write: “Very few foods now contain problematically high tyramine levels, that is a result of great changes in international food production methods and hygiene regulations. Cheese is the only food that, in the past, has been associated with documented fatalities resulting from hypertension. Nowadays most cheeses are quite safe, and even ‘matured’ cheeses are usually safe in healthy-sized portions. The variability of sensitivity to tyramine between individuals, and the sometimes unpredictable amount of tyramine content in foods, means a little knowledge and care are still required.” In summary, while old guidelines for tyramine-restrictive diets may be unnecessarily restrictive for patients who take MAO inhibitors [2], patients should still be mindful of the foods they eat as being unnecessarily relaxed about dietary restrictions may result in dangerous rises in blood pressure. [3, 4] 

A list of tyramine-rich foods that patients on MAO inhibitors should avoid is shown in the table above. Additionally, some supplements (e.g., L-Tyrosine, Levodopa) may be converted to tyramine in the gut thereby raising blood pressure. [5, 17, 18]

 

Presentation of Hypertensive Crisis

 

Significant rise in blood pressure can lead to a hypertensive crisis. While a hypertensive crisis may not always have symptoms, if any of the following are present, urgent in-person evaluation and possible treatment with a medical provider is necessary given risk of end-organ damage and heart failure. [6]

  • Severe headaches
  • Abdominal pain
  • Blurred vision or vision changes
  • Angina or chest pain or pressure
  • Shortness of breath
  • Mental status changes

 

Management of Hypertensive Crisis

 

DO NOT TAKE A BETA-BLOCKER LIKE PROPRANOLOL. DOING SO MAY BE DANGEROUS BECAUSE HEART RATE MAY ALREADY DROP DURING A TYRAMINE-INDUCED HYPERTENSIVE CRISIS AND YOU MAY CAUSE UNOPPOSED ALPHA-ADRENERGIC ACTIVITY RESULTING IN A FURTHER INCREASE BLOOD PRESSURE.

Because these hypertensive crises rarely last more than 2 hours, emergency interventions are rarely needed. [7] In cases of significant or potentially significant tyramine consumption, patients may be advised to follow the following algorithm, but you should check with your medical provider prior to starting MAO inhibitor treatment to determine the best course of action in cases of suspected or confirmed hypertensive crisis.

 

Sample algorithm:

  • If you are experiencing or at any point began to experience severe headaches, abdominal pain, blurred vision or vision changes, angina or chest pain, shortness of breath, or mental status changes, call 911 or immediately go to the emergency room for blood pressure monitoring and possible interventions.
  • If you suspect a very large amount of tyramine was consumed, call 911 or immediately go to the emergency room for blood pressure monitoring and possible interventions.
  • If you do not have immediate access to a reliable blood pressure monitor, call 911 or immediately go to the emergency room for blood pressure monitoring and possible interventions.
  • If none of the above conditions are met, you should immediately begin to monitor your blood pressure with a reliable blood pressure monitor. Sequential pressure readings should be obtained at least every 5-10 minutes until blood pressures have returned to normal and stayed normal. Attempts to reduce anxiety including take 1 mg of Ativan during this period can help keep their blood pressures down. If your blood pressure ever goes above 200 mm Hg (assuming normal baseline blood pressure; if low baseline blood pressures, a lower threshold exists) or if blood pressure remains elevated for more than 2.5 hours, call 911 or immediately go to the emergency room for blood pressure monitoring and possible interventions.

 

As a side note, we generally do not prescribe “rescue” or “emergency use” medications for lowering blood pressure during a tyramine-induced hypertensive crisis as these medications almost certainly do more damage than good as highlighted by a neuropsychiatrist and world-renowned leader of MAO inhibitors, Dr. Ken Gillman. An important limitation of this advice, however, is that studies that have shown use of Procardia (Nifedipine), a fast-acting and short-lived calcium channel blocker, as a rescue drug for tyramine-induce hypertension to cause a dangerously low blood pressure highlighted examples where the drug was used for moderately but not severely high blood pressure. Thus, Procardia (Nifedipine) use may be safer if patients are instructed to wait to take it at a higher blood pressure. Additionally, a smaller dose of Procardia (Nifedipine) may be more appropropriate, such as 3-5 mg which requires opening a 10 mg capsule and dumping 1/2 to 2/3rd of the content into the trash before resealing the capsule for consumption. For faster onset, patients can directly swallow the remaining beads in the capsule instead of resealing the capsule. However, any patient who takes Procardia (Nifedipine) should immediately go to the emergency room for evaluation. The role rescue medications is to prevent a delay in medical care, not to be a substitute for evaluation and care from a medical provider.

