The results of a 59-patient trial of psilocybin versus escitalopram (a common SSRI) for depression published this week, attracting a great deal of attention. Commentary on this paper constitutes the bulk of this week’s bulletin, which we’re dubbing a Special Edition for that purpose.
Special Edition: Psilocybin vs. SSRI
Expert Commentary on the Highly-Anticipated SSRI vs. Psilocybin Publication
A long-awaited study that pitted psilocybin against the SSRI escitalopram (brand names include Cipralex, Lexapro) was published in the New England Journal of Medicine (NEJM) this week.
Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., . . . Nutt, D. J. (2021). Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine, 384(15), 1402-1411.
The study’s publication in the NEJM—one of the oldest and most prestigious medical journals—is, in itself, a significant moment. It was also covered widely in mainstream media outlets, including NBC; Scientific American; BBC; Rolling Stone; the Guardian; and others.
However, the results don’t appear to have met the lofty expectations of many. This is due, in part, to the study’s design, including the scales of depression that were chosen as the primary outcomes.
Speaking to Psilocybin Alpha, Psilera Bioscience’s Co-Founder and CEO Chris Witowski explained, “By primary endpoints there was no difference in efficacy, however, when you look at other endpoints there seem to be better outcomes trending towards psilocybin.”
Part of the issue is also to do with the size of the trial, and its length, explained Witowski: “Many psychiatric disorders like depression are difficult to quantify which is why large trial populations are needed to prove significance. Perhaps longer observational periods can better assess side effect profiles and quality of life, which aren’t great for most antidepressants (weight gain, sexual dysfunction, sleep issues, etc.), and likely tend to favor psilocybin.”
“When seeking drug approval,” Witowski continued, “you have to show better effectiveness than current treatments, which this trial does not, so this underlies the importance of proper clinical design.”
Ending on a forward-looking note, which I’m sure readers will agree with, Witowski explained: “There is still promise for psilocybin in the treatment of depression but more studies are needed to prove this in the eyes of regulators; the best way to do this and increase access is through top-quality science and clinical research.”
In a similar vein, Chair of Columbia University College of Physicians and Surgeons, Jeffrey A. Lieberman, MD, placed this study in its broader context:
“Recent clinical trials, such as the Carhart-Harris studies, are promising. But the research is still in the early stages; sample sizes, for the most part small; and there are major knowledge gaps. For example, we still don’t understand how these drugs produce their mind-altering effects. Before the new wave of interest once again swamps our best intentions, we must provide the solid scientific foundation to identify and address the risks and benefits of these experimental medicines and apply renewed rigor to the investigation of their therapeutic benefits and safety. If we don’t, the novelty of the idea might once again scuttle their game-changing potential.”
Given the significance of this publication, we invited a domain expert to present a deeper dive. Below, Boris D Heifets does just that.
Readers are also encouraged to review Science Media Centre’s roundup of expert reaction to the trial, with comments from Prof Kevin McConway, Prof David Owens, Prof Guy Goodwin, Prof Anthony Cleare, Dr James Rucker, Dr Paul Keedwell, Dr Sameer Jauhar, Dr Andreas Reif, Prof Gitte Moos Knudsen, Prof Phil Cowen, and Dr Eric Ruhe.
In the spirit of bringing experts to the table (or, your screen/inbox), we asked Boris D. Heifets, MD, PhD to provide a more in-depth commentary on the paper. This commentary is reproduced below.
First off, the authors should be congratulated on pulling off the first randomized, controlled study of psilocybin for the treatment of major depressive disorder. These studies are expensive and difficult (we are starting a similarly designed trial of psilocybin for chronic pain with colleagues at UCSF & UC Berkeley) and despite all the caveats attached to their findings, the fact that it’s appearing in NEJM speaks to the incredible importance of finding better treatments for severe psychiatric disease. However, this study has some very unfortunate (and unlucky) design features that make it difficult to interpret.
- Largest study yet, and the first randomized study with an appropriate comparison group to study how effective psilocybin might be;
- psilocybin shown to be safe with a side effect profile comparable, or maybe better than, the leading SSRI;
- authors used several different scales to assess symptoms of depression, including measures that the study participants reported and standardized ratings by the study clinician.
- Despite many strong positive signals that psilocybin actually did out-perform the SSRI, the study was designed in a way that prevents drawing any conclusion about their results. Deciding on your primary outcome measure is something clinical researchers routinely do before a study (and post publicly), to prevent cherry-picking data that favors a particular outcome. Out of the nearly dozen clinical scales they used to measure depression symptoms, they somehow happened to pick the one scale that showed no difference between the two treatments as their major (primary) outcome measure. Despite having favorable comparisons in the secondary outcomes, In the authors’ own words: “Because of the absence of a prespecified plan for adjustment of confidence intervals for multiple comparisons of secondary outcomes…no clinical conclusions can be drawn from these data.”
