A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy

This meta-analysis of nine placebo-controlled trials (n=211) showed a very large effect size (g=1.21) of treatment on four mental health conditions (PTSD, end-of-life anxiety, depression, social anxiety among autistic adults).

Abstract of A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy

“After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a significant mean between-groups effect size of 1.21 (Hedges g), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. For the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. Overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions – post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. While study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. Larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.”

Authors: Jason B. Luoma, Christina Chwyl, Geoff J. Bathje, Alan K. Davis & Rafael Lancelotta

Notes on A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy

This paper is included in our ‘Top 10 Articles for Psychedelic Novices‘

The studies selected were all from between 2011 and 2018 and all were double-blind, randomized, placebo-controlled, (open-label) crossover or parallel arm. The studies were the following:

• Danforth et al. (2018) Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: A randomized, double-blind, placebo-controlled pilot study
• Gasser et al. (2014) Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases
• Griffiths et al. (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial
• Mithoefer et al. (2011) The safety and efficacy of ±3,4-methylenedioxymethamphetamine- assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: The first randomized controlled pilot study
• Mithoefer et al. (2018) 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: A randomised, double-blind, dose-response, phase 2 clinical trial
• Oehen et al. (2013) A randomized, controlled pilot study of MDMA (±3, 4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD)
• Ot’alera et al. (2018) 3, 4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: A randomized phase 2 controlled trial
• Palhano-Fontes et al. (2019) Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: A randomized placebo-controlled trial
• Ross et al. (2016) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial

The three studied that reported long-term (seven weeks to six months) follow-up showed a decrease of 7.5% effect size, Hedges g = 1.36, “indicating that effects were largely sustained over the follow-up period.”

The authors are very positive about the studies they included, the critique they did have might be interesting for future studies:

• An analysis could compare psychedelic therapy (so the combination that was used in these studies) with other pharma and therapy interventions (vs only looking at those separately)
• Another meta-analysis with a larger sample size has historically shown to diminish the effect size
• Future studies could focus on the type of placebo given
• The long-term follow-up data is very tentative (as only three studies reported on it)
• Reviewing the blinding procedures and implementing other ways of blinding than normally done and evaluated should also be implemented
• Randomizing the amount of psychotherapy (whilst keeping the drug dosing the same) would also shed interesting light into how effective/necessary that part is

The total number of participants in the nine studies was 211. Of these, 165 received an active/high dose at least once, 125 received a placebo (and some received a high dose at a later date).

The participants received, on average, 1.9 active drug doses, if averaged over the 9 studies. If averaged over all non-placebo participants, they received 1.5 active doses. Two of the five MDMA studies had 3 dosing sessions.

The Hedges g is a measure of effect size. A score of 1 indicates a difference of 1 standard deviation between the groups. Everything above 0.8 can be interpreted as a high result. The mean between-groups effect size of 1.21 can thus be interpreted as a good validation of the effect size of psychedelics in combination with psychotherapy.

“The overall between-group effect size at the primary endpoint for psychedelic-assisted therapy compared to placebo was very large (Hedges g = 1.21). This effect size reflects an 80% probability that a randomly selected patient undergoing psychedelic-assisted therapy will have a better outcome than a randomly selected patient receiving a placebo (McGraw and Wong 1992)… Overall, results suggest that psychedelic-assisted therapy is effective with minimal adverse effects.”

“Although we compared the effect size in our study to those reported in prior reviews and meta-analyses, future research would benefit from directly comparing the effectiveness of psychedelic-assisted therapy to more traditional pharmacological, psychotherapeutic, or combined interventions. Future studies would also benefit from examining cost-effectiveness, given that psychedelic-assisted therapy, as currently delivered, may be relatively expensive compared to single-modality treatments.”

What was missing from many of the studies was the total number of psychotherapy hours (when reported it was around 10 hours). This may mean that the costs of such treatment (for the populations studied) might still be quite high. But, if compared to a multi-year psychotherapy treatment protocol without much effect, this may be much more effective.

Summary of A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy