Evaluating the Risk of Psilocybin for the Treatment of Bipolar Depression: A Review of the Research Literature and Published Case Studies

This review (2021) finds that in the current literature there are some known, but limited, risks of activating mania with psilocybin for those with bipolar depression (BD). The review describes 17 cases of BD and the use of a range of psychedelics.

Abstract

“Growing evidence suggests that psilocybin, the active ingredient in hallucinogenic mushrooms, can rapidly and durably improve symptoms of depression, leading to recent breakthrough status designation by the FDA and legalization for mental health treatment in some jurisdictions. Depression in bipolar disorder is associated with significant morbidity and has few effective treatments. However, there is little available scientific data on the risk of psilocybin use in people with bipolar disorder. Individuals with bipolar disorder have been excluded from modern clinical trials, out of understandable concerns of activating mania or worsening the illness course. As psilocybin becomes more available, people with these disorders will likely seek psilocybin treatment for depression and have likely already been doing so in unregulated settings. Our goal here is to summarize the known risks of psilocybin use (and similar substances) in bipolar disorder and to systematically evaluate examples of published case history data, in order to critically evaluate the relative risk of psilocybin as a treatment for bipolar depression. We found 17 cases suggesting that there is potential risk for activating a manic episode, thereby warranting caution. Nonetheless, the relative lack of systematic data or common case examples indicating risk appears to show that a cautious trial, using modern trial methods focusing on appropriate ‘set’ and ‘setting’, targeted at those lowest at risk for mania in the bipolar spectrum (e.g., bipolar 2 disorder), is very much needed, especially given the degree to which depression impacts this population.”

Authors: David Gard, Mollie M. Pleet, Ellen R. Bradley, Andrew Penn, Matthew L. Gallenstein, Lauren S. Riley, Meghan DellaCrosse, Emily Garfinkle, Erin E. Michalak & Joshua D. Woolley

Summary

Corresponding author: David E. Gard, Ph.D.

We evaluated the risk of using psilocybin (and similar substances) as a treatment of depression in bipolar disorder, including a systematic assessment of published case histories. We concluded that there is some evidence of risk of activating mania with these substances, but that the risk does not appear to be strong or overwhelming.

Bipolar disorder is associated with high suicide rates, decreased quality of life, and impaired overall functioning. Psilocybin, a psychedelic compound, has recently received breakthrough therapy designation by the Food and Drug Administration. Psilocybin, a hallucinogenic compound found in several species of mushrooms, has been used in religious and healing practices by Indigenous peoples for millennia. Although societal views of psychedelic use have been critical, recent research suggests that use of these drugs may be associated with mental health benefits.

Modern psilocybin trials have emphasized optimal conditions for the psychedelic experience, including rapport-building with study staff, attention to the physical space to enhance comfort and safety, and post-drug session meetings to discuss the experience.

Modern clinical trials with psychedelics exclude individuals with bipolar disorder or a family history of bipolar disorder, for several reasons, including the potential for adverse events and the potential for TEAS.

Psilocybin and transcranial magnetic stimulation can induce TEASs, but the risk is higher in response to serotonergic antidepressants, such as SSRIs, SNRIs, and most tricyclic antidepressants. However, evidence suggests that serotonergic antidepressants may be effective without inducing enduring switches of mood polarity. Although the risk of TEAS after a single psychedelic dose is currently unknown, there are reasons to be concerned because psilocybin is a potent antidepressant and psilocin, the active metabolite of psilocybin, has related serotonin mechanisms of action, which could theoretically promote TEASs. Psilocybin is administered in a distinctly different way from standard antidepressants, and produces profound subjective effects during the period of intoxication.

Although all individuals with bipolar disorder or a first degree relative with bipolar disorder have been excluded from recent psychedelic research, there have been no instances of prolonged psychosis, mania, persisting perceptual changes, or other long-term functional impairment in any participants. Early research on LSD and other psychedelics did attempt to treat individuals with bipolar disorder. However, there was no reported follow up on how the patients fared, and it is impossible to disentangle the immediate effects of the substance from what might have occurred later. Epidemiology research on psychedelic use indicates that psilocybin and other psychedelics are not associated with bipolar disorder. However, there are reports of people using psychedelics who have experienced psychotic symptoms or have experienced a manic episode. Researchers examined the number of cases of psychosis and bipolar disorders following ayahuasca use and concluded that the number of cases was slightly less than the expected in the base rate of the population.

