Combating Suicidality: A Role for Psilocybin and Ayahuasca?

Suicidality broadly encompasses behaviors involving thoughts, intent, or plans pertaining to suicide, a critical determinant of suicide that affects more individuals than completed suicides.¹ In the United States in 2019, approximately 12 million individuals reported suicidal ideation, with 3.5 million having planned for suicides and 1.4 million making actual attempts.² Thus, timely interventions are of increasingly high necessity. One such intervention that has shown early promise is psychedelics-assisted therapy.

With the recent advancements in research, the conventional fear about psychedelics as substances precipitating suicidality or self-harm brought about by the moral panic of the mid-1900s is slowly starting to fade. A new wave of clinical trials show that psychedelics may exhibit therapeutic properties, in contrast to historical beliefs about its adverse outcomes such as in the instances of Frank Olson in 1953 and Diane Linkletter in 1969, both of whom died under the influence of LSD.³ Although anecdotal reports of elevated suicidality still permeate to this day, mounting evidence to the contrary points to psychedelics’ potential as a promising therapy for suicidality. In particular, a survey study published in 2016 examining the immediate and enduring effects of challenging psilocybin experiences noted increased suicidality in 5/1993 (0.25%) individuals and remission of suicidality in 6/1993 (0.3%).⁴ Previous work by Hendricks and colleagues have shown significant reductions across all parameters of suicidality associated with lifetime psychedelic use: past-year suicidal thinking, past-year suicidal planning, and past-year attempt.⁵

The Clinical Efficacy of Psilocybin and Ayahuasca

A recent meta-analysis by Zeifman and colleagues investigated the impact of psychedelic therapy on suicidality.⁶ Seven studies, consisting of both open-label and crossover designs, were included as part of the analysis. Two of the studies used ayahuasca whereas the rest involved psilocybin. The samples analyzed included indications such as recurrent major depressive disorder (MDD), treatment-resistant MDD, AIDS-associated demoralization, and terminal cancer distress. 31 subjects were analyzed during the acute period (40 to 240 minutes) following dosing for the two studies with ayahuasca, and 168 subjects administered ayahuasca or psilocybin were assessed in the post-acute period (1 day to 3-4 months) for all 6 studies.

Broadly, the results revealed that psychedelics significantly lowered suicidality in the acute period post-dosing that persisted for as long as 6 months later in the post-acute period, with the exception of the 7-8 weeks timepoint. The magnitude of the effects during the acute and post-acute periods were especially large, and at 6 months post-treatment a medium magnitude of change from baseline was reported. Of note, two subjects among the 31 (6.5%) in the ayahuasca group evaluated during the acute period had +1 increase in their suicidality score–one at 40 and the other at 140 minutes–compared to baseline, which decreased to 0 at subsequent time points of assessment. Five of the 168 subjects (3.0%) showed +1 increase in their suicidality score at the first post-acute assessment, with four of them returning to baseline by the end of treatment.

It is worthwhile to mention that the decrease in suicidality was observed across a range of psychopathologies. None of the included studies reported a suicide-related adverse event, but an updated correction to the publication reported two suicidality-related events pertaining to psilocybin administration. However, they were later deemed likely not attributable to the psychedelic therapy. Although the safety profile of psychedelics seem promising from these observations, it is crucial to proceed with caution with regards to future study designs.

The putative underlying mechanisms contributing to the reduction in suicidality with psychedelics include their modulation of inflammation, modification of the serotonergic pathways, altered connectivity, augmentation of brain-derived neurotrophic factors, neurogenesis, and neuroplasticity.⁶ Psychologically, the acute psychedelic trips can also serve to open up the mind and pave the way for profound insights by means of relaxing maladaptive beliefs of the past, which may include beliefs surrounding guilt or worthlessness that drive one toward suicidal thoughts and behaviors.

A few limitations of this meta-analysis warrant discussion. For one, the data were extracted from a relatively small sample size of participants, as well as a heterogeneous sample of studies that was not examining the impact of psychedelics on suicidality in particular. Furthermore, the exclusion criteria for many of these trials covered participants with a history of suicide attempts or high risks for suicide, effectively singling out the subset of individuals with milder cases for analyses. Another source of concern is the open-label design used by three of the studies–meaning that the participants are aware of the treatment given, and therefore, the potential confounding with placebo effects.

Risk Minimization

In order to minimize the adverse effects of increased suicidality and improve treatment outcomes, integration of psychedelics with behavioral therapies, such as cognitive-behavioral therapy, is essential. Additionally, the judicious use of a controlled setting with expert facilitators, inclusion of a specific protocol for suicide risk management, and regular assessments of suicidality throughout the course of therapy can all can promote safety and effectiveness.^7,8  Rigorous screening prior to participant enrollment in trials for high-risk indications such as psychosis-related disorders and bipolar I disorder is also warranted.⁹

Conclusion and Future Directions

The recently published meta-analysis by Zeifman and colleagues sheds light on the potential therapeutic efficacy of psychedelics-assisted psychotherapy for suicidality in commonly encountered mental health conditions such as depression and existential distress. The overwhelming majority of subjects in these trials experienced symptomatic improvement, with only a handful of exceptions that resolved by end of the dosing session or the course of treatment. Further clinical trials are warranted to elucidate the impact of individual psychedelics (e.g. psilocybin, LSD, ayahuasca), dosage, therapy modalities, and amount of psychological support. More significantly, as noted in the limitations, robust studies are needed to assess the subset of individuals with higher risks for suicidality, if such trials can be conducted safely and ethically. It is important to tease out whether the therapeutic effects of psychedelics may be stratified by the severity of the indication, or whether they may be efficacious regardless of the severity.

Melinda Wang

Mengning (Melinda) Wang is a medical student at the David Geffen School of Medicine at UCLA and a research assistant at the Translational Psychedelic Research Program at UCSF, investigating the therapeutic potential of psychedelic compounds for various neuropsychiatric indications.

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