This review (2021; 64 studies) investigated the literature and found no clear relationship (finding correlation both ways, and non-significant results) between non-clinical use of psychedelics and suicidality. There is preliminary evidence for acute and sustained decreases in suicidality after psychedelic therapy.
Use of classic psychedelics (e.g., psilocybin, ayahuasca, and 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.
Papers cited by this study that are also in Blossom
Nichols, D. E. · Pharmacological Reviews (2016)
Nour, M. R., Carhart-Harris, R. L. · British Journal of Psychiatry (2017)
Carhart-Harris, R. L., Erritzoe, D., Haijen, E. C. H. M. et al. · Psychopharmacology (2017)
Richards, W. A., Garcia-Romeu, A. · International Review of Psychiatry (2018)
Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)
Earlier research on classic psychedelics (for example psilocybin, ayahuasca, and LSD) presents a mixed picture regarding their relationship with suicidality. Some epidemiological and case-based reports have suggested increased suicidal ideation or behaviour following use, while other studies — including more recent cohort work and clinical investigations of psychedelic therapy — have suggested potential protective or therapeutic effects. Heterogeneity in samples (adolescents versus nationally representative adults), varying control for confounders (such as other substance use and psychiatric history), and differences in context (recreational, ceremonial, or clinical) have contributed to these conflicting findings. To address this uncertainty, Zeifman and colleagues conducted a systematic review to synthesise available evidence on the association between classic psychedelics and suicidality. The review considered both non-clinical (recreational or ceremonial) psychedelic use and psychedelic therapy in clinical settings, with the aim of clarifying whether classic psychedelics are linked to increased suicide risk, decreased suicidality, or show no clear association, and to highlight gaps for future research. The authors frame the work as timely given rising lifetime use of psychedelics and ongoing interest in psychedelic therapy as a novel psychiatric intervention.
The systematic review followed PRISMA guidance and was registered on PROSPERO (CRD42020158443). The investigators searched MEDLINE, PsycINFO, and PubMed from inception to 28 March 2020, and repeated the search on 5 November 2020. Search terms combined psychedelic-related keywords (psychedelic*, hallucinogen*, psilocybin, ayahuasca, DMT, mescaline, peyote, LSD) with a broad set of clinical and symptom terms including suicid*. Reference lists of eligible papers and reviews were also checked. Eligibility included any study reporting on associations between classic psychedelics (non-clinical use or psychedelic therapy) and suicidality outcomes. Studies of microdosing or non-classic psychoactive compounds (for example ketamine, MDMA, cannabis, benzodiazepines) were excluded. No restrictions were placed on participant age, gender, psychiatric diagnosis, or year of publication. Screening and data extraction were performed in duplicate: two reviewers independently screened titles/abstracts and full texts, resolving disagreements by discussion with a third reviewer when needed. Extracted items included study design, sample characteristics, details of psychedelic exposure or intervention, suicidality measures and outcomes, and follow-up duration. The review team used the Oxford Centre for Evidence Based Medicine (OCEBM) Levels of Evidence to appraise methodological quality (levels 1–5, with 1 highest). The extracted text does not indicate that a quantitative meta-analysis was performed; data synthesis appears to be narrative, integrating findings across study designs.
