- 🎢 Off-Label = Off the Rails?
- 🏷️ Prices Are Out, But Who’s Priced Out? Oregon’s Psilocybin Training Programs
- 🎤 Guest Commentary from Sandeep Nayak (Johns Hopkins), who shares his reanalysis of the NEJM psilocybin vs. escitalopram trial
- 📃 NIH Responds to Senators’ Questions on Psychedelic Research
- ⚖️ California’s Decrim. Bill is Back on the Agenda
Psychedelic Sector News
Off-Label = Off the Rails? Anticipating the Off-Label Promotion of Psychedelics
In a new Viewpoint piece in JAMA Psychiatry, Anna Wexler and Dominic Sisti sound the alarm about potential ethical issues that may arise with any FDA approval of MDMA and/or psilocybin; notably those resulting from off-label use.
“If and when psychedelics are approved by the FDA,” the pair write, “they will almost certainly be used not just for their approved indication(s) but for off-label ones as well.”
Reminder: off-label = a medication being used to treat a condition for which it does not have FDA approval.
Wexler and Sisti anticipate “3 main ethical issues”. We paraphrase them here (but, the Viewpoint is only a page long, you really should read the original which can be viewed for free when you make a JAMA Network account):
- Clinics will “likely overhype the use of the drugs and advertise that psychedelics can effectively treat certain indications even in the absence of scientific evidence.” The authors note that these claims are particularly ethically concerning given that some patient populations may end up “paying significant costs out of pocket”, given that off-label conditions are generally not covered by insurance.
- Credentials do not guarantee competency. While physicians have the necessary credentials to legally offer off-label treatments, the authors note that “any ethical administration of a treatment requires health care professionals to have competency, not just relevant credentials.” One might argue this is especially true in the case of psychedelic-assisted therapies, given the idiosyncratic nature of both the treatment paradigm and the patient experiences it gives rise to.
- Heterogeneity in protocols and dosing practices confounds attempts to harness real-world evidence on off-label indications. The evidence base for PATs “is built on protocols that typically include a psychotherapy session usually provided by highly specialized clinicians,” along with prep and integration work. Without guarantees of fidelity to these established protocols, can we confidently assess efficacy for a broader array of indications? The authors suggest that any attempts to do so will be “dampened”.
The authors urge:
“With high public enthusiasm, extremely bullish investors, and hundreds of newly established brain wellness clinics, all the pieces are now in place for expansive off-label promotion and use of psychedelics to quickly mushroom beyond what is safe. While off-label use may be a useful way to provide access to promising treatments, it must be done responsibly and with an eye toward future evidence-based advancements in medical science; regulators, policy makers, and health authorities must carefully examine and create guardrails for the promotion and off-label use of psychedelics.”
We don’t have to speculate too hard to imagine what this might look like: the authors cite TMS clinics as one such example, and the case of ketamine ‘spas’ are perhaps the most pertinent prospective analog here. Many of these clinics already market themselves as offering ‘psychedelic’ treatment, and as Wexler and Sisti point out, “[m]any of these same clinics are poised to begin offering psychedelics if and when they garner FDA approval.”
Some have raised concerns about the marketing and care practices of ketamine clinics/spas, which we have reported in earlier Bulletins. As such, the authors of this Viewpoint are right to raise concerns.
A first thought might be: what about REMS (refresher), won’t they ensure psychedelics remain safe and effective? While we expect that REMS with Elements to Assure Safe Use (ETASU) may dampen off-label prescribing*, it certainly does not preclude it. Remember, the FDA does not regulate the practice of medicine (or psychotherapy, for that matter) and as such in principle will not restrict a physician from prescribing an FDA-approved drug in an off-label manner.
* While it’s difficult to definitively account for the depressant effect of REMS with ETASU on off-label prescribing of medicines, our Pharmaceutical Advisor Michael Haichin reviewed a number of case studies and datasets in this endeavour. Based on these, comparing pre- and post-REMS program prescribing behaviour of a number of drugs, Haichin concludes that REMS with ETASU may reduce the extent of prescribing for off-label indications.
Manufacturers—in this case psychedelics companies like MAPS PBC and COMPASS Pathways—must refrain from marketing off-label prescribing: civil and criminal proceedings were brought against Jazz Pharmaceuticals for its promotion of Xyrem (sodium oxybate, also known as GHB) for off-label applications, for example.
But, it’s a grey area for clinicians and clinics. And, shouldn’t we expect manufacturers to turn a blind eye? After all, any patient registry (which we expect to be required by early psychedelics REMS programs) is owned by the manufacturer, and this could generate valuable signal-generating data regarding safety and efficacy in other indications.
Note: In the UK, rules surrounding the advertising of prescription-only medicines like ketamine are stringent and led to the MHRA upholding a complaint against Save Minds UK, a London-based ketamine treatment centre. But, what this author finds even more frustrating than the inappropriate advertising of prescription drugs is the company’s insistence on using American English on its website – it’s centre, not center!
The authors’ concerns are important and should encourage vigilance. But, off-label use shouldn’t be made a pariah. Where it’s evidence-based and thoughtfully controlled, off-label use can generate important insights into the safety and efficacy of medicines, potentially increasing the addressable patient population that could benefit from psychedelic medicine.
