End of year Psychedelic Research Review

As 2021 is wrapping up into another Covid-winter(!), we thought it would be good to finish the year with a daily review of progress in psychedelic research these past 12 months and related matters, with our particular emphasis on their application to pain states. There were high expectations for many of these trial and often the data was nuanced and complicated, requiring deeper examination and analysis, but were largely stellar.

For our first highlight, the Imperial College study of psilocybin vs Escitalopram for major depressive disorder, with lead author Dr. Robin Carhart-Harris, set a notable milestone, which we previously wrote about here. The first psychedelic trial to be published in the prestigious New England Journal of Medicine in 60 years, participants with significant depression were randomly selected for either the psilocybin or Escitalopram (a top selling SSRI) arm. After multiple depression and accessory data inventories were collected from each participant, those in the experimental arm were given 25 mg of psilocybin on the first day of the trial and then given a daily placebo. Those in the Escitalopram arm were given a low dose (1 mg) of psilocybin as an “active” placebo in order to counter the expectancy bias and then a daily 10 mg dose of Escitalopram.

At three weeks the psilocybin group received another 25mg dose, considered a fairly high dose, and resumed with the daily placebo. The Escitalopram arm received another 1 mg dose of psilocybin and then their daily dose of Escitalopram was increased to 20mg. Both cohorts received extensive psychotherapy of 30-40 hours, employing investigator Dr. Rosalyn Watts therapeutic model of Accept, Connect, Embody (ACE). 

After the first week, in two of the secondary outcome inventories, 52-28% of the participants in the psilocybin cohort were in remission from depression and these numbers increased to 59-29% in remission at the end of the six-week trial.  The response rates (at least 50% improvement in symptoms) are similarly striking; 78-66% by trial end. Escitalopram came in roughly half of those outcomes; 29-6% for remission, 48-20% in response rates. 

The wrinkle in this study is that on it’s primary measure, the QIDS depression inventory, it didn’t show a statistically significant difference in performance between psilocybin and Escitalopram; that can also be read as psilocybin is at least as, if not more, effective than a current major standard of care SSRI. But that measure is now largely acknowledged as a false negative, because in the secondary measures and outcomes is where this study truly thrives, with psilocybin outpacing Escitalopram, often 2 to 1, on nearly all measures. In fact when describing these accessory data scores, even the stodgy NEJM described them thusly; All contrasts favoured psilocybin. None favoured escitalopram.”

As lead author Dr. Carhart-Harris meticulously Tweeted in the week before the release of the study in NEJM, the real outcome and story of this study is in the tables and appendices of the accessory data. Crucial measures like suicidality, the flourishing scale, anhedonia (with it’s significant implications for the bi-directionality between chronic pain and depression), well-being, etc.

Notable issues that have been raised post-study that likely affected the outcome are;

–Not all participants discontinued taking their anti-depressants pre-study or not for a long enough washout period necessary for dealing with SSRI withdrawal syndrome, so some the effect size was altered by those whose withdrawal symptoms were improved by getting back on Escitalopram. We also know that generally those who don’t have as long a washout period don’t have as good a response to psilocybin and other psychedelics, and right now the literature does not match what is well known in the clinical community, which is the washout period for SSRI is far longer than what is written.

–The QIDS scale frequently doesn’t match what other established scales show in findings and very likely is a poor assessment of the type of remission and response that psychedelics offer in relief in contrast to traditional anti-depressants. The rapidity and quality of the remission that occurs with psilocybin is almost impossible to describe to non-patients; it can be an extraordinary change in the state of consciousness in less than eight hours, from significantly depressed to not even a trace of it remaining, with an almost overwhelming sense of wonder and relief left in its place. QIDS really does not measure those outcomes, so once again, the accessory data is where these crucial results can be found.

And it was almost certainly a false negative. Some of the criticism  post-trial is that it was “underpowered”, that is to say not large enough to clearly show statistical significance. Total participants here were 59; contrast that with the millions of participants in mRNA vaccine trials for Covid.

We’re going to be highlighting other, significant research from this year, but in terms of participant/patient outcome and experience, this study has probably the largest impact  It shows there is a genuine therapeutic alternative to the standard of care and that it is superior in many respects once you examine the accessory data. It has fewer side effects and doesn’t need to be taken chronically (read: daily). And the remission rates can not be underscored enough; for some period of time (months or longer for a few) after a single dose  they were no longer depressed. It’s now a matter of determining best practices in therapeutic application and continuity of care to cement and create this new category of treatment.