The review synthesised heterogeneous evidence spanning non-clinical use, early (mid-20th century) clinical reports, and modern clinical trials and observational studies. Study designs varied widely and included longitudinal cohorts, cross-sectional surveys, case reports/series, and clinical trials; many early studies were retrospective and of limited methodological rigour. Non-clinical psychedelic use: Among prospective longitudinal work, five cohort studies were noted (all within the past five years), with two providing evidence consistent with a protective effect of lifetime psychedelic use on subsequent suicidality. Three prospective studies reported reductions in suicidal ideation following psychedelic use in ceremonial or observational clinical contexts, with reductions linked to decreased experiential avoidance in at least two studies. Of 17 cross-sectional studies, the extracted text reports that 10 found an association between psychedelic use and increased suicidal ideation/attempts, whereas eight reported either reduced suicidality or no clear association; the authors note that some discordant findings arise from analyses of the same national data sets but differing adjustment for confounders. The review identified 11 deaths deemed reasonably linked to non-clinical psychedelic use (methods reported included jumping from heights, drowning, self-stabbing and others), though the authors emphasise such events were rare and that intent or substance confirmation was often unclear. The narrative cautions that non-controlled settings where individuals are alone and have access to lethal means may pose particular risks. Early psychedelic therapy reports: Sixteen early studies (case reports, case series, and clinician surveys) were summarised. Most did not demonstrate a clear elevation in suicidality attributable to psychedelic therapy beyond the baseline risk in severely ill psychiatric patients; several case reports described improvements in chronic suicidality. The authors identified six deaths temporally linked to early clinical psychedelic administration. Two survey-derived crude suicide rates from historical clinician reports were presented: Malleson’s UK data yielded 0.7/1,000 patients (from approximately 4,300 patients), and Cohen’s US survey reported 0/1,000 in experimental subjects and 0.4/1,000 in patients (from roughly 5,000 subjects). The authors compare these figures to a global suicide rate of 11.4/100,000 and to a substantially higher rate among psychiatric patients after hospital discharge (484/100,000), noting limitations of these historical data. Modern psychedelic therapy trials: The review identified two randomised controlled trials and three open-label trials that reported suicidality outcomes, although none were designed primarily to test effects on suicidality and many excluded participants at serious suicide risk. A wait-list-controlled crossover trial of psilocybin in major depressive disorder (N = 25) showed no significant between-group reduction in suicidality before crossover, but a significant decrease post-crossover with a large effect size; the authors note this could reflect regression to the mean or insufficient power. Open-label psilocybin trials in treatment-resistant depression reported significant reductions in suicidality at 1 and 2 weeks post-treatment, with later timepoints showing reductions that did not survive correction for multiple comparisons. A small RCT of ayahuasca versus placebo (N = 29) did not find a statistically significant between-group reduction in suicidality, though medium between-group and large within-group effect sizes were reported at early timepoints (days 1, 2, and 7). An open-label ayahuasca study reported rapid (within 40 minutes) and sustained decreases in suicidality up to 21 days. Across these trials, reductions in suicidality were strongly correlated with reductions in non-suicidal depressive symptoms, suggesting overlapping mechanisms. Key limitations noted by the authors include small sample sizes, exclusion of individuals with high suicide risk (creating possible floor effects where baseline suicidality is low), short follow-up durations (no assessments beyond 6 months reported), and frequent reliance on a single suicidality item drawn from depression scales rather than dedicated suicidality measures. Safety and adverse events: Modern trials did not report adverse suicide-related events or marked escalations in suicidality attributable to psychedelic administration. The authors attribute improved safety reporting in contemporary research to stricter screening (exclusion of serious suicide risk, bipolar or psychotic disorders) and greater attention to therapeutic setting. Nonetheless, early trials documented suicide-related adverse events, and the reviewers recommend careful risk-management when treating individuals with elevated suicidality.
