- 🍸 Largest Ever Published Psilocybin Trial Shows Promise for Alcohol Use Disorder
- 📝 ARK Invest Publishes Analyst Research Into Psychedelic Therapeutics
- ⚖️ Complaint Alleges MindMed Co-Founder Stephen Hurst Syphoned IP to Ceruvia
Psychedelic Sector News
Largest Ever Published Psilocybin Trial Shows Promise for Alcohol Use Disorder
Analysis by Psychedelic Alpha Medical Advisor Michael Haichin, words by Josh Hardman.
- A Phase 2a trial of psilocybin-assisted psychotherapy for alcohol use disorder (AUD) found that heavy drinking days decreased by about 80% among those in the psilocybin group.
- This is the largest psilocybin trial published to date, despite the enrolment being around half the number planned (n=93 vs. an original target of 180)
- During follow-up, those in the psilocybin group had around 24% fewer heavy drinking days compared with a reduction of around 10% in the active placebo group.
- Less than 4% of patients with AUD are receiving an FDA-approved medication to treat it.
- Non-profit psychedelic drug developer B.More will continue this line of research via a Phase 2b trial, expected to commence early 2023.
In last week’s Bulletin (#116) we shared a high-level overview of a new study from NYU researchers that’s received a great deal of media attention: Michael Bogenschutz et al.’s psilocybin-assisted psychotherapy for alcohol use disorder (AUD) trial.
Participants (n=93) met the DSM-IV alcohol dependence standard, which represents moderate-to-severe alcohol use disorder, and had experienced at least four heavy drinking days in the month preceding treatment. Diphenhydramine, an antihistamine that can cause drowsiness, was used as an active placebo in the study.
The high-level finding was that, in the psilocybin group, heavy drinking days decreased by around 80% from baseline. What’s more, this effect seems sustained in many participants: around six months after the drug sessions, rates of abstinence in the psilocybin group were almost double that of the diphenhydramine group. We’re not likely to get any longer-term data from this study comparing psilocybin to the active placebo, as all participants were offered an open-label psilocybin session at week 38 (provided they continued to meet safety criteria, and had participated thus far).
There were no serious adverse events in the psilocybin group.
Notes and Nuance
Psychedelics for AUD: a lineage of anecdotes and exploratory research
It’s LSD, not psilocybin, that has the richest history of anecdotal evidence in the treatment of alcohol use disorder in the West. Many are aware of the tale of Alcoholics Anonymous (AA) co-founder Bill Wilson, who was effectively expelled from his own organisation after extolling the benefits of LSD for overcoming alcohol use disorder.
Back in 2012, Teri Krebs and Pål-Ørjan Johansen published the first quantitative meta-analysis of randomized controlled trials of LSD for alcoholism. The studies had been published in the late 1960s and early ‘70s, during the ‘first wave’ of psychedelic research. The pair concluded that a single dose of LSD, given in the context of an alcohol treatment program, “is associated with a decrease in alcohol misuse.”
Today, amidst the so-called ‘psychedelic renaissance’, psychedelics are once again being explored in the clinic for myriad conditions. Substance use disorders, or ‘addictions’, feature heavily: the present study represents the largest psilocybin trial ever published (Compass Pathways’ Phase 2b study remains unpublished), and a study of psilocybin for smoking cessation was the first to receive federal funding to investigate the therapeutic potential of classical psychedelics in over fifty years (just 200 miles down the road from NYU at Johns Hopkins).
Enrollment: Slower and Lower than Hoped
The study recruited participants from March 2014 through March 2020, a whopping six year period. This long period of time was due to a number of factors including the lack of staff availability due to limited funding, as well as Bogenschutz’s move from the University of New Mexico to NYU in 2015.
Originally, investigators had planned to enrol 180 participants, but a COVID-induced mandatory suspension (which was indefinite) ultimately halted the trial at just over half of its planned enrolment: 95 randomised participants. While the number of participants was lower than researchers may had originally hoped, the retention of participants was excellent.
Throughout the trial, psilocybin was provided by “the Usona Institute, Nicholas Cozzi at the University of Wisconsin-Madison, and David Nichols at Purdue University.”
The value of therapy
Both drug groups received 12 weeks of manualized motivational enhancement and cognitive behavioural therapy; both of which are evidence-based interventions for AUD. Four of these sessions took place prior to the first psilocybin session, four took place between the two dosing sessions, and the remaining four were delivered after the second and final dosing session.
