Classic Psychedelics Are Generally Well Tolerated by Research Participants

Participants who are administered classic psychedelics in research studies rarely report serious/severe adverse events (SAEs), according to research published in JAMA Psychiatry.

Classic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), mescaline, dimethyltryptamine (DMT), and 5-methoxy-N,N-DMT (5-MeO-DMT), have been increasingly evaluated for their utility in treating psychiatric disorders. However, a comprehensive understanding of potential adverse events (AEs) associated with these compounds is lacking.

To this aim, investigators performed a systematic review of the literature and meta-analysis of published AE data to clarify the risks associated with classic psychedelics in clinical trial and research settings. The investigators searched publication databases from inception through February 8, 2024 to identify studies in which participants were monitored following administration of psilocybin, LSD, DMT, or 5-MeO-DMT. All reported AEs were captured for the study and International Conference on Harmonization (ICH) consensus terminology was adopted to stratify seriousness/severity of AEs. Prespecified AEs of special interest included psychotic disorder, manic symptoms, suicidal ideation or behavior, cardiovascular events, and hallucinogen persisting perception disorder.

A total of 214 studies were included in the analysis. Of the 214 studies included, 53.3% (k=114) had reported AEs among 3504 participants. The investigators stratified AEs by both population and time scale. For population, participants were categorized into 3 groups: 1) healthy participants without active medical or neuropsychiatric disorders, 2) participants with outpatient treatment for neuropsychiatric disorders, and 3) participants undergoing continuous inpatient hospital or facility care for a neuropsychiatric disorder at the time of psychedelic exposure. For timescale, AEs were categorized as either early (ie, within 48 hours post-administration) or delayed (ie, 48 hours after administration).

Among healthy participants (n=1726), psilocybin, LSD, and DMT were not associated with any SAEs at either the early or delayed phase.

For participants receiving outpatient treatment, early SAEs were reported by 0.8% of participants receiving LSD and 16.7% of those who received DMT, while 5.2% of the LSD group reported delayed SAEs. For participants receiving inpatient treatment, 2.1% experienced early SAEs and 1.5% experienced delayed SAEs following LSD administration.

Non-serious AEs (NSAEs) involving suicidality requiring medical or psychiatric attention were not reported among healthy participants who were administered a classic psychedelic and no cases of sustained psychosis were observed.

Overall, SAEs were reported in approximately 4% of participants with preexisting neuropsychiatric disorders.

However, the investigators found that only 17% of studies before 2005 and 23.5% of studies published since 2005 had a systematic approach to reporting and assessing AEs. Further, less than one-third of recent studies reported documentation of severity or attribution of event causality.

“Classic psychedelics were generally well tolerated in clinical or research environments according to existing literature, although SAEs and medically significant NSAEs did occur, which demonstrates the importance of improved pharmacovigilance to understand and quantify the risk and benefit profiles of classic psychedelic substances,” the researchers concluded. “The reality of risks associated with classic psychedelics, as well as their prevalence and severity, should be communicated to potential participants during the informed consent process and to the public in general.”

The primary limitations were the lack of placebo-control in the included studies, as well as methodological heterogeneity.

This article originally appeared on Psychiatry Advisor