Decreases in Suicidality Following Psychedelic Therapy: A Meta-Analysis of Individual Patient Data Across Clinical Trials

This meta-analysis (2022) assessed patient-level data on the effects of psychedelics on suicidality across seven clinical trials. It was found that, relative to baseline, psychedelic therapy was associated with large effect sizes and sustained decreases in suicidality. The effect size was medium at 6 months while reductions in suicidality were significant at all time points except 7-8 weeks.

Abstract

“Objective: Suicide is a global health concern, and innovative interventions that target suicidality are needed. While psychedelic therapy shows promise for a range of mental health concerns, including suicidality, not all psychedelic therapy trials have published their suicidality results and no meta-analysis has been published on the topic. Therefore, we completed the first meta-analysis of patient-level data on the effects of psychedelics on suicidality.

Data Sources: We conducted a systematic search of MEDLINE, PsycINFO, and PubMed for all psychedelic therapy clinical trials (last search: November 5, 2020).

Study Selection: We identified all psychedelic therapy trials that included a measure or measure-item that assesses suicidality.

Data Extraction: Suicidality data were requested from study authors and extracted using a data extraction form developed for this study.

Results: We identified 8, and successfully collected data from 7, relevant trials. Analysis of standardized mean differences (SMDs) indicated that, relative to baseline, psychedelic therapy was associated with large effect sizes for acute (80–240 min) and sustained (1 day, 1–8 weeks, and 3–4 months) decreases in suicidality (SMD range = −1.48 to −2.36; 95% CI range, −4.30 to 0.23). At 6 months, the effect size was medium (SMD = −0.65; 95% CI, −1.14 to −0.16). Reductions in suicidality were significant at all time points except for 7–8 weeks. Acute and post-acute elevations in suicidality were rare (6.5% and 3.0%, respectively).

Conclusions: Limitations include heterogeneous samples and interventions, as well as limited sample size and the number of studies. Results provide preliminary support for the safety of psychedelic therapy and its positive effect on suicidality. Controlled trials that specifically evaluate the effect of psychedelic therapy on suicidality may be warranted.”

Authors: Richard J. Zeifman, Dengdeng Yu, Nikhita Singhal, Guan Wang, Sandeep M. Nayak & Cory R. Weissman

Notes

The authors have added the following note – not directly influencing the results – to the analysis:

“Our group recently published in JCP the first meta-analysis of patient-level data on the effects of psychedelics on suicidality. While not described in our article, it is noteworthy that 2 suicidality-related events that had been deemed not attributable to the administration of a psychedelic (by the authors of the primary outcome studies) occurred within the studies included in our meta-analysis.

Griffiths et al. describe in their supplementary materials that 1 individual in their very low-dose (placebo-like) psilocybin condition completed suicide 11 days after being administered 1 mg/70 kg psilocybin. The individual reported feeling bored during the session and was discontinued from the study after leaving the session early. They also report that there was no behavioral impairment or adverse sequelae during the follow-up later that day or on subsequent days. Andersen et al. report that 1 individual attempted suicide approximately 2 months after being administered an active dose of psilocybin (21–25.2 mg/70 kg). The suicide attempt occurred after the individual learned about the sudden death of a former partner, subsequently used methamphetamine and crack cocaine, and then experienced a brief psychotic episode. They reported that the actual lethality of the attempt was 0 and the potential lethality was a 2 on the Columbia Suicide Severity Rating Scale.”

Summary

In 2019, 1.4 million adults in the United States attempted suicide, 3.5 million individuals made suicide plans, and 12 million individuals reported serious suicidal ideation. Suicidality is prevalent among individuals with major depressive disorder.

No gold-standard intervention exists for targeting suicidality. Several interventions have been shown to lead to decreases in suicidality, but they are generally limited by a range of factors, including modest effect sizes, long treatment times, and safety concerns. Although additional pharmacologic interventions have been found to reduce suicidality, these findings are generally specific to certain populations. Additionally, little research has examined whether psychedelic therapy is associated with elevations in acute and post-acute suicidality.

To fill these gaps, we identified all published psychedelic therapy clinical trials that included a suicidality measure and/or suicidality item and conducted a patient level meta-analysis on the effects of psychedelic therapy on suicidality.

METHODS

A search was conducted on March 28, 2020, and repeated on November 5, 2020, to retrieve any articles that had been published since the initial search. Reference lists of eligible studies and review articles were manually searched to identify additional relevant studies.

We included clinical trials involving the administration of a classic psychedelic and a suicidality measure at baseline and post-psychedelic administration. The possibility of publication bias was evaluated using funnel plots.

We examined whether administration of a psychedelic was associated with subsequent elevations in suicidality. We examined the frequency at which elevations of 1 point, 2 points, and 3 points occurred among all participants who were administered a psychedelic.

Study Selection

A total of 9,667 potentially relevant records were identified through our initial literature search, and 8 studies were included after full-text review.

There was large variability in heterogeneity of studies by time point, with fail-safe N values ranging from 11 to 101 and being highest at 1 day and 1 week. Publication bias was limited to no publication bias.

Elevations in Suicidality

A total of 31 individuals were assessed for suicidality during the acute effects of ayahuasca. Two individuals showed a suicidality score increase of +1 at a single time point, and both showed decreases to a suicidality score of 0 at all subsequent acute time points and at their post-acute assessment.

The effect of psychedelic therapy on suicidality is rapid-acting and may last as long as 6 months post-treatment. Furthermore, psychedelic therapy shows a strong safety profile with little potential for abuse or harm.

We analyzed data from individuals with treatment-resistant MDD, recurrent MDD, AIDS-related demoralization, and distress related to life-threatening cancer. We observed large effect sizes for reductions in suicidality across these samples, suggesting that psychedelic therapy may have a positive effect on suicidality across a range of clinical presentations.

Limitations and Future Directions

Our study includes several limitations, such as the use of a single-item measure of suicidality and the limited number of studies on the topic. Future research would benefit from using a more fine-grained approach that examines and assesses each of these components individually. We did not distinguish between various research designs, including the specific diagnosis that individuals had, the specific psychedelic that was administered, the number of administrations, and the amount of psychological support that was provided. The present meta-analysis included data from heterogeneous trials that included a range of psychiatric presentations. It is recommended that future studies specifically recruit individuals with elevated suicidality and integrate psychedelic therapy with evidence-based psychotherapeutic interventions.