To systematically examine the effectiveness and tolerability of psilocybin for treating end-of-life anxiety symptoms.
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.
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.
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.
Patients with cancer might suffer from multidimensional psychological distress during diagnosis, treatment, and survival [
Similarly, patients with human immunodeficiency virus (HIV) might experience challenges related to the uncertainty regarding their future, which could induce significant psychological distress [
Psilocybin—a substance obtained from psilocybin mushrooms—has been identified as a controlled substance in several countries including the United States to its dependence potential [
Although psychopharmacological and psychosocial interventions are applied in treating anxiety in patients with cancer and HIV, the efficacy is mixed and limited [
The current study thus analyzed the effectiveness and tolerability of psilocybin in treating end-of-life anxiety symptoms in patients with cancer or HIV and explored its sustained effect on anxiety symptoms at different follow-up timepoints.
This study was conducted per the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Our search strategy is described in detail in the
The following eligibility criteria were applied; 1) peer-reviewed articles of clinical trials investigating the effectiveness of psilocybin in patients with life-threatening conditions, such as cancer and HIV; 2) inclusion of both controlled studies (compared with a placebo) and uncontrolled studies (open-label single-arm); and 3) written in English language.
We excluded nonclinical trials, such as case reports and case series. Moreover, we excluded studies published as conference abstracts and those published in languages other than English.
The primary outcome was changes in anxiety symptoms, including state anxiety and trait anxiety [
The secondary outcomes were all-cause discontinuation; peak changes in heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP); and serious adverse events.
Two authors (Yu CL and Liang CS) independently extracted data from the recruited studies. The GetData Graph Digitizer 2.26 was used to capture data from figures when necessary. In the cases of unavailable data in the literature, the corresponding authors were contacted and requested for the original data in at least two different occasions.
Two authors (CL Yu and DJ Li) independently assessed the quality of each included study. Disagreements were resolved through discussion with a third author (Liang CS). Moreover, to assess the quality of the included studies, we used the Cochrane risk-of-bias (ROB) tool, which consists of seven main domains (random sequence generation, allocation concealment, blindness of participants and personnel, blindness of outcome assessment, incomplete outcome data, selective reporting, and other source of bias) [
This meta-analysis was conducted using a random-effects model. Hedges’ g with 95% confidence interval (CI) was calculated for the primary outcomes. Negative values of Hedges’ g indicated anxiety score improvement. Weighted mean difference (WMD) was calculated for HR, SBP, and DBP. Odds ratio (OR) with 95% CI was calculated for all-cause discontinuation. The time points of anxiety assessment were day 1 and month 1, 3, and 6 after single session of psilocybin treatment. In addition, the pre–post changes in the primary outcome at the last follow-up time point was examined for all included studies. Heterogeneity was examined using Cochran’s Q test and using the I2 statistic [
The details of search results are illustrated in
The mean sample size of the five included studies [
Except for the blinding of outcome assessment, the quality of the other six domains were low or unclear ROBs for three RCTs [
At day 1 after treatment (
Regarding the effects of psilocybin on the circulatory system (
For all-cause discontinuation (
No small-study effects were observed (
The current study comprehensively analyzed the effectiveness of psilocybin on different types of end-of-life anxiety (state and trait) at different time points after a single treatment session. The main findings revealed that psilocybin was superior to placebo in treating state anxiety after a single treatment session, with the effectiveness observed 1 day and 1 month after psilocybin treatment. In addition, psilocybin exhibited effectiveness in managing trait anxiety at the time points of 1 day and 1, 3, and 6 months after a single treatment session. Regarding the secondary outcomes, no serious adverse events were observed after single session of psilocybin treatment, and group difference related to all-cause discontinuation was not significant. Although psilocybin significantly affected the SBP and DBP, these effects were transient and self-limited and required no medical intervention.
Notably, trait anxiety has more long-term effects on patients than does state anxiety. Trait anxiety is associated with stress coping strategies and could be considered part of the personality dimension of neuroticism rather than emotional stability [
Therefore, analyzing the short-term and long-term effectiveness of a single session psilocybin treatment on end-of-life anxiety is crucial in individuals with life-threatening illnesses. Most often these patients receive polypharmacy for their life-threatening illnesses, such as chemotherapy or highly active antiretroviral therapy. Therefore, a single session of psilocybin treatment might reduce the risk of intolerance and drug–drug interaction. Notably, our study demonstrated that the effectiveness of a single psilocybin treatment session on trait anxiety could persist up to 6 months. Moreover, psilocybin exhibited merit in tolerability, revealing no significant differences in all-cause discontinuation and HR compared with placebo, and the effects on SBP and DBP were transient and self-limiting. These promising findings regarding psilocybin use in end-of-life anxiety symptoms could prove helpful for clinicians in hospice care or psycho-oncology.
