Steve Kisely, Metro South Health, Queensland
Mark Connor, Macquarie University, Faculty of Medicine and Human Sciences
Andrew Somogyi, University of Adelaide, Faculty of Health and Medical Sciences
There has been increasing interest in the use of methylenedioxymethamphetamine (MDMA) and psilocybin in the treatment of mental, behavioural or developmental disorders. Although there have been several recent systematic reviews, studies and participants have been limited, and the field is rapidly evolving with the publication of more studies.
With the aid of a professional librarian, we therefore searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials and CINAHL for randomised controlled trials (RCTs) of MDMA and psilocybin with either inactive or active controls. Articles were independently assessed. Outcomes were psychiatric symptoms measured by standardised, validated and internationally recognised instruments at least two weeks following administration. Quality was assessed using the Cochrane risk of bias assessment tool.
There were eight studies included on MDMA and six on psilocybin. Diagnoses of interest included post-traumatic stress disorder (PTSD), treatment-resistant depression (TRD), obsessive-compulsive disorder, social anxiety in adults with autism, and anxiety or depression in life threatening disease (LTD).
MDMA: Six of the eight studies were on post-traumatic stress disorder, one on anxiety due to a life-threatening disease and the other on social anxiety in adults with autism. Half of the studies on PTSD used inactive placebo as the control while the remainder used low doses of MDMA. In all studies both the intervention group and controls received supplementary intense psychotherapy.
In general, between four and twelve weeks following administration, there were statistically significant differences for MDMA doses of greater than 100 mg in comparison with inactive or active controls. Most information was on MDMA symptom scores compared to active controls in post-traumatic stress disorder (Standardised Mean Difference=-0.86, 95%CI=-1.23 to -0.50; k=4). We consider a standardised mean difference of this magnitude to be a strong effect size.
MDMA also resulted in statistically significant improvements in social anxiety in adults with autism when compared to placebo. However, the results for anxiety in life threatening disease were non-significant although participant numbers were low. Effect sizes were large in all comparisons but with wide confidence intervals.
MDMA was well tolerated in all the studies. The main adverse effects were anxiety, restlessness, fatigue, jaw-clenching, headache and transient increases in blood pressure. Serious events such as suicidal ideation were rare and occurred almost entirely in the placebo arm or were otherwise unrelated to the therapy.
Psilocybin: Four of the six studies were for anxiety or depression for a life-threatening disease, two on treatment-resistant depression and one on obsessive-compulsive disorder. Two used low-dose psilocybin as the control and another two used the vasodilator niacin as it induces a mild physiological reaction (e.g. flushing) without any psychological effects.
One study reported statistically significant differences between psilocybin and niacin, and another between high and low dose psilocybin, for subjects with anxiety or depression due to life threatening disease. Psilocybin was also superior to remaining on a wait-list in a study of treatment resistant depression. In another study of treatment resistant depression, there was no significant difference between psilocybin and a registered antidepressant (escitalopram) in the pre-determined primary outcome, although changes in secondary outcomes almost uniquely favoured psilocybin. In the fifth study, there were no statistically significant differences between psilocybin and controls at the two-week follow-up, although both groups showed longer-term improvements following cross-over. In the final study there was no significant effect of dose on obsessive-compulsive symptoms possibly because of low numbers and unexpectedly high response to the very low dose placebo.
Three studies also assessed whether participants had shown a clinically significant response or were in remission as regards depression or anxiety. There were statistically significant differences favouring psilocybin as opposed to both active placebo (niacin or low dose psilocybin) and the antidepressant escitalopram (for all but one measured outcome in the case of the latter).
Psilocybin was also well tolerated in all the studies. The main effects were anxiety, headache and transient increases in blood pressure.
By combining the effects of small and possibly underpowered studies, meta-analyses can help to establish the relative efficacy of interventions such as MDMA and psilocybin where large studies may be impractical. Although we were only able to combine results from 9 studies for either beneficial or adverse effects, we did demonstrate statistically significant differences of the two psychedelic agents between both inactive and active treatments for either continuous scores or dichotomous responses. However, it is important to note that this was in highly supportive and structured environments including intense psychotherapy sessions in many cases.
Both agents were well-tolerated in supervised trials with or without additional use of psychotherapy. However, trial quality including blinding and follow-up was variable and only a small proportion of potential participants were included in the randomised phase.
We conclude that MDMA and psilocybin may show promise in highly selected populations but only where these medicines are administered in closely clinically supervised settings and with intensive professional support.