Research Suggests Psychedelics Are Well Tolerated, but Calls for Improved Monitoring

Classic psychedelics like LSD and psilocybin are generally well tolerated in clinical and research settings, with serious adverse events (AEs) being rare, according to a new study published in JAMA Psychiatry. However, concerns over incomplete AE reporting highlight the need for improved safety monitoring as these substances gain traction in therapeutic use.

While the findings indicate psychedelics are well-tolerated in clinical settings, the investigators emphasized the need for more rigorous pharmacovigilance practices.

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To assess the nature, frequency, and severity of AEs associated with LSD, psilocybin, dimethyltryptamine (DMT), and 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), investigators conducted a systematic review and meta-analysis that examined data from 114 studies involving 3504 participants.

The research found that serious AEs (SAEs) and nonserious AEs (NSAEs) requiring medical or psychiatric attention were rare in studies involving classic psychedelic administration in monitored clinical or research settings. Among participants with preexisting neuropsychiatric disorders, approximately 4% experienced SAEs, such as worsening depression, suicidal behavior, psychosis, and convulsive episodes. However, no SAEs were reported among healthy participants. NSAEs, including paranoia and headaches, were similarly uncommon.

The investigators noted that most studies had significant gaps in adverse event reporting, raising concerns about underdetection or incomplete data. Among the 68 studies published since 2005, only 23.5% systematically assessed AEs, and just 29.4% reported all AEs rather than only adverse drug reactions.

The studies included in the meta-analysis were drawn from databases such as Scopus, MEDLINE, PsycINFO, and Web of Science, covering research published up to February 8, 2024. Two independent reviewers screened and selected articles focusing on clinical or research settings where classic psychedelics were administered.

Adverse events were categorized by timescale and study population type. The researchers applied a hybrid approach to capture all reported AEs following high-dose classic psychedelic exposure and confirmed the presence of AEs of special interest, such as suicidality, psychotic disorders, manic symptoms, cardiovascular events, and hallucinogen persisting perception disorder (HPPD).

In modern research settings, the study found that there were no reported cases of death by suicide, persistent psychotic disorders, or HPPD following high-dose psychedelic administration. However, due to the inconsistent quality of adverse event monitoring and reporting across studies, the risk of underestimating the true incidence of AEs remains a concern.

While the findings indicate psychedelics are well tolerated in clinical settings, the investigators emphasized the need for more rigorous pharmacovigilance practices to accurately quantify the risks and benefits of psychedelic substances. Improved reporting standards can help ensure that future studies provide a clearer picture of potential adverse events, thereby safeguarding participants and informing public understanding.

These results also highlight the difference in safety profiles between clinical and recreational settings, the study stated. Many catastrophic events reported in recreational use, such as persistent psychotic disorders or suicides, were not observed in contemporary trial participants. This suggests that the controlled environments of clinical research may mitigate some of the risks associated with psychedelic use.

“We are developing generalizable templates for detecting and characterizing AEs that can be incorporated into existing protocols to account for FDA recommendations,” investigators wrote. “Since AEs may be subjectively or functionally impactful but not hazardous to participant health (eg, a debilitating headache), we recommend adopting ICH [International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use] language to differentiate intensity (severity) from medical significance and intervention.”

Reference

Hinkle JT, Graziosi M, Nayak SM, Yaden DB. Adverse events in studies of classic psychedelics: a systematic review and meta-analysis. JAMA Psychiatry. Published online September 4, 2024. doi:10.1001/jamapsychiatry.2024.2546