Similar to the biomedical mechanism of psychedelics, psilocybin exerts psychoactive effects through the agonistic effects on 5-HT2A receptors [
Regarding the rates of all-cause discontinuation and HR, psilocybin is not different from placebo, suggesting that it is well tolerated by patients with advanced physical illnesses. However, psilocybin revealed significantly higher SBP and DBP than placebo during treatment session. Although these changes were transient and self-limited, it should be noticed that these temporal changes might result in harmful reactions in some patients with life-threatening illnesses. For instance, long-term AIDS survivors had a predominant burden of cardiovascular disease [
Nevertheless, in addition to the promising effectiveness of psilocybin, the possibility of its abuse has garnered attention. Although psilocybin has been reported to not induce dependence, craving, or withdrawal [
This study had several limitations. First, the power of analysis of publication bias is limited owing to insufficient trials. We could identify only five studies meeting our inclusion criteria. Second, significant heterogeneity was observed regarding the effectiveness of psilocybin on state and trait anxiety, particularly for long-term effectiveness. Therefore, large-scale RCTs for validating the efficacy of psilocybin use for end-of-life anxiety symptoms are warranted. Third, the index population in the current study included those with life-threatening diseases, which might limit the generalizability of the current study. Finally, some studies used psychotherapy combined with psilocybin [
In conclusion, the current study reported the promising effectiveness of psilocybin in treating end-of-life anxiety symptoms. Furthermore, it manifested the long-term effectiveness in trait anxiety after a single treatment dose, indicating its advantages in patients intolerable to severe adverse effects owing to their physical illnesses. Psilocybin could be prescribed cautiously along with adequate monitoring for the probability of potential abuse and transient changes in blood pressure during treatment. 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. Clinicians should consider the clinical status of each patient before applying the current findings to clinical practice.
The online-only Data Supplement is available with this article at
The details of search results
PRISMA flow chart.
Risk of bias for included randomized controlled trials. A: Risk of bias summary. B: Risk of bias graph.
Risk of bias for all included studies. A: Risk of bias summary. B: Risk of bias graph.
All-cause discontinuation of psilocybin versus placebo.
Publication bias for state anxiety: 1 day after psilocybin treatment. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
Publication bias for state anxiety: 1 month after psilocybin treatment. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
Publication bias for state anxiety: 3 months after psilocybin treatment. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
Publication bias for state anxiety: 6 months after psilocybin treatment. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
Publication bias for trait anxiety: 1 day after psilocybin treatment. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
Publication bias for trait anxiety: 1 month after psilocybin treatment. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
Publication bias for trait anxiety: 3 months after psilocybin treatment. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
Publication bias for trait anxiety: 6 months after psilocybin treatment. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
Publication bias for state anxiety: Last follow-up time point for all included studies. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
Publication bias for trait anxiety: Last follow-up time point for all included studies. A: Linear estimator. B: Run estimator. C: Quadratic estimator.
The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.
The authors have no potential conflicts of interest to disclose.
Conceptualization: Dian-Jeng Li, Chih-Sung Liang. Data curation: Chia-Ling Yu, Fu-Chi Yang, Szu-Nian Yang, Ping-Tao Tseng, Brendon Stubbs, Ta-Chuan Yeh, Chih-Wei Hsu. Formal analysis: Dian-Jeng Li, Chih-Sung Liang. Investigation: Chia-Ling Yu, Fu-Chi Yang, Szu-Nian Yang, Ping-Tao Tseng. Methodology: Dian-Jeng Li, Chih-Sung Liang. Project administration: Dian-Jeng Li, Chih-Sung Liang. Writing—original draft: Chia-Ling Yu, Fu-Chi Yang. Writing—review & editing: Szu-Nian Yang, Ping-Tao Tseng, Brendon Stubbs, Ta-Chuan Yeh, Chih-Wei Hsu, Dian-Jeng Li, Chih-Sung Liang.
None
Changes in state anxiety after psilocybin treatment. A: Day 1. B: Month 1. C: Month 3. D: Month 6.
Changes in trait anxiety after psilocybin treatment. A: Day 1. B: Month 1. C: Month 3. D: Month 6.
Pre–post changes in primary outcomes at last follow-up time point. A: State anxiety. B: Trait anxiety.
Peak heart rate and blood pressure after psilocybin treatment versus placebo. A: Heart rate. B: Systolic blood pressure. C: Diastolic blood pressure.
Characteristics and demographics of the included studies
Study | Dx | Sample size | Female (%) | Age | Dosing | Psychiatric comorbidities | Study design | Dropout | Serious AE |
---|---|---|---|---|---|---|---|---|---|
Grob et al. [ |
Cancer | 12 | 91.6 | 36–58 | Oral single dose, 0.20 mg/kg | Yes. Specific psychiatric disorders were not mentioned | Double-blind RCT | 0 | No |
Griffiths et al. [ |
Cancer | 56 | 49.0 | 56.3 (10.0) | Oral single dose, 0.32 mg/kg (22 or 30 mg) | Adjustment disorder; dysthymia; GAD, and MDD | Double-blind RCT | 5 | No |
Ross et al. [ |
Cancer | 31 | 62.1 | 56.3 (12.9) | Oral single dose, 0.3 mg/kg | Adjustment disorder and GAD | Double-blind RCT | 3 | No |
Agin-Liebes et al. [ |
Cancer | 15 | 60.0 | 53 (13.5) | Oral single dose, 0.3 mg/kg | Adjustment disorder and GAD | Long-term follow-up after RCT | 1 | No |
Anderson et al. [ |
HIV/cancer | 18 | 0.0 | 59.2 (4.4) | Oral single dose, 0.30–0.36 mg/kg | Mood disorder, anxiety disorder, and insomnia | Open-label single-arm trial | 0 | No |
AE, adverse event; Dx, diagnosis; GAD, generalized anxiety disorder; MDD, major depressive disorder; RCT, randomized controlled trial