Largest psychedelic therapy trial to date delivers mixed results
Early data from the largest trial to date testing psilocybin therapy for depression indicates the psychedelic treatment may be somewhat effective at reducing symptom severity. However, concerns over some adverse effects indicate there is more work to be done before psilocybin is ready for clinical approval.
Mental health care company Compass Pathways’ Phase 2B psilocybin therapy trial for treatment-resistant depression was granted Breakthrough Therapy designation by the US Food and Drug Administration (FDA) in late 2018. Although there have been larger trials examining the therapeutic potential of MDMA, it isn’t considered a classical psychedelic (unlike LSD, psilocybin, DMT or mescaline), making this the largest blinded control study completed to date exploring the efficacy of this kind of novel psychedelic-assisted therapy.
The company has now announced the first top-line results from its landmark trial, reporting a “rapid and sustained” response from just one dose of psilocybin accompanied by psychotherapy sessions. The results have yet to be peer-reviewed and published in a journal.
The trial recruited 233 patients with treatment-resistant depression who were randomly, and blindly, split into three dosage arms: 25 mg, 10 mg, and 1 mg. The 1-mg group essentially served as a placebo group, still receiving all the pre and post psychotherapy treatments. Depression was measured using the Montgomery–Åsberg Depression Rating Scale (MADRS), a widely-used method for calculating depression severity.
The trial tested a multi-week treatment protocol, with preparatory psychotherapy before a single active psilocybin session and several follow-up sessions in the weeks afterwards. The primary endpoint looked at the change in total MADRS score from baseline to three weeks after the psilocybin session.
At week 3 the results indicate 29.1 percent of patients in the 25-mg psilocybin group were in remission, based on MADRS scores. This compared to 7.6 percent of the 1-mg placebo group in remission. By week 12 the study saw 26.6 percent of the 25-mg psilocybin group sustaining remission (21 out 79). Overall, the study saw an average 6.6-point greater reduction in MADRS scores from baseline to week 3 in the 25-mg psilocybin group compared to the 1-mg group.
Suresh Muthukumaraswamy, a neuropsychopharmacologist working with psychedelics at the University of Auckland, sees the results released so far as mixed. And the press release from Compass Pathways announcing these results is far from clear.
“I would say the results are a mixed bag,” says Muthukumaraswamy in an email to New Atlas. “There are certainly some promising looking results in terms of efficacy but also some safety concerns around the number of SAEs [serious adverse events] (mostly suicidality). The durability of the response is also unknown.”
Five patients (6.3 percent) in the 25-mg group and six patients (8 percent) in the 10-mg group experienced at least one serious adverse event in the follow-up period after the psilocybin treatment. This compared to just one serious adverse event reported in the 1-mg placebo group.
These serious adverse events included suicidal ideation and suicidal behavior. Muthukumaraswamy says a 35-percent response rate and a 5-percent SAE rate means for every seven patients positively responding to the treatment, one person will experience serious negative outcomes.
In response to Muthukumaraswamy's comments regarding potential negative outcomes from this kind of psilocybin therapy, Compass Pathways says there is no evidence of a link between the adverse effects seen in the trial and the administration of psilocybin.
"This assumes a causal relationship between the drug and all the reported adverse reactions – we don’t know that to be the case," the company says in an email to New Atlas. "COMP360 was administered on a single day, on which there were mild/moderate adverse reactions for some patients (eg. headache, nausea, fatigue). However, of the 12 patients experiencing serious adverse events, only 1 of them occurred within 24 hours of the dosing. The other 11 experienced theirs up to 62 days later. Therefore it is not clear that there is a direct link with administration of the drug.
"... treatment-resistant depression is directly associated with higher rates of suicidal thoughts, suicide attempts and completed suicide, so these adverse events may be related to the illness rather than the drug," the Compass Pathways statement continues. "None of the 12 patients who experienced serious adverse events achieved remission in this trial, so it is not unreasonable to suggest that this might be linked to the occurrence of these adverse events."
Compass Pathways say analysis of this Phase 2B data is ongoing, and the next steps will be to meet with the FDA in early 2022 to discuss design of the Phase 3 trials, which are hoped to begin later next year.
There are also a number of other ongoing Phase 2 trials testing psilocybin for a variety of conditions including major depressive disorder, alcoholism, anorexia, chronic pain, and cluster headaches. So undoubtedly there will be plenty more data to pore over as those trials deliver results in the coming months and years.
Muthukumaraswamy is a little more circumspect in his reading of the new data, suggesting lots more work is needed to home in on the most effective ways to administer these new psychedelic medicines.
“It looks to me like that there is going to need to be a bit of digging around in the data to work out how to optimize the trials / treatment / patient selections to improve both safety and efficacy,” he says. “This might take some time.”
Editor's note: This article has been edited to include a response from Compass Pathways regarding the serious adverse effects reported in the trial.
Source: Compass Pathways