Richard J. Zeifman, Nikhita Singhal, Leah Breslow, & Cory R. Weissman

ACS Pharmacology & Translational Science, 2021, 4, (2), 436-451

Doi : 10.1021/acsptsci.1c00024

Use of classic psychedelics (e.g., psilocybin, ayahuasca, lysergic acid diethylamide) is increasing and psychedelic therapy is receiving growing attention as a novel mental health intervention. Suicidality remains a potential safety concern associated with classic psychedelics and is, concurrently, a mental health concern that psychedelic therapy may show promise in targeting. Accordingly, further understanding of the relationship between classic psychedelics and suicidality is needed. Therefore, we conducted a systematic review of the relationship between classic psychedelics (both non-clinical psychedelic use and psychedelic therapy) and suicidality. We identified a total of 64 articles, including 41 articles on the association between non-clinical classic psychedelic use and suicidality and 23 articles on the effects of psychedelic therapy on suicidality. Findings on the association between lifetime classic psychedelic use and suicidality were mixed, with studies finding positive, negative, and no significant association. A small number of reports of suicide and decreased suicidality following non-clinical classic psychedelic use were identified. Several cases of suicide in early psychedelic therapy were identified; however, it was unclear whether this was due to psychedelic therapy itself. In recent psychedelic therapy clinical trials, we found no reports of increased suicidality and preliminary evidence for acute and sustained decreases in suicidality following treatment. We identify some remaining questions and provide suggestions for future research on the association between classic psychedelics and suicidality.

Keywords : Suicidality; Classic psychedelics; Psychedelic therapy; Systematic review

Classic psychedelics are a class of pharmacological agents, including psilocybin, lysergic acid diethylamide (LSD), mescaline, and dimethyltryptamine (DMT; typically contained in the ayahuasca brew),1 that act as serotonin 5-HT2AR receptor agonists.2 These pharmacological agents have a range of effects, including altered perception, affect, and cognition.2 At higher doses, classic psychedelics drugs also produce profound alterations of consciousness, including changes in one’s sense of self3 and relationship to others,4 as well as peak or mystical-type experiences.5 Over the past two decades, a growing body of research has begun to evaluate the mental health effects, including the effects on suicidality, associated with both non-clinical classic psychedelic use (i.e., recreational and ritualistic use outside the context of a clinical intervention) and psychedelic therapy (i.e., administration of a classic psychedelic in a supportive, legally sanctioned clinical environment and often in combination with psychological preparation and integration).6,7 Accordingly, there remains a need for a synthesis of the literature on the effects of classic psychedelic use and psychedelic therapy on suicidality.

Research suggests that the lifetime prevalence rate of classic psychedelic use is increasing.8-13 Epidemiological research indicates that, among United States adults, the lifetime use of classic psychedelics increased from 5.8% in 2001-2002 to 9.3% in 2012-2013.10 Similarly, lifetime use of both LSD12 and psilocybin13 was found to increase from 2015 to 2018. While the cause of this increase in lifetime psychedelic use remains unclear, it may be attributable to increased psychedelic use among college students,8 efforts toward decriminalization,14 or increased research on their potential therapeutic benefits.15 The use of classic psychedelics may be associated with both positive (e.g., lower psychological distress)16 and negative (e.g., hallucinogen persisting perception disorder)17 mental health outcomes. Several studies have also suggested that there is a link between classic psychedelic use and suicidality, with some studies suggesting that classic psychedelic use is associated with decreased suicidality,16,18 some studies finding no evidence for such a relationship,19 and others reporting that classic psychedelic use is linked with increased suicidality.20 These conflicting results may be due to differences in samples (e.g., small adolescent samples vs. nationally representative adult samples) or due to controlling (or failing to control) for potential confounds (e.g., use of other substances). Given these conflicting findings, alongside the increasing lifetime use of classic psychedelics8-13 and suicide rates21 within the United States, a more complete understanding of the relationship between non-clinical classic psychedelic use and suicidality is needed.

Psychedelic therapy is receiving growing attention in the field of psychiatry and has been examined as an intervention for a range of mental health presentations (for a review, see22), including major depressive disorder (MDD),23-26 distress associated with life-threatening illness,27,28 alcohol abuse,29,30 smoking cessation,31,32 and obsessive-compulsive disorder.33 To date, no clinical trials have specifically been designed to examine the effects of psychedelic therapy on suicidality and several have excluded individuals with serious suicide risk.25 The existing evidence on this topic is indeed mixed and patchwork, as several early studies report instances of suicidality in the context of psychedelic therapy34 and recent clinical trials have found that psychedelic therapy may be associated with decreases in suicidality among individuals with MDD.23,24,35,36 Given the importance of maximizing safety in psychedelic therapy7 and the need for innovative and rapid-acting interventions for suicidality,37-39 further understanding of the effects of psychedelic therapy on suicidality is needed.

In sum, lifetime non-clinical classic psychedelic use is increasing and psychedelic therapy is receiving growing attention as a novel mental health intervention. Although a growing body of research has examined the association between classic psychedelics and suicidality, this research has yielded unclear results and, importantly, there has not yet been a systematic review on the topic. Therefore, we conducted a systematic review on the association between classic psychedelics (both non-clinical psychedelic use and psychedelic therapy) and suicidality.

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