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Assessing the risk–benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research

Abstract

Rationale

A broad reassessment of the potential benefits of psychedelic drugs has led to the initiation of multiple major clinical trials in an effort to advance their status to become FDA-approved medications, as well as local legislative efforts to legalize or decriminalize their use.

Objectives

To use recently published data to assess potential risks and benefits of psychedelic drugs as therapeutics, as well as to synthesize what is currently known in order to generate fruitful future research directions.

Methods

A review of studies conducted since 1991 identified 14 clinical trials of classical psychedelics, including 11 of psilocybin (N = 257 participants), 1 of lysergic acid diethylamide (N = 12 participants), and 2 of ayahuasca (N = 46 participants). Other published studies (e.g., of healthy volunteers, survey studies, case reports, neuroimaging) were also considered for review.

Results

Published studies since 1991 largely support the hypothesis that small numbers of treatments with psychedelic-assisted psychotherapy can offer significant and sustained alleviation to symptoms of multiple psychiatric conditions. No serious adverse events attributed to psychedelic therapy have been reported. Existing studies have several limitations, including small sample sizes, inherent difficulty in blinding, relatively limited follow-up, and highly screened treatment populations.

Conclusions

Substantial data have been gathered in the past 30 years suggesting that psychedelics are a potent treatment for a variety of common psychiatric conditions, though the ideal means of employing these substances to minimize adverse events and maximize therapeutic effects remains controversial. Unique factors related to study design are vital for clinical researchers in the field to address.

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Abbreviations

LSD:

Lysergic acid diethylamide

MDMA:

3,4-Methylenedioxymethamphetamine

PTSD:

Post-traumatic stress disorder

HPPD:

Hallucinogen persisting perception disorder

MDD:

Major depressive disorder

MEQ:

Mystical Experience Questionnaire

BPD:

Borderline personality disorder

QIDS:

Quick Inventory of Depression Symptoms

BDI:

Beck Depression Inventory

HADS:

Hospital Anxiety and Depression Scale

STAI:

State-Trait Anxiety Inventory

GAD:

Generalized anxiety disorder

GRID-HAM-D:

GRID Hamilton Depression Scale

HAM-A:

Hamilton Anxiety Scale

DMN:

Default mode network

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Correspondence to David J. Hellerstein.

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DB: no conflicts. DH: Dr. Hellerstein has received research funding support from Compass Pathways for psilocybin studies and from Pfizer, Lilly, Takeda, GeneSight, Marinus, Relmada, and IntraCellular Therapies for other studies. He is on the scientific advisory board for Reset Pharmaceuticals.

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Bender, D., Hellerstein, D.J. Assessing the risk–benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research. Psychopharmacology 239, 1907–1932 (2022). https://doi.org/10.1007/s00213-021-06049-6

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Keywords

  • Psychedelics
  • Psilocybin
  • LSD
  • Ayahuasca
  • Clinical review
  • Depression
  • Hallucinogens
  • Adverse events