Psychedelics And Treatment-Resistant Depression: Reactions To COMPASS' Published Results

(Part two of a four-part series)

See previous story in this series: Psychedelics And Treatment-Resistant Depression: An Overview Of COMPASS’ Latest Trial Outcomes

COMPASS CMPS’ Phase 2 trial published results elicited several comments from experts in the field as well as media coverage -see CNN’s Dr. Sanjay Gupta’s report. 

Yet, they all agree on one thing: more research is needed to determine psilocybin’s efficacy and safety profile.

Associate professor at UCL Dr. Ravi Das said that the results shown at week 3 were positive yet not ‘spectacular’ for psychiatric treatment and that the study reveals “some evidence for greater incidence of adverse effects” as referred to the three reported cases of suicidal behavior in the highest dose group, and lastly pointed out that there were “significantly fewer severely depressed people in the apparent ‘effective’ (25mg) dose group.” 

The latter critique was somewhat dismissed by Dr. Matthew Johnson, Ph.D., Professor of Psychiatry and Behavioral Sciences at Johns Hopkins, as not significant to the findings.

Dr. Natalie Gukasyan, a psychiatrist and post-doctoral research fellow at that same university, launched a Twitter thread regarding the definition of adverse events in psychedelics and their significance in a relatively small sample of people with TRD.

Yet another thing to consider about the publication of the trial’s results is that they were accompanied by an editorial by professor of psychobiology at Harvard Medical School Dr. Bertha Madras, PhD., stating several concerns regarding the trial’s standard of evidence and displayed efficacy being potentially compromised by expectancy or selection biases and its ability to scale up psychedelic therapy while retaining fidelity to the clinical trials protocols, and “unregulated clinics” together with an increasing push for broader, such as recreational access to psychedelics.

In Dr. Madras’ words, “The findings are both intriguing and sobering.”

Professor and head of psychiatry at the University of Edinburgh Dr. Andrew McIntosh seems to agree with the concern for expectancy bias. 

“Participants were not asked if they could guess whether they were in the arm of the study that received a higher dose of the psychedelic. This is important because psilocybin is associated with euphoria and changes in perception that may reveal that they are in a higher-dose or ‘more active’ treatment arm. People who believe they are in a higher-dose treatment group are potentially more likely to report treatment benefits, regardless of whether the intervention works, undermining the double-blind design,” McIntosh said.

Anthony Cleare, professor of psychopharmacology at King’s College London, is of the opinion that “there are several issues that need further study before this can become part of regular clinical practice,“ including psilocybin’s potential worsening of existing symptoms as part of side effects within a larger patient population. 

Specifically referring to the fact that the effects started to wear off by three months, he said: “We need to know how best to prevent the depression returning. This might involve adding in other treatments, such as psychological therapies, or repeating the psilocybin treatment periodically.”

Other research limitations so far would include the difficulty of finding a sound placebo, over-representation of certain participants -namely white and college-educated, with prior hallucinogenic experience and an interest in spirituality,  difficulty in understanding if and how the work of patients with therapists impacts their treatments vis-a-vis the drug itself, and standardizing the treatment outside supervised trials.

Now, the publication found some support, noticeably by University of Edinburgh head of psychiatry Prof Andrew McIntosh, who told the BBC that the trial provided "the strongest evidence so far to suggest that further, larger and longer randomized trials of psychedelics are justified".

Neuroscience and psychedelics researcher at Stanford University, Boris Heifets explained the durability of the psilocybin response was strong compared to ketamine: “Single ketamine infusion lasts about a week, but for psilocybin you can still see a clear separation in the study at six weeks, after a single dose. It’s impressive, looks real, and is hard to explain as a ‘placebo effect’ given that this population isn’t particularly prone to placebo effects that last weeks and weeks.”

Photo by Pawel Czerwinski on Unsplash

Next up: Psychedelics And Treatment-Resistant Depression: What Fellow Companies Are Thinking