Psilocybin for End-of-Life Anxiety Symptoms: A Systematic Review and Meta-Analysis

This review paper (2021) provides further evidence for the use of psilocybin-assisted therapy for the treatment of end-of-life anxiety in the absence of serious adverse effects.

Abstract

“Objective: To systematically examine the effectiveness and tolerability of psilocybin for treating end-of-life anxiety symptoms.

Methods: The Medline, Embase, CENTRAL, and PsycINFO databases were searched up to November 25, 2020. We enrolled clinical trials investigating psilocybin for treating end-of-life anxiety symptoms. Meta-analysis was conducted using random-effects model.

Results: Overall, five studies were included, revealing that psilocybin was superior to the placebo in treating state anxiety at 1 day (Hedges’ g, -0.70; 95% confidence interval, -1.01 to -0.39) and 2 weeks (-1.03; -1.47 to -0.60) after treatment. Psilocybin was more effective than placebo in treating trait anxiety at 1 day (-0.71; -1.15 to -0.26), 2 weeks (-1.08; -1.80 to -0.36), and 6 months (-0.84; -1.37 to -0.30) after treatment. Psilocybin was associated with transient elevation in systolic (19.00; 13.58–24.41 mm Hg) and diastolic (8.66; 5.18–12.15 mm Hg) blood pressure compared with placebo. The differences between psilocybin and placebo groups with regard to allcause discontinuation, serious adverse events, and heart rates were nonsignificant.

Conclusion: Psilocybin-assisted therapy could ameliorate end-of-life anxiety symptoms without serious adverse events. Because of the small sample sizes of the included studies and high heterogeneity on long-term outcomes, future randomized controlled trials with large sample sizes are needed.”

Authors: Chia-Ling Yu, Fu-Chi Yang, Szu-Nian Yang, Ping-Tao Tseng, Brendon Stubbs, Ta-Chuan Yeh, Chih-Wei Hsu, Dian-Jeng Li & Chih-Sung Liang

Summary

INTRODUCTION

Patients with cancer might suffer from multidimensional psychological distress during diagnosis, treatment, and survival. The potentially life-threatening characteristic of cancer and the uncertainty related to its progression might also contribute to the stress.

Patients with cancer and HIV might experience mental health problems due to the uncertainty regarding their future, and the stigma associated with HIV can contribute to poor mental health.

Psilocybin, a substance obtained from psilocybin mushrooms, has been shown to enhance spiritual wellbeing and ameliorate anxiety symptoms in patients with cancer and HIV. It can be considered a treatment option under controlled clinical practice for patients with end-of-life anxiety symptoms.

Database search

This study was conducted per the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses and involved two authors who independently searched the platforms. A third author was consulted in situations where the two authors could not achieve consensus.

Inclusion and exclusion criteria

We reviewed peer-reviewed articles of clinical trials investigating the effectiveness of psilocybin in patients with life-threatening conditions, and excluded nonclinical trials and studies published in languages other than English.

Primary and secondary outcomes

The primary outcome was changes in anxiety symptoms, including state anxiety and trait anxiety. Individuals with high levels of trait anxiety were more susceptible to stress.

Data extraction and quality appraisal

Two authors independently extracted data from the recruited studies. The corresponding authors were contacted for the original data when necessary.

Two authors independently assessed the quality of each included study, and disagreements were resolved through discussion with a third author.

Statistical analysis

This meta-analysis was conducted using a random-effects model, and Hedges’ g, weighted mean difference, SBP, and DBP were calculated. The pre – post changes in the primary outcome at the last follow-up time point was examined for all included studies.

Selection protocol

The search results showed that 45 studies were eligible for full-text review. Five studies met the inclusion criteria.

Characteristics and methodological quality of the included studies

Five studies were included in the analysis, and the mean age was 54.4 years and 52.5% were female. The studies measured changes in state and trait anxiety symptoms.

Except for blinding of outcome assessment, all six domains were low or unclear in three R C Ts. The single-arm study by Anderson et al.24 had high ROB on blinding of outcome assessment.

Primary outcome: changes in state and trait anxiety

Psilocybin was superior to placebo in treating state anxiety at day 1 and month 1 without significant heterogeneity. However, the effect sizes were not significant at 3-month and 6-month follow-ups.

Figure 2 illustrates that psilocybin was superior to placebo in treating trait anxiety at day 1 after treatment, and was still superior at 3-month and 6-month follow-ups. However, the heterogeneity was significant at both time points.

Psilocybin was associated with significant changes in state and trait anxiety symptoms, whereas the heterogeneity was significant.

Secondary outcome: effects on circulatory system and all-cause discontinuation

Psilocybin did not differ from placebo regarding heart rate or blood pressure, but was significantly associated with elevation in SBP and DBP. The elevation was self-limited and required no medical intervention.

Main findings of the current study

The current study showed that psilocybin was superior to placebo in treating state anxiety and trait anxiety after a single treatment session, and that there were no serious adverse events after a single treatment session.

Trait anxiety is more long-term than state anxiety and is associated with stress coping strategies. Trait anxiety is also associated with neuroticism. A single session of psilocybin treatment could improve trait anxiety in individuals with life-threatening illnesses, and the effects were sustained for up to 6 months. Moreover, psilocybin exhibited merit in tolerability, with no significant differences in all-cause discontinuation and HR compared with placebo.

Potential anxiolytic mechanisms of psilocybin

Psilocybin exerts psychoactive effects through the agonistic effects on 5-HT2A receptors, and might destabilize the local brain network hubs and global network connectivity by enhancing the neuronal avalanches, probably causing the “resetting” effect after the acute effects of treatment and altering the brain network activity for a long-term.

Tolerability of psilocybin and probability of abuse

Psilocybin showed similar rates of discontinuation and HR to placebo, suggesting that it is well tolerated by patients with advanced physical illnesses. However, it revealed significantly higher SBP and DBP than placebo during treatment session.

Although psilocybin has been reported to not induce dependence, craving, or withdrawal, the possibility of its abuse cannot be neglected. It can provide therapeutic benefits with manageable adverse effects.

Limitations

This study had several limitations, including insufficient trials, heterogeneity, and a limited generalizability. Large-scale RCTs are warranted to validate the efficacy of psilocybin use for end-of-life anxiety symptoms.

Psilocybin showed promising effectiveness in treating end-of-life anxiety symptoms. It could be prescribed cautiously along with adequate monitoring for the probability of potential abuse and transient changes in blood pressure during treatment.