1. Shulman KI, Walker SE. Refining the MAOI diet. J Clin Psychiatry. 1999;60:191-193.

2. Sullivan EA, Shulman KI. Diet and monoamine oxidase inhibitors: a re-examination. Can J Psychiatry. 1984 Dec;29(8):707-11. doi: 10.1177/070674378402900814. PMID: 6394124.

3. Gardner DM, Shulman KI, Walker SE, Tailor SA. The making of a user friendly MAOI diet. J Clin Psychiatry. 1996 Mar;57(3):99-104. PMID: 8617704.

4. McCabe B, Tsuang MT. Dietary consideration in MAO inhibitor regimens. J Clin Psychiatry. 1982 May;43(5):178-81. PMID: 7076627.

5. Hinz M, Stein A, Cole T, Ryan P. Administration of supplemental L-tyrosine with phenelzine: a clinical literature review [retracted in: Clin Pharmacol. 2021 Mar 03;13:39]. Clin Pharmacol. 2014;6:107-110. Published 2014 Jul 22. doi:10.2147/CPAA.S67271

6. Alley WD, Schick MA. Hypertensive Emergency. [Updated 2020 Nov 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470371/

7. Sathyanarayana Rao TS, Yeragani VK. Hypertensive crisis and cheese. Indian J Psychiatry. 2009;51(1):65-66. doi:10.4103/0019-5545.44910

8. Sabri MA, Saber-Ayad MM. MAO Inhibitors. [Updated 2020 Jun 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557395/

9. Sub Laban T, Saadabadi A. Monoamine Oxidase Inhibitors (MAOI) [Updated 2020 Aug 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539848/

10. Young SN. Use of tryptophan in combination with other antidepressant treatments: a review. J Psychiatry Neurosci. 1991;16(5):241-246.

11. Pardo JV. Mania following addition of hydroxytryptophan to monoamine oxidase inhibitor. Gen Hosp Psychiatry. 2012;34(1):102.e13-102.e14. doi:10.1016/j.genhosppsych.2011.08.014

12. Müller WE. Current St John’s wort research from mode of action to clinical efficacy. Pharmacol Res. 2003 Feb;47(2):101-9. doi: 10.1016/s1043-6618(02)00266-9. PMID: 12543057.
13. Haddjeri N, Seletti B, Gilbert F, de Montigny C, Blier P. Effect of ergotamine on serotonin-mediated responses in the rodent and human brain. Neuropsychopharmacology. 1998 Nov;19(5):365-80. doi: 10.1016/S0893-133X(98)00038-4. PMID: 9778659.
14. Leone M, Rigamonti A, D’Amico D, Grazzi L, Usai S, Bussone G. The serotonergic system in migraine. J Headache Pain. 2001;2(Suppl 1):s43-s46. doi:10.1007/s101940170008
15. Petzer A, Pienaar A, Petzer JP. The interactions of caffeine with monoamine oxidase. Life Sci. 2013 Aug 28;93(7):283-7. doi: 10.1016/j.lfs.2013.06.020. Epub 2013 Jul 11. PMID: 23850513.
16. van der Hoeven N, Visser I, Schene A, van den Born BJ. Severe hypertension related to caffeinated coffee and tranylcypromine: a case report. Ann Intern Med. 2014 May 6;160(9):657-8. doi: 10.7326/L14-5009-8. PMID: 24798537.
17. Jameson KG, Hsiao EY. A novel pathway for microbial metabolism of levodopa. Nat Med. 2019;25(8):1195-1197. doi:10.1038/s41591-019-0544-x
18. http://labeling.pfizer.com/showlabeling.aspx?id=638

19. Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13(4):533-540.

20. Simon LV, Keenaghan M. Serotonin Syndrome. [Updated 2021 Jan 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482377/

21. Scotton WJ, Hill LJ, Williams AC, Barnes NM. Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions. Int J Tryptophan Res. 2019;12:1178646919873925. Published 2019 Sep 9. doi:10.1177/1178646919873925

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