Zeifman and colleagues interpret the evidence as preliminary and mixed but cautiously encouraging regarding therapeutic potential. They conclude that psychedelic therapy may be associated with acute and sustained reductions in suicidality in some clinical populations, and that non-clinical classic psychedelic use in some contexts may be associated with reduced suicidality; conversely, unmonitored use in unsafe environments can, on rare occasions, be linked to fatal outcomes. The authors emphasise that these conclusions are tentative given the limitations of the literature: only a small number of prospective trials exist (they state three small randomised trials and four additional prospective open-label trials), most reports are retrospective case series or case reports, and many studies did not measure suicidality as a primary outcome or use standardised suicidality instruments. The reviewers highlight methodological issues that likely contribute to inconsistent findings, including failure to control for psychiatric confounders in some cross-sectional analyses, publication bias (a tendency to publish negative outcomes while positive recreational outcomes go unreported), and reliance on self-report data. They also discuss plausible mechanisms for both increased and decreased suicidality: acute harms might arise from transient executive dysfunction or challenging experiences in uncontrolled contexts, whereas reductions might stem from decreases in experiential avoidance, improvements in depressive symptoms, psychological insight or emotional breakthroughs, immunomodulatory effects, or neurobiological changes such as altered functional connectivity or neuroplasticity. The extracted text notes that mechanistic work remains very limited. For clinical practice and future research, the authors recommend cautious, staged investigation of psychedelic therapy in individuals with elevated suicidality. Suggested safeguards include integrating psychedelic interventions with established suicidality-focused psychotherapies (for example dialectical behaviour therapy or cognitive behavioural therapy for suicide prevention), implementing suicide risk management protocols, maintaining participants in controlled environments until acute risk subsides, ongoing safety monitoring between sessions, and considering inpatient or residential settings when appropriate. They propose initially excluding imminently suicidal individuals or those with recent life-threatening attempts, with the possibility of expanding inclusion criteria if accumulating safety data support such a step. Finally, the authors call for larger prospective cohort studies of non-clinical use, adequately powered randomised controlled trials that recruit participants with clinically significant suicidality, use of validated suicidality measures (for example the Scale for Suicide Ideation, implicit association tests for death/suicide, and clinician-administered tools such as the Columbia Suicide Severity Rating Scale), and mechanistic research to clarify how classic psychedelics might influence suicidality.
others reporting that classic psychedelic use is linked with increased suicidality.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 psychedelicsand suicide rateswithin 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, see ref 22), including major depressive disorder (MDD),distress associated with life-threatening illness,alcohol abuse,smoking cessation,and obsessive-compulsive disorder.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.The existing evidence on this topic is indeed mixed and patchwork, as several early studies report instances of suicidality in the context of psychedelic therapy,and recent clinical trials have found that psychedelic therapy may be associated with decreases in suicidality among individuals with MDD.Given the importance of maximizing safety in psychedelic therapyand the need for innovative and rapidacting interventions for suicidality,a 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.
Study Selection and Inclusion. The initial database search yielded a total of 9667 potentially relevant records; 278 self-reported suicidal ideation or attempt over the past 6 months (yes/no) Lifetime use of a psychedelic was associated with reduced risk of onset of suicidality (aHR = 0.40, 95% CI 0.17-0.94). Argento et al.2018 N = 900; cohort of female sex workers; analyses conducted among individuals (n = 340) without lifetime suicidality at BL (n = 95 with lifetime psychedelic use). An overlapping (but nonidentical) sample was described in Argento et al.lifetime use of a psychedelic (LSD, psilocybin mushrooms, and MDMA) self-reported suicidal ideation or attempt over the past 6 months (yes/no) Lifetime use of a psychedelic moderated the relationship between prescription opioid use and risk of onset of suicidality (aHR = 0.64, 95% CI 0.94-7.14).
Ditman et al. descriptive Ten years after smoking cannabis that "...was presumed to be laced with LSD or PCP...", the patient was admitted to an acute psychiatric unit with symptoms consistent with hallucinogen persisting perception disorder. Prior to admission, the patient had attempted suicide three times. In the months following his discharge, patient completed suicide. LSD use descriptive The authors reported two cases of accidental death which may have been suicides. In one case, a young man walked into traffic shouting "halt" after he had taken LSD. In the other, a frequent user of LSD drowned soon after he had taken LSD alone on a beach. patient reported that a friend once tried to jump out of a window because he believed his body to be weightless. There are also reports of people walking out into the ocean but being stopped before any serious harm could occur." No significant decreases in suicidal ideation occurred over time, with a medium effect size (ηp2 = 0.12). At 1 day post-psilocybin, remission of suicidal ideation occurred (mean suicidal ideation = 0) across participants (mean reduction = -0.5). descriptive The authors described post-LSD therapy suicidal behavior not reported elsewhere in the present review: one completed suicide, two suicide attempts, and one instance of wrist slashing with a razor blade (not identified as a suicide attempt). The authors reported that "In only a very few instances a direct connection between the LSD experience and the movement toward self-destruction could be discerned..." and that "...all suicidal acts have been in disturbed patients rather than normal subjects." Among individuals that received psychedelic therapy, estimated rates were attempted suicide = 1.2/1000 and completed suicide = 0.4/1000, and in "experimental subjects", the rate was 0/1000 for both attempted and completed suicides. after LSD therapy). The authors described one suicide attempt (2 days after LSD therapy) and one instance of "...short-lived paranoid state with suicidal impulses..." immediately following LSD therapy and 3 months later. They also indicated that four individuals were "...considered to be in danger of injuring himself or committing suicide...".
