Serotonin toxicity of serotonergic psychedelics

Combining psychedelic substances with common psychiatric medications such as SSRIs carries varying risks of serotonin toxicity, a potentially severe reaction. True serotonin toxicity typically arises only from overdoses or combinations involving a monoamine oxidase inhibitor (MAOI). Serotonergic psychotropics without MAOIs pose low risk when combined with psychedelics that also lack MAOIs. Symptoms that require immediate medical attention include myoclonus, extreme and fluctuating vital signs, agitation or coma, muscle rigidity, pronounced fever, and seizures. The review concludes that some drug combinations present significant risk for serotonin toxicity while others are likely benign, depending on their specific serotonergic mechanisms.

Study at a glance

Abstract

RationaleIn recent years, psychedelic substances with serotonergic mechanisms have accumulated substantial evidence that they may provide therapeutic benefits for people suffering with psychiatric symptoms. Psychiatric disorders targeted by these psychedelic-assisted therapies are managed with serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs) as the current standard of care, so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents.ObjectivesA critical evaluation of the scientific literature is necessary to delineate the risks of ST when combining psychedelics with available serotonergic pharmacotherapy options. This review article describes signs and symptoms of ST, characterizes mechanisms of ST risk, summarizes what is known about serotonergic psychedelic drug interactions, and outlines potential management strategies.ResultsTrue ST typically occurs with a serotonergic drug overdose or in combinations in which a drug that can increase intrasynaptic serotonin is combined with a monoamine oxidase inhibitor (MAOI). Serotonergic psychotropics that do not contain MAOIs are low risk in combination with psychedelics that also do not contain MAOIs. Signs and symptoms warranting immediate medical attention include myoclonus, extreme and fluctuating vital signs, agitation or comatose mental state, muscle rigidity, pronounced hyperthermia (fever), and/or seizure activity.ConclusionsSerotonin-related adverse reactions exist along a spectrum with serotonin syndrome being the most severe manifestations of ST. Due to varying serotonergic mechanisms of psychedelics and psychotropics, with varying propensities to increase intrasynaptic serotonin, some combinations may present a significant risk for serotonin toxicity (ST) while others are likely benign.