Participants were not reimbursed for attending any of these therapy sessions (both drug-assisted and conventional), but did receive compensation for completing assessments throughout the course of the trial (up to $560).
The impact of this therapy is tentatively reflected in the data. Prior to the first dosing session, in both the psilocybin and diphenhydramine groups the number of heavy drinking days was less than half that reported at screening four weeks earlier. While this should be hedged with the recognition that this was not a main outcome nor corrected for the multiple comparisons problem, the magnitude of the reduction probably hints at the not-insignificant efficacy of therapy alone (note also that participants were required to attempt to remain abstinent during the week immediately preceding the drug administration sessions).
Editor’s note: researcher Matthew Baggott also noted this screening to pre-drug session drop in drinking in a short Twitter thread. He pointed out that this is “a common phenomenon in substance use treatment research”, with a partial explanation being that people “disproportionately seek help when things are particularly bad”. Such lows are “usually followed by a return to more typical use patterns”, he explained, adding that another factor “is that the feeling of getting help orients people in a positive direction”.
In a sentiment echoed by this author, Baggott goes on to express: “To the extent that this 2nd factor is important, it’s an implicit indictment of how bad healthcare is in the US. Just enrolling in the study, feeling hopeful, and having 4 talk therapy sessions has, at least superficially, about as much positive impact as psilocybin!”
We know that high-quality therapy is effective, and it’s been reflected in late-stage psychedelic trials such as MAPS’ first Phase 3 trial of MDMA-AT for PTSD. In that trial, placebo with therapy had a substantial effect on patients’ PTSD severity scores.
Dose Escalation; One Trip is All it Takes?
The investigators employed a dose escalation protocol, starting with 25mg/70kg bodyweight for psilocybin, or a typical 50mg dose of diphenhydramine (e.g., Benadryl). If the first dose is tolerable and participants agreed, the second dose was increased: in the psilocybin group, the dose increase depended on the participant’s Mystical Experience Questionnaire score (a score of 0.6 or above would lead to a 30mg/70kg dose, while a score below 0.6 would lead to a 40mg/70kg dose to increase the likelihood of a mystical-type experience), while the diphenhydramine group’s dose was simply doubled to 100mg which would increase any sedative effects.
The 40mg/70kg dose rivals some of the largest psilocybin doses used in modern trials, such as the 42mg/70kg (0.6mg/kg) dose used in a Phase I trial by the University Wisconsin-Madison in healthy volunteers. Because the study used weight-based dosing, at least one participant’s second session had a psilocybin dose of 64.5 mg, though the average second session psilocybin dose was 37.7 mg.
These second session doses of psilocybin are higher than the fixed doses seen in studies of psilocybin for depression, where 25 mg is most commonly employed. Investigators pursuing psilocybin for other substance use disorders, meanwhile, are also employing dose escalation protocols (e.g., a University of Wisconsin, Madison, study of psilocybin for methamphetamine use disorder) or higher doses (e.g., a Johns Hopkins study of psilocybin for opioid use disorder).
Notably, there’s a large reduction in various drinking outcomes following the first psilocybin session, but not the second (likely larger) dose. It is possible that the second session could be contributing to the maintenance of effects, but without a comparison of one vs. two dosing sessions it’s impossible to know.
Interestingly, the planned Phase 2b study by B.More (see below) will deliver just one administration of a fixed dose (30mg) of synthetic psilocybin (or the active placebo, niacin), perhaps hinting at a hunch that one trip is all it takes.
As is the case with many psychedelic trials, blinding is a significant issue. The present trial employed an active placebo, which is intended to produce subjective effects that may partially imitate those of the psilocybin arm – at least to psilocybin-naive participants (note: the present trial did not require that participants be psilocybin- or even psychedelic-naive; so long as they had not used a hallucinogen in the past year, or more than 25 times in their life).
However, the active placebo proved ineffective in generating blinding integrity. 93.6% of participants guessed their treatment arm in the first session, with 94.7% guessing correctly in the second. Study therapists were effectively unblinded, too, with over 90% of them guessing the treatment arm correctly in both sessions (by the second session, therapists guessed correctly 97.4% of the time).
Given that only a handful of participants were effectively blinded (and even in these cases, we don’t know for sure that their accompanying therapists remained blinded as well), should we even be calling this a “double-blind randomized clinical trial” at all?
