The Impact of Ayahuasca on Suicidality: Results From a Randomized Controlled Trial

This analysis of a double-blind, parallel-arm, randomized placebo-controlled trial (n=29) investigates the impact of ayahuasca on suicidality (SI) in individuals with treatment-resistant depression (TRD). It found that ayahuasca may show potential as a fast-acting and innovative intervention for SI but didn’t find significant results (only a trend with a large effect size). This is the first study to investigate ayahuasca for SI.

Abstract

“Suicide is a major public health problem. Given increasing suicide rates and limitations surrounding current interventions, there is an urgent need for innovative interventions for suicidality. Although ayahuasca has been shown to target mental health concerns associated with suicidality (i.e., depression and hopelessness), research has not yet explored the impact of ayahuasca on suicidality. Therefore, we conducted secondary analyses of a randomized placebo-controlled trial in which individuals with treatment-resistant depression were administered one dose of ayahuasca (n = 14) or placebo (n = 15). Suicidality was assessed by a trained psychiatrist at baseline, as well as 1 day, 2 days, and 7 days after the intervention. A fixed-effects linear mixed model, as well as between and within-groups Cohen’s d effect sizes were used to examine changes in suicidality. Controlling for baseline suicidality, we found a significant effect for time (p < .05). The effect of the intervention (i.e., ayahuasca vs. placebo) trended toward significance (p = .088). At all time points, we found medium between-group effect sizes (i.e., ayahuasca vs. placebo; day 1 Cohen’s d = 0.58; day 2 d = 0.56; day 7 d = 0.67), as well as large within-group (ayahuasca; day 1 Cohen’s d = 1.33; day 2 d = 1.42; day 7 d = 1.19) effect sizes, for decreases in suicidality.

Conclusions: This research is the first to explore the impact of ayahuasca on suicidality. The findings suggest that ayahuasca may show potential as an intervention for suicidality. We highlight important limitations of the study, potential mechanisms, and future directions for research on ayahuasca as an intervention for suicidality.”

Authors: Richard J. Zeifman, Fernanda Palhano-Fontes, Jaime Hallak, Emerson Arcoverde, João Paulo Maia-Oliveira & Draulio B. Araujo

Summary

INTRODUCTION

Suicide is a public health issue of major concern, and suicide rates have been increasing within the United States. Individuals with comorbid major depressive disorder and borderline personality disorder exhibit especially heightened levels of suicidality.

A number of interventions are effective for treating suicidality, including electroconvulsive therapy, psychotherapy, and pharmacological interventions. However, there remain a number of important limitations surrounding current interventions for suicidality, including non-immediate effects, limited treatment availability, negative side-effects, and the need for ongoing administration.

Novel Interventions for Suicidality

A recent meta-analysis of randomized controlled trials found that ketamine had medium to large between-group effect sizes on suicidality, but the effects began to decrease within a week after administration. Moreover, there is no evidence that ketamine’s effects were long-lasting.

Psychedelics are potentially promising novel interventions for suicidality, as they induce changes in affect, cognition, and perception, as well as non-ordinary states of consciousness at high doses.

Cross-sectional and longitudinal research indicates that lifetime use of psychedelics is associated with lower levels of suicidality. However, it is unclear whether these effects are due to factors associated with psychedelic use, such as personality.

To date, only one study has explored the impact of psychedelics on suicidality. The study used self-reported suicidality and an open-label design, and was limited by the open-label design and self-reported design.

Research suggests that psychedelics, such as psilocybin and ayahuasca, can reduce mental health concerns associated with suicidality, such as depression and hopelessness. However, suicidality can occur independent from depressive symptoms, and decreases in depressive symptoms are not always associated with decreases in suicidality.

Suicide is an increasingly problematic mental health concern, and ayahuasca and psilocybin have shown promise as interventions for a wide range of mental health issues associated with suicidality. However, research has not yet explored whether the administration of ayahuasca leads to decreases in suicidality.

Procedures

We conducted secondary analyses of a double-blind, parallel-arm, randomized placebo-controlled trial for individuals with treatment-resistant major depressive disorder (MDD). Participants were recruited via referral from outpatient psychiatric units and advertisement, and were randomly assigned to either the ayahuasca or placebo group.

