Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis

This meta-analysis (s=7, n=233) explored the therapeutic effects of psilocybin, LSD and ayahuasca on depressive symptoms in the clinical setting. When administered with psychological support, all psychedelics led to short and long-term reductions in depressive symptoms while symptom reduction was significant at the 1-day, 1-week, and 3–5 weeks time points. Some limitations include the small sample sizes used in the individual studies and the use of a cross-over design for the follow-up.

Abstract

“Background: Psychedelic therapy shows promise for Major Depressive Disorder, especially when treatment-resistant, as well as life-threatening illness distress. The objective of this systematic review, inclusive of meta-analysis, is to examine recent clinical research on the therapeutic effects of classic psychedelics on depressive symptoms.

Methods: Fourteen psychedelic therapy studies, utilising psilocybin, ayahuasca, or LSD, were systematically reviewed. For the meta-analysis, standardised mean differences were calculated for seven randomised controlled trials.

Results: The systematic review indicated significant short- and long-term reduction of depressive symptoms in all conditions studied after administration of psilocybin, ayahuasca, or LSD, with psychological support. In the meta-analysis, symptom reduction was significantly indicated in three time points out of four, including 1-day, 1-week, and 3–5 weeks, supporting the results of the systematic review, with the exception of the 6–8 weeks follow-up point which was less conclusive.

Limitations: The absence of required data for 2 studies necessitated the less precise use of graphical extraction and imputation. The small sample size in all but one study negatively affected the statistical power. None of the studies had long-term follow-up without also utilising the cross-over method, which did not allow for long-term results to be included in the meta-review.

Conclusions: This review indicates an association between psychedelic therapy and a significant reduction of depressive symptoms at several time points. However, the small number of studies, and low sample sizes, calls for careful interpretation of results. This suggests the need for more randomised clinical trials of psychedelic therapy, with larger and more diverse samples.”

Authors: Kwomonk Ko, Emma I. Kopra, Anthony J. Cleare & James J. Rucker

Author Highlights

• Review of classic psychedelic therapy studies for reduction of depressive symptoms
• Fourteen studies reviewed show robust short- and long-term symptom reduction.
• On meta-analysis of 7 studies, significant symptom reduction at 3 out of 4 time points.
• Includes a large-scale randomised controlled trial of 233 subjects over 22 sites.

Summary of Psychedelic therapy for depressive symptoms

The systematic review indicated significant short- and long-term reduction of depressive symptoms in all conditions studied after administration of psilocybin, ayahuasca, or LSD, with psychological support.

Limitations: The study had small sample sizes and no long-term follow-up, which prevented including long-term results in the meta-review.

This review indicates that psychedelic therapy can reduce depressive symptoms. However, more studies are needed with larger samples.

Classic psychedelics, which are serotonin 2A receptor partial agonists, are undergoing a renaissance in the mental health field. While definitive clinical efficacy has not yet been determined, symptom reduction has been suggested by earlier reviews.

Reviews have been conducted on the application of psychedelics for various psychological conditions, including depression, anxiety, alcoholism and substance use disorder, and post-traumatic stress disorder.

Rucker et al (2016) reviewed 21 early studies (1949-1973) that used psychedelic therapy to treat unipolar mood disorders. They found that the majority of subjects showed clinical improvement.

Later reviews have focussed on more recent clinical studies, and included studies examining the effects of classic psychedelics and compounds with secondary psychedelic effects on healthy as well as mentally ill subjects. All reviews demonstrated significant clinical improvement.

While mechanisms for psychedelic therapy have not yet been determined, a number of possibilities have been identified, including increased ‘insight’, enhanced social cognition and emotional processing, psychological flexibility, and mystical experience.

Psychedelics are well tolerated and have few side effects, including anxiety, nausea, mild hypertension and heart rate increase, and a post-dose tension headache. They are given intermittently, which reduces the risk of treatment failure due to non-adherence.