Eisner and Cohen1958 N = 2; review; describes suicide-related outcomes not reported elsewhere experimental administration of LSD descriptive On the basis of personal communication, the authors reported two completed suicides. They also reported that "Personal contact with therapists using LSD-25 have turned up other cases of suicidal preoccupation and of actual suicide..." and "We are inclined to believe... that the possibility of suicide may be a real hazard, as it is in the treatment of any serious mental illness. From our experience... this danger appears to be restricted to the higher dosage level-those above 75 gamma-and an unfamiliarity with the drug."(psychedelic therapy) for the quality ratings of each study. See Tablefor an overview of all included studies' designs and quality appraisal ratings. The studies included in our review reflect the highly variable nature of evidence in this field, both in study design and in year of publication, and thus also in scientific standards and terminology used. The study methodologies used tend to approach the effects of psychedelics on suicidality from either a detrimental or beneficial therapeutic lens, a methodological bias that remains an unresolved issue in the field.Below, evidence from non-clinical classic psychedelic use and its association with suicidality is explored first, followed by a review of results from both early and late psychedelic therapy research. We conclude with an overview of the significance of these findings and their implications for future psychedelic research. Non-Clinical Classic Psychedelic Use and Suicidality. Several studies included in this review focused on classic psychedelic use outside the context of clinical studies. These studies describe the effects of recreational and ritualistic nonclinically sanctioned psychedelic use on suicidality across several population sample types, and they include data from as early as 1965. The five longitudinal cohort studies published were all completed within the past 5 years. Two of these studies provide support for a protective effect of classic psychedelic use on suicidality.Three studies showed support for classic psychedelic use (within contexts including ceremonial settings and within an observational clinical context) being associated with subsequent reductions in suicidal ideation.Both studies also found that reductions in suicidal ideation were associated with decreases in experiential avoidance, providing preliminary support for its potential role as a mechanism underlying the effects of classic psychedelic use on suicidality. As these studies are prospective, they lack the retrospective design bias of the studies below and point to the possibility that classic psychedelics may have a protective effect and may lead to reductions in suicidality in these specific populations. Of the 17 cross-sectional studies included in this review, 10 demonstrated an association between classic psychedelic use and increased suicidal ideation and/or attempts, while 8 studies showed either a potential association between classic psychedelic use and either reduced suicidality or no clear association. Of these studies, the largest and most compelling are from national survey data from the United States. Several cross-sectional studiessuggest that classic psychedelic use is associated with lower levels of suicidality, while two studiessuggest that psychedelic use is associated with higher levels of suicidality. Interestingly, the analysis of Nesvag et al.,which suggested that psychedelic use is associated with higher levels of suicidality, used the same data as Johansen and Krebs,who found that psychedelic use was associated with lower levels of suicidality. In response to the article by Nesvag et al.,Krebs and Johansenrebutted that there could be no clear conclusion drawn from the data and that there was no evidence to suggest an increased risk of suicidality in psychedelic users when accounting for multiple confounders (i.e., age, gender, race/ethnicity, income, education, marriage status, risky behaviors, presence of a depressive episode before age 18, and use of other illicit drugs), for which Nesvag et al.did not account. This is important, as many psychiatric covariates can significantly affect levels of suicidality in and of themselves. Similarly, Yockey et al.found an association between LSD use and past suicidal ideation in American young adults but failed to control for psychiatric confounds. Wong et al.also corroborated the finding of a positive association between psychedelic use and suicidality, although this analysis was done exclusively in high school students. Importantly, causality cannot be inferred from these results due to the crosssectional study designs. Additionally, few studies have included confounders of personality disorders (e.g., borderline personality disorder), another known major contributor to substance use 103 and suicidality.Of the 20 case reports, case series, and surveys (including convenience samples, general surveys, patient interviews, and a survey of adolescents in a drug treatment program) included in our systematic review, 13 