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Serotonin toxicity of serotonergic psychedelics

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Abstract

Rationale

In 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.

Objectives

A 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.

Results

True 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.

Conclusions

Serotonin-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.

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Authors and Affiliations

  1. Spirit Pharmacist https://www.spiritpharmacist.com/

    Benjamin Malcolm PharmD, MPH

  2. Touro University California, Vallejo, CA, 94590, USA

    Kelan Thomas PharmD, MS

Authors
  1. Benjamin Malcolm PharmD, MPH
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  2. Kelan Thomas PharmD, MS
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Contributions

BJM contributed to the project design and conception. BJM and KT authored the manuscript. BJM created Figs. 1, 2, and 3 with KT providing editorial suggestions.

Corresponding author

Correspondence to Benjamin Malcolm PharmD, MPH.

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The authors declare no competing interests.

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Key Points

• The clinical relevance concerning risks of serotonin toxicity with serotonergic psychedelics in combination with other psychotropics is increasing due to positive evidence for a role of MDMA and psilocybin in treating mental illnesses.

• Serotonin-releasing agents (e.g., MDMA) with monoamine oxidase inhibitors (MAOIs) can precipitate serotonin toxicity, while use of serotonin-releasing agents (e.g., MDMA) with serotonin specific reuptake inhibitors (SSRIs) tends to attenuate MDMA drug effects.

• Serotonin agonists (e.g., psilocybin) appear to have a lower risk for development of serotonin toxicity, alone or in combination with other serotonergic agents.

This article belongs to a Special Issue of Psychopharmacology on Psychedelic Drugs

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Malcolm, B., Thomas, K. Serotonin toxicity of serotonergic psychedelics. Psychopharmacology 239, 1881–1891 (2022). https://doi.org/10.1007/s00213-021-05876-x

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