People with treatment-resistant depression may benefit from this emerging category of pharmaceuticals.

This review assesses recent studies of classic psychedelics for their effects on depressive symptoms. It includes both open-label studies and randomised controlled trials.

The authors searched for studies on psychedelics and depression in Embase, MEDLINE, PsychINFO, and Cochrane Central Register of Controlled Trials (CENTRAL). They selected 13 studies and reviewed the reference lists of selected studies and relevant systematic reviews that emerged from the searches.

Studies with healthy volunteers and application of micro-doses were excluded. The studies included adult subjects with depressive disorders and/or distress related to life-threatening diagnoses and terminal illness.

Quality assessment was performed using the Newcastle Ottawa Quality Modified Scale and the Revised Cochrane Risk of Bias Tool for Randomised Trials. Risk of bias was assessed independently by each of two reviewers.

Data were extracted on treatment effect on depressive symptoms, length of follow-up, and treatment modality, including substance administered, dosage, number of dosing sessions, and model of support provided.

For the meta-analysis, clinically similar randomised controlled trials were included. The medium dose group was not included as a medium dose was not included in any other studies.

The formula used to calculate the 95% CI was square root of N * (upper 95% CI – lower 95% CI) / 3.92.

To perform the meta-analysis, RevMan 5.4.1 (Cochrane, 2022) was utilised. Standardised mean differences [SMD] for depressive scores were utilised to determine effect size.

Fourteen studies were identified for systematic review, 10 of which were randomised controlled trials, and the remaining 3 were long-term follow ups of already included studies.

Of the 14 studies, 8 targeted Major Depressive Disorder, and Davis et al. and Gukasyan et al. utilised the same dataset.

In 14 studies, psychedelics were used to treat anxiety, depression, and/or adjustment disorder related to life-threatening cancer diagnosis. Psilocybin was used in 11 studies, with 1 study using LSD, 2 studies using ayahuasca, and 1 study using psilocybin.

Among the psilocybin studies, the majority dosed according to body mass, but some studies administered 10mg-25mg, irrespective of body mass.

Studies of psychedelic therapies must assess isolated efficacy, unaffected by prior use of other psychoactive medications.

The washout period used in studies to eliminate similar psychiatric medications from subjects’ systems prior to trial varied widely.

Supportive interventions were provided pre-, during, and post-psychedelic therapy sessions.

In a randomised and double-blinded active placebo-control pilot study, 12 participants with anxiety associated with life-threatening diagnoses were administered 200g of LSD in 2 sessions with 2 to 3 weeks between the sessions. The mean HADS-D score decreased from 10.0 at baseline to 7.5 in the experimental group.

Two studies utilised ayahuasca to investigate its effects on recurrent MDD and TRD. Both studies demonstrated significant clinical effects of ayahuasca for symptomatic relief of depression.

In Sanches et al. and Palhano-Fontes et al., administration of ayahuasca resulted in significant decrease of both HAM-D and MADRS scores from day 1 to day 21 (p.001).

Eight clinical trials investigating the clinical efficacy of psilocybin were included in this review. Two follow-up studies were also generated, one at 12 months following Davis et al. (2021) and one at 6 months following Carhart-Harris et al. (2018).

All studies of MDD demonstrated positive results. Twelve TRD subjects were enrolled in an open-label feasibility study of psilocybin with psychological support, and significant reductions in QIDS-SR16 scores were observed at 1 week, 2 weeks, 3 weeks, 5 weeks, and 6 months.

Two hundred and thirty-three subjects were randomised into 25mg, 10mg, and 1mg psilocybin therapy arms in a 1:1:1 ratio. The 25mg group showed the best response and remission rates, and the 25mg group’s results were sustained up to 12-weeks.

Carhart-Harris et al. (2021) conducted a double-blinded randomised controlled trial comparing the clinical efficacy of psilocybin and escitalopram in patients with chronic moderate-to-severe MDD. Psilocybin was found to be more effective than escitalopram, but no definitive conclusion can be drawn.