suggest a possible association between psychedelic use and increased suicidality, while 5 do not suggest any clear association (see refs 59, 65, 66, 73, and 75). Several studies found evidence for cases of self-reported remission of suicidality following classic psychedelic use.In all the studies included in our review, we identified 11 deaths presumed to be completed suicides that can be fairly confidently linked to classic psychedelic use in a non-clinical context (four jumping from a height [of which one of these individuals was also intoxicated on alcohol], one walking into traffic [unclear intent], one drowning [alone on the beach with unclear intent], two self-stabbing with a sharp object or knife, and three with unclear methods). This supports the notion that noncontrolled environments where individuals are by themselves and have access to means for suicide, such as heights with no barriers and objects that can lead to hanging or self-stabbing, are likely unsafe contexts for psychedelic use, especially among individuals presenting with prior suicide risk. There is much evidence suggesting that restricting access to lethal means is a key method for suicide prevention in general,and it stands to reason that for those using psychedelic substances in non-clinical settings, the pre-emptive restriction of lethal means could help reduce the risk of suicide. It is important to note that it was often unclear if the substance used was, in fact, a classic psychedelic, and that instances of suicide associated with psychedelic use were rare. Accordingly, while classic psychedelic use is not without potential risks, the results of the present systematic review are in line with past research suggesting that classic psychedelics show a fairly strong safety profile (e.g., low risk of abuse or harm).Additionally, this relative risk needs to be considered in comparison with the greater risk associated with other substances that have been linked with suicide and suicide attempts, including recreational (e.g., acute alcohol use is strongly associated with increased likelihood of attempting suicide, OR = 6.97, 95% CI = 4.77-10.17) 109 and pharmaceutical drugs (e.g., benzodiazepines 110 and potentially selective serotonin reuptake inhibitors).It is also likely the case there is a publication bias toward negative outcomes in this portion of the literature, as positive outcomes of recreational psychedelic use are rarely brought to medical attention and are therefore unlikely to be published. Overall, research on the effects of non-clinical psychedelic use on suicidality is mixed and hampered by reliance on selfreported data. This is in addition to the fact that suicidality is an inherently difficult area of study given the rarity of actual suicide completions. Preregistered analyses, using large prospective national registries with extensive information on substance use history and psychiatric and demographic factors, will be important for shedding light on the true nature of the effects of psychedelic use on suicidality outside clinical settings. Psychedelic Therapy and Suicidality. Early Psychedelic Therapy Research and Suicidality. Results from our review tabulate 16 early studies that describe the effects of psychedelic therapy (specifically classic psychedelics) on suicidality. These are limited to case reports, case series, and surveys, which echo the above notion of the limited evidence available in this field up until the past several years. These studies were not prospectively designed to investigate the effects of psychedelics on suicidality and represent retrospective reports. In these 16 studies, there are several large case series completed on patients with a mixture of psychiatric diagnoses, many with antiquated diagnoses no longer in use. Nonetheless, the majority of these studies do not suggest an increased suicidality risk with psychedelic therapy above baseline, especially given the high inherent risk of suicide in these subjects diagnosed with chronic and severe mental illness.In addition to these case series, several individual case reports attempt to shed light on the relationship between psychedelic therapy and suicidality. Two studies suggest a potential causative effect of psychedelics on increased suicidality in patients treated with psychedelic therapy.However, several case reports specifically describe clear improvement in chronic suicidality attributed to psychedelic therapy.In these studies, we identified a total of 6 deaths presumed to be completed suicides that can be reasonably linked temporally to early psychedelic therapy (1 after LSD treatment in a previously suicidal patient; 1 after LSD treatment in a patient with character neurosis; 3 with a temporal relation to psychedelic administration; and 1 in an inpatient with schizophrenia receiving weekly LSD treatment who completed suicide on a day pass). Overall, while limited in number and quality of evidence, these reports do not suggest a strong association between psychedelic therapy and suicidality from this first wave of early research. Analysis of the rate of completed suicide in these study populations can