Participants were instructed to stop their antidepressants 2 weeks prior to the intervention and to stop using benzodiazepines 7 days post-intervention. They listened to a predefined music playlist throughout the intervention.

Participants were administered a single 1 ml/kg dose of either ayahuasca or a placebo, and were observed for 7 days. Suicidality was assessed at baseline, 1 day, 2 days, and 7 days after the intervention.

MEASURES

The Montgomery-sberg Depression Rating Scale is a 10-item, clinician-administered measure of depression severity. It includes one item that assesses current suicidality, and the sum of the remaining nine items is used to measure non-suicidal-related depressive symptoms.

Statistical Analysis

We used a modified intention-to-treat analysis to examine changes in MADRS-SI and MADRS-totalnonSI scores 1 day, 2 days, and 7 days after the intervention, in both the ayahuasca and placebo groups. We calculated Pearson correlation coefficients for the relationship between changes in MADRS-SI and MADRS-totalnonSI scores 7 days after the intervention.

Demographics

The majority of participants were female, Caucasian, unemployed, had a lifetime suicide attempt, and a comorbid personality disorder. Nine participants had a diagnosis of BPD.

Clinical Response

Results showed that time and ayahuasca had a significant effect on suicidality, but the interaction between time and ayahuasca was not significant.

We found medium between-group and within-group effect sizes for decreases in MADRS-SI for ayahuasca, as well as large within-group effect sizes for decreases in MADRS-SI for ayahuasca, as well as small effect sizes for placebo, 1 day and 7 day after the intervention.

Association Between Changes in Suicidality and Depressive Symptoms

Seven days after the intervention, the association between changes in suicidality and changes in non-suicide-related depressive symptoms approached significance in the ayahuasca group.

DISCUSSION

This study aimed to fill a gap in the research on ayahuasca and suicidality by exploring the impact of ayahuasca on suicidality.

Although there was a significant decrease in suicidality across groups, the effect for the treatment group (i.e., ayahuasca vs. placebo) trended toward but did not reach significance. This could be because the study was underpowered to detect the impact of ayahuasca on suicidality.

Ayahuasca administration is associated with improvement in mental health concerns associated with suicidality, but the impact on non-suicide-related depressive symptoms was larger than the impact on suicidality.

Ayahuasca may have a fast-acting impact on suicidality, similar to the fast-acting effects of ketamine on suicidality. This is important because the time between the emergence of suicidality and suicide can be very short.

We found that ayahuasca, psilocybin, and traditional interventions for suicidality all had similar medium between-group and large within-group effect sizes for decreases in suicidality at all time points. These results suggest that ayahuasca may show promise as an intervention for suicidality that does not require repeated administration. Within the ayahuasca group, the relationship between suicidality and non-suicide-related depressive symptoms approached significance, with a large effect size. Research indicates that suicide functions as a means of escaping intense emotional distress. Ayahuasca may decrease emotional distress via increased mindfulness-related capacities, which are associated with decreased levels of emotion dysregulation. Neurobiological research suggests that ayahuasca may impact suicidality by decreasing emotion dysregulation, and that administering psychedelics to rats promotes neuroplasticity, within the prefrontal cortex, a region of the brain implicated in emotion dysregulation and suicidality.

Personality Disorder

In a study of individuals with BPD traits, ayahuasca administration led to decreases in components of emotion dysregulation, but no serious adverse events occurred and no clinically significant suicidality was reported 1 or 2 days after administration. The results of this study must be interpreted with caution, but the wide-ranging mental health concerns for which psychedelics have shown promise warrant further research.

Strengths, limitations, and Future Direction

This study utilized a double-blind randomized placebo-controlled design and included individuals without past experience with psychedelics. The sample used in the study showed severe psychiatric comorbidity and had failed to respond to as many as 10 interventions.

The primary limitation of the present study is that suicidality among those in the placebo group was low, and the sample size was small. Therefore, additional placebo-controlled research on the impact of ayahuasca on suicidality will be important. The present study did not include individuals with imminent suicide risk, and the suicidality exclusion criteria were less strict than past studies on pharmacological interventions for suicidality. Future research should explore the impact of ayahuasca on suicidality among individuals with higher levels of suicidality.

This study suggests that ayahuasca may show promise as a fast-acting and innovative intervention for suicidality, but more research is needed to determine its long-term impact.