Psychedelic researcher Balázs Szigeti suggested that this points to a broader issue regarding the inadequacies of active placebos in psychedelic trials: they “wont [sic] solve the blinding issue of #psychedelic trials”, he wrote in a Twitter thread. Given the “very specific subjective effects of psychedelics”, Szigeti continued, “in most cases its [sic] easy to decipher whether its [sic] due to a psychedelic or some other drug.”
Even if a participant is genuinely psychedelic-naive, research ethics standards dictate that participants are informed of the types of physiological and subjective effects they may experience during a trial. Szigeti points out that this might make blind-breaking even easier.
It doesn’t look like the blinding issue in psychedelic trials will be solved anytime soon.
Note: one of the very few participants in the trial that did not correctly guess their treatment arm was featured as one of two patients at a post-publication press conference. As Rich Haridy reports for New Atlas, trial participant Paul Mavis described the treatment as “significant” and “game-changing”, in spite of the fact that he had just one week prior found out that he received diphenhydramine, the placebo. Even after receiving psilocybin as part of the open-label session, Mavis was still unable to identify that he had received the placebo in the first two sessions.
Haridy suggests that NYU downplayed the fact that Mavis was a participant from the placebo arm of the study, for example by neglecting to include it in a patient bio distributed to press. Haridy concludes:
“The findings in the new research are undeniably promising, indicating psilocybin could be helpful in treating alcohol use disorder. But in presenting this new study, and underplaying the impact of the placebo problem, the researchers have somewhat revealed a bias that is relatively prevalent in the world of modern psychedelic science. A [sic] underlying belief that these drugs work, will be approved soon, and the research currently being conducted is generated to serve and validate that pre-existing belief.”
The Path Forward for Psilocybin for AUD
The day after this study was published, non-profit psychedelic drug developer B.More announced that it has received the all-clear from the FDA to commence a Phase 2b clinical trial of its synthetic psilocybin (SYNP-101) in AUD.
Michael Bogenschutz will be principal investigator for the trial, which is expected to commence early 2023. B.More, which is led by Carey Turnbull, hopes to enrol 226 patients who will receive either 30mg of the synthetic psilocybin or an active placebo, niacin.
The present study has been captured in a provisional patent application filed by NYU Grossman School of Medicine, on which Bogenschutz appears as an inventor. However, the researcher has “formally waived all rights and has no prospect of financial gain”, according to the conflict of interest disclosures at the foot of the paper.
The declaration goes on to explain that the data presented in the study has been licensed to B.More “for a nominal sum”.
ARK Invest Publishes Analyst Research Into Psychedelic Therapeutics
ARK Invest explores psychedelic therapeutics in its latest analyst research piece. The article has a significant focus on presenting a cost-benefit analysis of psilocybin therapy versus standard of care, then using these assumptions to project a market size for medical psilocybin.
Ultimately, the report’s author Pierce Jamieson lands on a $5.5bn 10-year net present value for psilocybin in the treatment of MDD and TRD in the U.S.
The article’s conclusion begins:
“In this article, we explored the therapeutic merits and investment prospects associated with psychedelics, specifically Psylocibin [sic]. While this abridged summary of the ongoing work on psychedelics is by no means comprehensive, we hope that it is a useful starting point for investors interested in evaluating the space. While psychedelics have the potential to improve the way psychiatric conditions like MDD, TRD, PTSD, and OUD are treated, they also come with economic, regulatory, and health risks that should be considered carefully by investors, drug developers, and patients.”
Complaint Alleges MindMed Co-Founder Stephen Hurst Syphoned IP to Ceruvia
In complaints filed with state courts (now bumped to federal court – here’s the California one), MindMed co-founder and former CMO Scott Freeman has sued fellow MindMed co-founder and former co-CEO Stephen Hurst. Freeman alleges that Hurst carried out a scheme to exercise control over MindMed at the expense of Freeman and other members of Savant HWP, where Freeman was also CMO.
Freeman’s complaint also alleges that Ceruvia Lifesciences and its founder Carey Turnbull benefited from Hurst’s alleged actions, which are alleged to include fraud, extortion, and embezzlement; among other claims. The complaint alleges that Ceruvia has ended up in a powerful position vis-a-vis MindMed in terms of IP, particularly related to LSD and BOL-148.
While this is the first time the allegations have become publicly known, the earliest of the two parallel complaints was filed back in July. Remember: complaints like this represent just one side of the story, and should certainly not be viewed as fact.
Note: See Bulletin #114 for background on Freeman, who has lately become a shareholder activist against MindMed.
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