crudely demonstrate the relative frequency of completed suicide in comparison to known modern suicide rates. The data from these early psychedelic therapy studies come from two nonsystematic survey studies in which authors attempted to survey, presumably by mail, local clinicians who were providing psychedelic therapy. In a UK sample, Malleson derived a suicide rate of 0.7/1000 patients out of 4300 total patients described by respondents.In a US survey, Cohen describes a suicide rate of 0/1000 in experimental subjects and 0.4/1000 in patients undergoing therapy out of a total of approximately 5000 subjects. It is important to note that the patients in these studies were often treated on multiple occasions potentially over several years and included individuals with psychotic and other severe mental illnesses. Also, psychedelic treatment could not always be causally linked to the completed suicide in these studies. These suicide rates are higher than the current global suicide rate of 11.4/100,000, yet they are far lower than the suicide rate of modern psychiatric patients around the time of hospital discharge, 484/ 100,000, which likely represents a more appropriate comparator sample.In sum, while these early studies lack rigorous methodology, they suggest that there is limited evidence to associate psychedelic therapy with increased risk of suicidality, and they point toward improvement in suicidality in select cases and the overall relative safety with regards to suicidality of administering psychedelics in controlled settings, even in presumed high-risk patient populations. Modern Psychedelic Therapy Research and Suicidality. To date, although no clinical trials have been designed to evaluate the effect of psychedelic therapy on suicidality, several trials have reported on the effect of psychedelic therapy on suicidality. Importantly, given that these trials have not specifically recruited individuals high in suicidality and have included individuals with no suicidality at baseline, these studies may be confounded by potential floor effects. We identified two randomized controlled trials and three openlabel trials that examined the effect of psychedelic therapy on suicidality. In a small (N = 25) wait-list-controlled crossover trial, individuals with MDD were assigned to either psilocybin therapy or wait-list control followed by psilocybin therapy. Before crossover, reductions suicidality in the psilocybin condition were not significantly greater than those in the wait list condition.Post-crossover, there was a significant decrease in suicidality with a large effect size. These results do not provide conclusive evidence for psilocybin therapy causing reductions in suicidality, as the post-crossover results may be due to the passage of time itself (e.g., regression to the mean). Alternatively, the non-significant effect before crossover may be attributable to a lack of power to detect significant effects relative to the control condition. In an open-label trial, following psilocybin therapy, individuals with treatmentresistant depression showed significant reductions in suicidality at 1 and 2 weeks post-treatment.Of note, individuals also showed decreases in suicidality at 3 and 5 weeks posttreatment; however, these reductions were no longer significant after Bonferroni correction. In an open-label trial, individuals with HIV-related demoralization received group therapy and a single dose of psilocybin.Results showed remission from suicidality across all participants at 1 day postpsilocybin administration and a non-significant reduction in suicidality at post-treatment (3 weeks post-psilocybin), with a medium-large effect size.Within a small (N = 29) randomized controlled trial, individuals with treatmentresistant depression received either ayahuasca or placebo. Compared with placebo, ayahuasca was not associated with a significant reduction in suicidality but was associated with a medium between-group effect size.Furthermore, ayahuasca was associated with a large within-group effect size for decreases in suicidality at 1, 2, and 7 days post-ayahuasca. Similarly, in an open-label study, following a single administration of ayahuasca, individuals with recurrent MDD showed rapid (i.e., within 40 min of administration) and significant decreases in suicidality, as well as large and sustained reductions in suicidality 1, 7, 14, and 21 days later.Both of these studiesfound a strong relationship between reductions in suicidality and non-suicidal depressive symptoms, suggesting that there may be overlapping mechanisms between the effects of psychedelic therapy on global depressive symptoms and suicidality. In sum, the above results provide preliminary evidence that psychedelic therapy may be associated with acute and sustained reductions in suicidality. However, the efficacy of psychedelic therapy compared with wait-list-or placebocontrolled conditions has not yet been established. Additional important limitations include the use of small sample sizes, studies not specifically recruiting individuals high in suicidality (and frequently excluding individuals high in suicide risk), relatively