Classic psychedelics, including LSD and psilocybin, demonstrate good tolerability in clinical and research environments, with serious adverse events (AEs) occurring infrequently, according to a recent study published in JAMA Psychiatry. The research underscores the necessity for enhanced safety monitoring as these substances gain traction in therapeutic applications.
The systematic review and meta-analysis encompassed data from 114 studies, involving a total of 3504 participants, to evaluate the nature, frequency, and severity of AEs associated with LSD, psilocybin, dimethyltryptamine (DMT), and 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT).
Adverse Event Profile
The study revealed that serious AEs (SAEs) and nonserious AEs (NSAEs) necessitating medical or psychiatric intervention were uncommon in studies involving classic psychedelic administration within monitored clinical or research settings. Among participants with pre-existing neuropsychiatric disorders, approximately 4% experienced SAEs, including worsening depression, suicidal behavior, psychosis, and convulsive episodes. Notably, no SAEs were reported among healthy participants. NSAEs, such as paranoia and headaches, were similarly infrequent.
Reporting Gaps and Pharmacovigilance
Investigators highlighted that a significant number of studies exhibited gaps in adverse event reporting, raising concerns about potential underdetection or incomplete data. Of the 68 studies published since 2005, only 23.5% systematically assessed AEs, and merely 29.4% reported all AEs rather than solely adverse drug reactions.
Methodology and Data Analysis
The studies included in the meta-analysis were sourced 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. Researchers employed 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).
Safety in Controlled Environments
In modern research settings, the study found no reported cases of death by suicide, persistent psychotic disorders, or HPPD following high-dose psychedelic administration. However, the inconsistent quality of adverse event monitoring and reporting across studies raises concerns about underestimating the true incidence of AEs.
Clinical vs. Recreational Settings
The results also emphasize the difference in safety profiles between clinical and recreational settings. 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.
Future Directions
“We are developing generalizable templates for detecting and characterizing AEs that can be incorporated into existing protocols to account for FDA recommendations,” the 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.”