- Like virtually every study of psychedelics, it is incredibly difficult to keep the subjects “blind” to their treatment condition – the effects of the drug are too obvious. This study used an active treatment (SSRI) as a comparison group, so the hope was that may have kept the expectations of treatment benefit somewhat balanced between the groups, but unfortunately this study did not test how well their blinding procedure worked.
- What I can’t wrap my head around is the way this study is written, with the authors’ perplexing claim in print (Section S2. Methods, end of paragraph) and on Twitter that they expected psilocybin to be no better than a standard SSRI (both with psychotherapy). The statistical analysis plan and calculation of how many subjects to recruit reads exactly as one would expect for a study that expects a massive difference between the two treatments. The authors (and a huge number of academics, myself included, and journalists) have described psilocybin as a “game changer” and potential “breakthrough”. The palpable excitement around this emerging area of medicine is all predicated on the idea that this new class of medicines and these new ideas about psychotherapy would up-end our dated, ineffective ways of thinking about and treating depression and other psychiatric disorders. The entire motivation for doing a trial like this, in my mind, would be to show the world, in a well-executed, rigorous fashion, that the new treatment beats the old treatment on all the gold-standard metrics. To my eye, that’s what this trial looks like it was designed to do, and unfortunately it missed the mark. If the authors really believed from the get-go that these treatments would be similar, they could have designed the trial to test for equivalence, and they would have analyzed it accordingly. What we are left with is very difficult to interpret, except to say that we need to do it again with many more subjects.
- It’s more likely than not that existing metrics for depression are just not well suited to studying psilocybin and measuring its impact, e.g. emotional breakthroughs, meaning-making, spirituality. Hopefully the field will evolve and broaden its horizons.
Outlook for medicalization and commercialization
- It is formally speaking a negative study, despite all the promising signals, which is a rather surprising outcome for the field of psychedelic medicine. I don’t know what impact this study will have on psilocybin’s FDA approval (which I am generally in favor of), though I suppose the study design and lack of interpretability really doesn’t address the basic question “does it work for depression”. The title of this paper could just as easily have been “Serious people take psilocybin seriously because, hey, the NEJM is publishing a study on it”.
- This study may have some unwelcome implications for the industry developing around psilocybin for medical use. It will be harder to make a case that psilocybin is the game changing panacea some had hoped for – and harder to convince insurers to pay an order of magnitude more for a therapy that’s no better than an SSRI. What’s more, the therapeutic model incorporated in this study strongly hints at what’s to come – repeat dosing sessions. I already have very mixed feelings about cash ketamine clinics catering to patients with crippling levels of depression and chronic pain… the price tag on this may be much higher.
Psychedelic Sector News
GH Research, Exploring 5-MeO-DMT for Depression, Closes $125m Round
Dublin-based GH Research announced this week the closing of a $125m Series B Financing. The round was led by U.S.-based pharmaceutical investment firms RA Capital and RTW Investments.
The company’s lead candidate, GH001, is a drug product for the administration of 5-MeO-DMT through an inhalation approach. GH001 has completed a Phase 1 trial, and is now conducting a Phase 1/2 trial in patients with Treatment-Resistant Depression (TRD) – see our Psychedelics Drug Development Tracker for more.
GH Research is also exploring an injectable 5-MeO-DMT product, GH002. It seeks to progress this to clinical development, in addition to other drug delivery approaches and target indications.
Cybin Advancing Shorter Duration Psychedelic Molecules Through Preclinical Work
Earlier this week, Cybin announced plans to advance preclinical work pertaining to its orally-dissolving tablet (CYB003) and inhaled formulation (CYB004) – both of which are deuterated tryptamine candidates.
According to the press release, these molecules are designed to have a shorter duration of action and faster onset, while maintaining the clinical benefits of psychedelics like psilocybin.
- Former GW Pharma CFO joins Beckley Psytech Board;
- Awakn inks deal with University of Exeter; launches digital unit;
- Mydecine announces launch of “cutting-edge” therapeutic compound screening;
- Silo Wellness licenses psilocybin nasal spray IP in Colombia and Brasil.
California Bill to Decriminalise Psychedelics Passes Second Key Committee
Senator Scott Wiener’s Bill 519, which would decriminalise most psychedelics in the Golden State, passed a second key committee this week. The Bill passed the Senate Health Committee by a vote of 6-1. Next, the Bill will face the Senate Appropriations Committee. Read more at CBS.
Bicycle Day: Monday 19th April
We will be sharing an interview with a very special guest to celebrate bicycle day, which takes place Monday 19th April.
Stay Informed in 2021
We can only expect the rate of change and development in the psychedelic space to continue accelerating in 2021. Stay informed via our various platforms and channels…
Join our newsletter to have our Weekly Bulletin delivered to your inbox every Friday evening. We summarise the week’s most important developments and share our Weekend Reading suggestions.