We reviewed the case study literature on adverse effects of psilocybin (and related psychedelics) in individuals with bipolar disorder, and the potential for these substances to activate a manic episode. We focused on the risk of activating a manic episode, and not a psychotic episode.

A comprehensive search was conducted using the following electronic databases: PubMed, Web of Science, and PsychInfo. Four non-overlapping case studies were found, and the search was expanded to include all classic psychedelics.

Additional inclusion/exclusion criteria

We included case studies if they described an individual who had taken a psychedelic substance and had persistent adverse effects, if the adverse effects were interpreted as mania or positive symptoms of psychosis, and if the adverse effects lasted at least 4 days. We included individuals who had psychosis symptoms or adverse events but did not also have mania or hypomania or a diagnosis of bipolar disorder.

Process

Two authors independently reviewed all electronic databases, and four authors conferred to make final decisions when it was unclear whether a case met specific criteria. In total, 43 cases were initially included, and 28 were excluded based on criteria 3-6.

In total, 15 published case studies met all of the selection criteria, four of which involved psilocybin. Two of the 15 cases involved individuals with a diagnosis of bipolar disorder or a previous history of manic/hypomanic symptoms who had an adverse outcome after taking a psychedelic substance. A psychiatrist with bipolar disorder type I self-medicated with DMT and phenelzine for 6 months. His manic episode was precipitated by factors unknown. A 30-year-old man developed symptoms of mania, delusions, and hallucinations two days after participating in a four-day ayahuasca retreat.

The author of this article may have developed mania even without using psychedelics, and he may have taken a psychedelic substance without any other substance or a polysubstance use history. A 31-year-old man took LSD one time, experienced decreased sleep and an increased focus on religious themes, broke into a neighbor’s house, and was hospitalized and treated successfully with lithium. A 21-year-old woman had persistent manic and psychotic symptoms one week after taking LSD. The authors of this paper found that 12 out of 15 cases of manic episodes after taking a psychedelic substance involved recreational use, leaving three exceptions: a psychiatrist who was self-medicating with DMT and a 30-year-old man with a history of hypomania who participated in a four-day ayahuasca retreat.

We found a number of published cases of serious adverse outcomes, including severe medical accidents, death, and possible suicides, but we did not find any published cases of an individual with a diagnosis of bipolar spectrum disorder dying due to an accident or suicide.

The present review focused on the evidence of risk that psilocybin confers in bipolar disorder. It found that several factors related to psychedelic use may contribute to the risk of a manic episode in this population. Though there are a significant number of case studies linking psychedelic use to mania induction, the overall rate of inducing mania may be relatively low, and there are no cases of people with or without a history of bipolar disorder developing mania after a clear single ingestion of a psychedelic. This systematic review of the published case study literature on psilocybin shows that little is known about the effects of psychedelics on individuals with bipolar disorder. More research is needed. While this review has focused on the potential risks of psychedelic treatments for individuals with bipolar disorder, one case study implicated an accidental LSD overdose in the remission of bipolar disorder for over 20 years. Psychedelic drugs may be challenging for people with bipolar disorder, especially given the feelings of euphoria that often accompany use. However, people with bipolar disorder carry a significant burden of depression that may respond positively to the antidepressant effects of psilocybin when carefully administered in a controlled setting.

To assess the risk of activating a manic episode in bipolar, a prospective study is needed. This study will optimize the set and setting, screen for relevant risk factors, use a conservative dose-escalation protocol, and require participants to have community and psychological support. The present study is limited to cases that clinicians and researchers chose to submit for publication, and it is possible that mania brought on by psychedelic use is not something that treatment providers would think to publish. There were several challenges in reviewing the case study literature, including sparse case details, unclear timelines, and minimal follow-up. Furthermore, the dosages were frequently unavailable or reliant on patient reports, and approximately half of the cases involved either concurrent polysubstance use or recent polysubstance use. A systematic review revealed some cases of manic behavior brought on by use of a psychedelic substance. However, it is important to conduct trials in a carefully regulated environment to examine the effects and safety.