MAO Inhibitors: Anesthetic Interactions

Overview of MAO Inhibitors

• MAOIs are antidepressant medications that block the enzyme monoamine oxidase, thereby increasing the availability of neurotransmitters such as serotonin, norepinephrine, and dopamine in the brain.
• MAO exists in two isoforms: MAO-A and MAO-B- located on the outer mitochondrial membrane.
• The classic antidepressant MAOIs, phenelzine, isocarboxazid, and tranylcypromine, are irreversible, nonselective inhibitors of MAO-A and MAO-B, resulting in increased synaptic concentrations of serotonin, norepinephrine, and dopamine and potentiation of responses to exogenous monoamines and indirect sympathomimetics.^1,2
• Selegiline is relatively selective for MAO-B at typical doses used in Parkinson’s disease; however, loss of selectivity with clinically relevant MAO-A inhibition can occur at higher doses or with formulations that increase systemic exposure.³
• From an anesthetic perspective, clinically important MAOI interactions fall into two principal categories: serotonin toxicity when MAOIs are combined with serotonergic drugs, and exaggerated hemodynamic responses to indirect-acting sympathomimetics or other agents that increase catecholamine availability.^1,4-7

Serotonin Toxicity and Analgesic Interactions

• The interaction between MAOIs and meperidine (Demerol) is the most well-documented and historically associated with severe and sometimes fatal reactions, but it is not unique.^4,8 Opioids with serotonin reuptake inhibition or serotonergic properties, including tramadol and methadone, also pose a risk of serotonin toxicity when combined with MAOIs, and this risk has been emphasized in anesthesia-focused reviews.^4-6 Fentanyl and related opioids have serotonergic effects described in mechanistic and clinical literature, prompting caution rather than an absolute contraindication.⁵
• Serotonin toxicity is characterized by neuromuscular hyperactivity (e.g., clonus, hyperreflexia), autonomic instability (e.g., hyperthermia, diaphoresis), and altered mental status.
• Please see the OA summary on serotonin syndrome for more details. Link
• In the perioperative period, diagnosis may be challenging because features overlap with malignant hyperthermia, neuroleptic malignant syndrome, and sepsis.⁷
• Methylene blue, which acts as a potent MAO inhibitor, is specifically recognized as a perioperative precipitant of serotonin toxicity and should be avoided or used with extreme caution in patients receiving MAOIs or other serotonergic drugs.⁷

Hemodynamic Interactions and Vasoactive Agents: Local Anesthetic Vasoconstrictors

• Indirect-acting sympathomimetics such as ephedrine may cause exaggerated hypertensive responses in patients taking nonselective MAOIs because of increased endogenous catecholamine release.
• Contemporary anesthesia reviews recommend avoiding indirect-acting agents and instead treating hypotension with carefully titrated direct-acting vasopressors such as phenylephrine or norepinephrine, with close hemodynamic monitoring.^1,6,8
• Ketamine has also been approached cautiously because of its sympathomimetic effects; isolated clinical reports describe its use in patients receiving MAOIs and are frequently cited in discussions of potential risk.⁹
• Concerns have been raised regarding the use of vasoconstrictors (e.g., epinephrine) in local anesthetic solutions. Dental and anesthesia literature addressing MAOI interactions suggests that exaggerated responses are not inevitable but supports conservative dosing, incremental injection, and vigilant cardiovascular monitoring rather than routine avoidance.¹⁰
• Modern consensus supports the continuation of MAOIs in selected patients when anesthetic plans explicitly avoid high-risk serotonergic drugs (particularly meperidine and tramadol), avoid indirect-acting sympathomimetics, and prioritize direct-acting vasopressors with careful titration. Vigilance for serotonin toxicity, including awareness of agents such as methylene blue, remains essential.^1,6-8