Psilocybin as a New Approach to Treat Depression and Anxiety in the Context of Life-Threatening Diseases-A Systematic Review and Meta-Analysis of Clinical Trials

This meta-analysis (n=92) highlights the large, and positive effects of psilocybin-assisted psychotherapy for depression and anxiety related to life-threatening diseases (end-of-life anxiety), it also recommends using it in the first-line (considering the safety profile).

Abstract

“Psilocybin is a naturally occurring tryptamine known for its psychedelic properties. Recent research indicates that psilocybin may constitute a valid approach to treat depression and anxiety associated with life-threatening diseases. The aim of this work was to perform a systematic review with meta-analysis of clinical trials to assess the therapeutic effects and safety of psilocybin on those medical conditions. The Beck Depression Inventory (BDI) was used to measure the effects in depression and the State-Trait Anxiety Inventory (STAI) was used to measure the effects in anxiety. For BDI, 11 effect sizes were considered (92 patients) and the intervention group was significantly favored (WMD = -4.589; 95% CI = -4.207 to -0.971; p-value = 0.002). For STAI-Trait, 11 effect sizes were considered (92 patients), being the intervention group significantly favored when compared to the control group (WMD = -5.906; 95% CI = -7.852 to -3.960; p-value ˂ 0.001). For STAI-State, 9 effect sizes were considered (41 patients) and the intervention group was significantly favored (WMD = -6.032; 95% CI = -8.900 to -3.164; p-value ˂ 0.001). The obtained results are promising and emphasize the importance of psilocybin translational research in the management of symptoms of depression and anxiety, since the compound may be effective in reducing symptoms of depression and anxiety in conditions that are either resistant to conventional pharmacotherapy or for which pharmacologic treatment is not yet approved. Moreover, it may be also relevant for first-line treatment, given its safety.”

Authors: Ana Sofia Vargas, Ângelo Luís, Mário Barroso, Eugenia Gallardo & Luísa Pereira

Notes

The studies included in the meta-analysis were:

• Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial (Ross et al., 2016)
• Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial (Griffiths et al., 2016)
• Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer (Grob et al., 2011)

Summary

Review

A systematic review with meta-analysis of clinical trials was performed to assess the therapeutic effects and safety of psilocybin on depression and anxiety associated to life-threatening diseases. The results were promising and emphasize the importance of psilocybin translational research in the management of symptoms of depression and anxiety.

1. Introduction

Major depressive disorder (MDD) is characterized by the persistence of negative thoughts and emotions that disrupt mood, cognition, motivation, and behavior. Several treatment options exist, including medication, ECT, and other neurostimulation strategies.

Anxiety is a very common psychiatric symptom in terminally ill patients. It contributes to poor recovery from medical procedures and lower survival time in terminally ill patients, and depression and anxiety are independent risk factors of early death in patients with life-threatening diseases.

Regarding the treatment of severe depression and anxiety, intranasal Spravato®, a ketamine enantiomer, was approved by the FDA in March 2019. Its active compound is esketamine, a non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist.

Research on classic hallucinogens like psilocybin is needed to provide patients with depression and anxiety associated with life-threatening diseases better chances of recovery and consequently better quality of life.

2.1. Search Strategy, Study Selection, Inclusion and Exclusion Criteria

The search for this systematic review with meta-analysis was performed on several electronic databases during January 2020. Studies presenting a true control group, patients with depression and anxiety associated with a life-threatening disease, drug psilocybin, and use of Beck Depression Inventory (BDI) and/or State-Trait Anxiety Inventory (STAI) were included.

BDI is a self-report questionnaire that measures the severity of depressive symptoms. STAI is a self-report questionnaire that measures the severity of anxiety symptoms.

2.2. Risk of Bias Assessment

The risk of publication bias of each included study was assessed using the Cochrane Collaboration’s tool for assessing risk of bias. The results were presented in a risk of bias summary and a risk of bias graph.

2.3. Data Extraction and Summary

The included studies were carefully analyzed, and data were extracted and summarized by two authors using a prespecified procedure.