short duration of suicidality assessment (i.e., no assessments more than 6 months post-treatment), and frequent measurement of suicidality using a single item from a depression severity measure. Additionally, to date, only one study has examined the acute effect of psychedelic therapy on suicidality. Therefore, while there may be preliminary evidence for the potentially rapid-acting effect of psychedelic therapy on suicidality, there remains a need for adequately powered randomized controlled trials that are designed to examine the effect of psychedelic therapy on suicidality. Importantly, within modern psychedelic therapy clinical trials, no adverse suicide-related events or significant escalations of suicidality due to the administration of a psychedelic have been reported, suggesting that modern psychedelic therapy shows a strong safety profile. Although we identified several instances of suicide-related adverse events that occurred in early psychedelic therapy trials, the positive safety outcomes associated with modern psychedelic therapy research may be attributable to several factors including more rigorous screening before participants are enrolled in trials (e.g., serious suicide risk was an exclusion in some trials, and the presence of bipolar and psychotic-related disorders have consistently been exclusion criteria)and closer attention to and understanding of the importance of the therapeutic frame within psychedelic therapy. As research continues to relax exclusion criteria (e.g., for a recent trial specifically recruiting individuals with bipolar disorder II; see clinicaltrials.gov NCT 04433845) and potentially aim to target individuals high in suicide-risk, even greater attention will need to be placed on the importance of the therapeutic intervention and the environment in which the psychedelic is administered. Accordingly, above and beyond the traditional psychedelic therapy safety guidelines,we provide several recommendations for minimizing risks when providing psychedelic therapy to individuals high in suicide risk. First, we suggest that integrating psychedelic therapies with evidence-based interventions for suicidality (e.g., dialectical behavior therapy, 114 cognitive behavioral therapy for suicide prevention) 115 may help to maximize safety and treatment outcomes (for further discussion, see ref 116). At a minimum, we advise that a suicide risk management protocol 117 should be included when providing psychedelic therapy to individuals high in suicide risk. Second, following psychedelic therapy sessions, participants should remain in a controlled environment until potential suicide risks are minimized or assessment indicates that there are no significant elevations in suicidality. Additionally, safety monitoring should occur between psychedelic therapy sessions. When feasible, providing psychedelic therapy within an inpatient or residential treatment context may also help to ensure that the intervention is tolerated and safe. Third, to minimize potential risks, initial research may examine the safety and efficacy of psychedelic therapy among individuals with elevated levels of suicidality (e.g., clinically significant suicidal ideation without current intent), while excluding individuals that are imminently suicidal or those with a recent (i.e., within the past 2 months) life-threatening suicide attempt. Should the safety-related data from such research continue to suggest that psychedelic therapy is safe, tolerable, and potentially efficacious within these populations, psychedelic therapy could then be examined among individuals with even more severe presentations. ■ CONCLUSIONS, LIMITATIONS, AND FUTURE DIRECTIONS This is the first systematic review to explore the effects of classic psychedelics on suicidality in both clinical and nonclinical settings. The results suggest that psychedelic therapy may be beneficial in reducing suicidality in certain diagnosed, clinical psychiatric populations and that classic psychedelic use may buffer against, and may be associated with reductions in, suicidality. However, within unsafe and un-monitored settings, psychedelic use can on rare occasions also lead to fatal consequences including suicide. These conclusions are preliminary given the highly limited nature of the source literature; this review includes only three small prospective, randomized trials and only four additional prospective, small open-label trials. The majority of the studies included are small case reports or case series with mostly retrospective data. Our study is limited by the publication record on this topic itself, as there was a significant paucity of published reports on psychedelics in general between the initial wave of studies in the 1960s and more recent trials. Also, the vast majority of the studies included do not list suicidality as a primary outcome, and many do not use standardized scales to measure suicidality in their reports. While there is support for using single-items from depression severity measures to assess suicidality,future research would benefit from including measures specifically designed to assess suicidality (e.g., Scale for Suicide Ideation), 120 implicit measures of suicidality (e.g., Death/ Suicide Implicit Association Test), 121 and clinician-administered measures that assess both suicidal ideation and suicidal behaviors (e.g., Columbia Suicide Severity Rating Scales).Finally, there remains a very limited understanding of the putative mechanisms of action through which classic psychedelics may affect suicidality, as explored below. In reviewing the theoretical mechanisms of action of psychedelics on suicidality, the potential for increased suicidality may be attributable to acutely impaired executive functioning 122 or challenging emotional experiences,especially when used without paying appropriate attention to context (e.g., within non-clinical contexts).In terms of reduced suicidality potentially associated with classic psychedelics, several studies suggest that this may be attributable to decreases in experiential avoidance and mechanisms that overlap with decreases in depression severity. However, this research remains preliminary. Additional research that examines the experiential (e.g., insight 124 and emotional breakthrough), 125 psychological (e.g., reduced distress,emotional avoidance,and revised maladaptive beliefs), 126 immunomodulatory,and neurobiological (e.g., potential neuroplastic effects, 128,129 acute increases in entropy,and changes in functional connectivity) 131 effects of psychedelics may shed light on how classic psychedelics affect suicidality. Such research may also provide guidance on how psychedelic therapy may be used to help those struggling with this potentially life-threatening presentation. Future large, prospective cohort studies may elucidate the effects of non-clinical classic psychedelic use on suicidality in the general public, while large, prospective clinical trials and meta-analyses of existing data sets may help to confirm the potential therapeutic role of psychedelic therapy in treating suicidality in psychiatric patients.
This systematic review is reported in accordance with the PRISMA guidelines.The protocol for this study was registered with PROSPERO (CRD42020158443). Search Strategy and Selection Criteria. We searched MEDLINE, PsycINFO, and PubMed databases on March 28, 2020 from their respective inception dates, without time or language restrictions, using the following terms: (psychedelic* OR hallucinogen* OR psilocybin OR ayahuasca OR DMT OR dimethyltryptamine OR mescaline OR peyote OR LSD OR lysergic acid diethylamide) AND (mood* OR distress* OR depress* OR suicid* OR PTSD* OR post-trauma* OR post trauma* OR posttrauma* OR anxiety* OR schizophren* OR bipolar). All studies involving the association between, or effect of, classical psychedelics (non-clinical classic psychedelic use and psychedelic therapy) and suicidality outcomes were eligible for inclusion in this systematic review. Studies were excluded if they focused on psychedelic microdosing or examined the effects of psychoactive compounds not considered classic psychedelics (e.g., ketamine, benzodiazepines, cannabis, 3,4-methylenedioxymethamphetamine [MDMA]). There were no exclusion criteria related to gender, age, psychiatric diagnoses, or year of publication. The search was repeated on November 5, 2020 to identify any articles published after the original search was performed. Additionally, we searched the reference lists of eligible studies and review articles to identify further relevant studies. Data Extraction. After duplicates were removed, two reviewers (N.S. and R.J.Z.) independently screened all titles and abstracts based on the identified inclusion and exclusion criteria to remove irrelevant records. They then independently screened all remaining full-text articles according to the same eligibility criteria. Consensus on all items was reached through discussion over any disagreements, with a third reviewer (C.R.W.) consulted when necessary. Two authors (R.J.Z. and L.B.) subsequently extracted the following data from the included studies: study authors, publication year, study design, study duration, inclusion/exclusion criteria, participant demographics, baseline characteristics, sample size and descriptions of groups, details on classic psychedelic use and interventions, suicidality outcome measures and items used, and suicidality outcomes. In cases where suicidality-related data were reviewed in a manuscript, but the primary source of the report was not accessible, available data were extracted from the secondary source. Quality Appraisal. We assessed the methodological quality of included studies using the Oxford Centre for Evidence Based Medicine (OCEBM) Levels of Evidence.This approach is designed to enable a critical appraisal of papers using any methodology, in contrast to tools that are specifically designed to evaluate only the quality of a given methodology (e.g., qualitative papers or randomized controlled trials). Scores are in the range of levels 1-5, with 1 corresponding with the highest quality of evidence and 5 with the lowest. This assessment was performed by one author (N.S.) and verified
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