Davis et al. (2021) conducted a randomised psilocybin trial for moderate-to-severe MDD, which was controlled by waitlist. They found that immediate treatment group had a significant between-group difference (p.001) in GRID-HAMD scores at weeks 1 and 4, compared to delayed treatment group at weeks 5 and 8.

A 12-month follow-up analysis was conducted by Gukasyan et al. (2022), and a large decrease in GRID-HAMD scores was detected at 1-, 3-, 6-, and 12-month follow-up, respectively.

Several clinical trials have investigated the effects of psilocybin assisted therapy on illness-related distress. All have yielded generally positive results.

In one of the earliest modern pilot trials of this kind, 12 subjects were selected who had advanced-stage cancer plus at least one of the following: anxiety disorder due to cancer, generalised anxiety disorder, adjustment disorder with anxiety, and/or acute stress disorder.

A crossover randomised controlled trial was conducted with 29 subjects with cancer-related anxiety and depression. The treatment group showed a 83% response rate according to BDI.

Agin-Liebes et al. (2020) conducted a long-term follow-up and found that BDI was significantly reduced over the course of all follow-up timepoints.

Griffiths et al. (2016) conducted a randomised, double-blind, crossover trial of 51 patients with life-threatening cancer diagnosis who had anxiety and depression symptoms. The immediate-treatment group had a significantly lower GRID-HAMD-17 and HAM-A score at 5 weeks compared to the delayed-treatment group.

Anderson et al. (2019) conducted an open-label study of psilocybin-assisted group therapy for long-term AIDS survivors with moderate-to-severe demoralisation. The study found that the score on the Center for Epidemiological Studies Depression Scale-Revised decreased significantly at both post-treatment and 3-month follow-up.

Standardised mean differences demonstrated a significant reduction of depressive symptoms at all timepoints with the exception of weeks 6-8.

The systematic review of 14 studies found that administration of psilocybin, ayahuasca, or LSD to adults with depressive disorders resulted in significant short- and long-term reduction of depressive symptoms, with the exception of the 6-8 weeks follow-up point, which was less conclusive.

There is a lack of long-term follow-up on double-blind randomised controlled trials of psilocybin. However, the longest results to date indicate sustained efficacy of psilocybin treatment.

Although the clinical efficacy of psychedelic therapy for depressive symptoms has not yet been demonstrated, early indications suggest that this effect may persist into the longer term.

This review has several key strengths, including a large-scale RCT that adds to the evidence base, and analysis at multiple timepoints that demonstrate results from acute to medium-term.

Psychedelic therapy can be administered intermittently, while standard antidepressants often require a longer-term course of treatment. Additionally, psychedelic therapy has fewer side-effects and may increase patient compliance in some groups who are dissatisfied with traditional antidepressant therapy.

Psilocybin therapy may be expensive for public healthcare systems, but for those who have failed to respond to multiple standard treatments, the case for psychedelic therapy may become more compelling.

Limitations of this meta-analysis include the absence of required data for 2 studies, the small sample size in all included studies, and the lack of long-term follow-up without also utilising the cross-over method.

The systematic review overall is limited by the exclusion criteria in all the underlying studies for those who are at significant risk of suicide, and by the lack of ethnic, cultural, gender, and socioeconomic diversity among subjects.

Several methods have been used to address the problem of true blinding in randomised trials, including using placebos, low-dose psychedelics, and requiring that subjects be naive to psychedelic substances.

Psychedelics are generally given with psychological support before, during and after the dosing session. This makes it difficult to assess the isolated effect of psychedelic substances.

Other limitations could be addressed in future studies, such as a larger sample size and a streamlining of the process. Additionally, more diverse recruitment methods could be considered.

In conclusion, this article reviewed the most recent trials of psychedelic therapies and found that they were effective in reducing depressive symptoms.