2.4. Statistical Analyses

A meta-analysis was performed on the pooled effect of the treatment with psilocybin in terms of weighted mean differences (WMD) between the change from pre- and post-treatment mean values of the intervention and control groups. The statistical data analysis was performed using the Comprehensive Meta-Analysis software (Version 2.0) .

3.1. Search and Selection of Studies

The detailed steps of the article selection process are depicted as a flow-diagram (Figure 1). After the initial search, 670 articles remained, and 32 were further evaluated for inclusion and exclusion criteria.

Seven articles were assessed for eligibility through full-text evaluation, four were excluded because they were secondary analyses of the same data, and three articles were included in qualitative synthesis. The three articles were divided into several effect sizes based on different times of follow-up after psilocybin administration.

3.2. Included Studies and Trials Characteristics

Three studies were included, with doses ranging from 0.2 to 0.4 mg/kg, and results were assessed through the scales, days after the administration of psilocybin, and in a longer follow-up, in some cases up to three months.

3.3. Risk of Publication Bias

The results of the assessment of the risk of publication bias from the included studies are summarized in Figure 2. The intervention group was significantly favored when compared to the control group, and a fixed effects model was used for the analysis.

STAI-Trait was used to evaluate 11 effect sizes in 92 patients with a diagnosis of depression and anxiety associated with a life-threatening disease.

For STAI-State, 41 patients with a diagnosis of depression and anxiety associated with a life-threatening disease were included. The intervention group was significantly favored.

3.5. Subgroup and Sensitivity Analyses

Psilocybin induces reduction in both BDI and STAI-Trait at all tested doses, but the reduction is not dose-dependent. The reduction is only statistically significant at doses of 0.4 mg/kg for BDI and of 0.3 and 0.4 mg/kg for STAI-Trait.

The results of the meta-analysis of studies on psilocybin in depression and anxiety are robust even when a few studies are omitted.

3.6. Publication Bias

Publication bias was examined through funnel plots and statistically using the Trim and Fill method. Egger’s regression test indicated evidence of publication bias for the effects of psilocybin on depression and anxiety.

Psilocybin significantly increases systolic blood pressure and diastolic blood pressure, and heart rate, up to 6 and 5 hours after administration, respectively. Heart rate tends to stabilize after 6 or more hours.

4. Discussion

Psilocybin, a molecule with structural similarities to serotonin, was synthesized in the laboratory and used to induce hallucinations and altered states of consciousness. It was withdrawn in the early 1970s and classified as a Schedule I drug, but has shown potential in the treatment of anxiety and depression.

Psilocybin, an agonist of 5-HT(2A) receptors, may act by deactivating the medial prefrontal cortex (mPFC) and attenuating amygdala activation on response to threat-related visual stimuli, which are correlated to negative mood states in depressed patients. Patients with a potentially life-threatening disease often experience considerable anxiety and psychological distress. Psilocybin may help address these symptoms when used in the correct environment and with trained professionals.

Psilocybin produces sustained reduction in symptoms of depression and anxiety. It may affect the default mode network (DMN), which is essential for the maintenance of cognitive integration and constraint under normal conditions. Psilocybin increases SBP and DBP, heart rate and pupil dilatation, but does not affect ionic balance, blood glucose or cholesterol.

There were no serious adverse effects reported following psilocybin administration. However, there are some references to nausea, both physical and psychological discomfort, transient episodes of psychological distress and anxiety, although literature points to these effects being quite dangerous and life-impairing following hallucinogen consumption.

Psilocybin may cause somatic symptoms such as dizziness, weakness, tremor, drowsiness, yawning, paresthesia, blurred vision, and increased tendon reflexes.

Classical hallucinogens do not cause addiction, as they act on the serotoninergic system. However, if a psilocybin-containing medicine is approved, it should be included in the Schedule IV of Controlled Substance Schedules.

5. Conclusions

Psilocybin may be effective in reducing symptoms of depression and anxiety. Further studies are needed to confirm these results.