Prices Are Out, But Who’s Priced Out? Oregon’s Psilocybin Training Programs
The tuition fees for a number of approved Oregon psilocybin training programs have been announced. We collated the information below:
Note: All four providers with tuition information available state that they will allow therapists to pay in instalments.
Some have at this average price of $11,500, questioning whether people will be willing to foot such a bill.
This is certainly a steep investment, and is undoubtedly a significant outlay that’s simply beyond the reach of many. However, it is not an outlier when compared to more ‘conventional’ training programs in similar fields.
But, folks who train as psychotherapists in the more traditional sense, for example (and, it’s a very loose example as Oregon facilitators are certainly not expected to act as psychotherapists), are likely eligible for a suite of financial aid and student loans in a way that aspiring Oregon psilocybin facilitators are not.
If we assume that the price tag is representative of the costs of producing and delivering the training, plus some margin, what can be done to increase access?
Well, at a minimum we would hope that providers (both training providers and service centres) will offer scholarships to serve less privileged prospective facilitators. The dearest program, Synthesis’, has an Interest List for scholarships, but says that they are not currently available. Other providers have mentioned that scholarships are in the works.
Of course, we know there is at least one charity dedicated to granting scholarships to those who might not otherwise have access to psilocybin facilitator training: the Sheri Eckert Foundation (SEF).
There may be other, more creative methods of increasing access to training programs without reproducing the misery of student loan type systems. Your answers on a postcard, please!
Featured Psychedelic Jobs
Oregon is hiring for a number of roles to ensure the smooth roll-out of Psilocybin services in the state. There are two openings at present:
- Oregon Psilocybin Services Tracking Systems Analyst (JD + Apply)
- Oregon Psilocybin Services GIS Mapping Liaison (JD + Apply)
Guest Commentary: Reanalysis of the NEJM Psilocybin vs. Escitalopram for Depression Trial
A trial of psilocybin versus the SSRI escitalopram, published in the New England Journal of Medicine found that psilocybin was not statistically significantly superior to escitalopram using the primary outcome measure, the QIDS depression scale (Carhart-Harris et al., 2021). However, the remaining three depression scales (BDI, MADRS, HAMD—the secondary outcome measures) were statistically significantly superior. However, there was no a priori plan to correct for the fact that several tests were done, some of which might be positive by chance.
Correctly following the requirements of the dominant statistical practices, the trial was reported as indeterminate, as the primary outcome measure was not significant. The secondary outcome measures were, again correctly, declared uninterpretable – “no clinical conclusions can be drawn from these data”.
Thus, the formally allowable conclusion is that no conclusions can be made. This is remarkably uninformative, but a consequence of dominant statistical practices.
There are other statistical approaches. Bayesian statistics works by establishing a prior distribution (an expectation of what an effect is), and updating it with data to get a posterior distribution. In this analysis, I used skeptical priors, which posit that there’s no group difference between psilocybin and escitalopram. This is actually more conservative than standard classical practices, and lowers the risk of false positives, which allows us to make better use of all the data.
Bayesian statistics makes it easy to look at the evidence for specific hypotheses. Is psilocybin better than escitalopram? Is it better by a clinically meaningful degree? Is it at least not worse? Looking at these hypotheses, and taking into account all of the data, we conclude that, as administered in this trial, psilocybin is probably superior to escitalopram but not to a degree that’s clinically meaningful. It’s almost certainly at least as good.
Standard statistical practices require sample sizes for a study to be rigidly specified beforehand. The bigger the effect of your intervention, the lower sample size you need and vice versa. But you don’t know the effect size (that’s why you’re running the trial!), so how do you estimate a sample size? Incredibly, we simply make it up. If the true effect size is smaller than your guess, you may end up with an underpowered study, with a sample size too small to show a true effect. Classical statistical practices cannot distinguish whether a negative finding is truly negative, or simply indeterminate and requiring more data.
Bayesian statistics can do this however. Our results suggest that, for the primary outcome, the study was underpowered and required more people. For the future, there are Bayesian trial designs that do not require one to make up an expected effect size. Rather, you can run the trial and continue collecting participants until the evidence clearly shows that the effect is present or absent. This is a really logical trial design for early stage psychedelic studies, and on average would save resources. We argue for this towards the end of the paper.
Although Bayesian statistics is actually older than the classical statistical practices I’m describing, it has been historically impractical as it can be quite computationally expensive. This is no longer the case with modern computers, and the barrier to expanding the use of Bayesian statistics is now predominantly cultural. We hope that clinical researchers in psychedelics begin to adopt these practices more.
Read the full reanalysis, and access data, here.
NIH Responds to Senators’ Questions on Psychedelic Research
Marijuana Moment with the scoop:
Officials at two agencies within the National Institutes of Health (NIH) have acknowledged in a letter to two U.S. senators that federal prohibition makes it harder to study the benefits of psychedelics, requiring researchers to jump through additional regulatory hoops.
Well, the authors of the NIH response (Joshua A. Gordon, NIMH and Nora D. Volow, NIDA) didn’t make this a significant point in their response. Rather, they briefly noted that, “these studies must also follow Drug Enforcement Administration (DEA) requirements, including registration, inspection, and certification of the drugs.”
The bulk of the letter (available here) refers to the Institutes’ involvement in supporting psychedelic research, which includes via direct funding. The table below shows NIH funding of psychedelic research, broken out by Institute or Center (IC) and basic versus applied (mainly clinical) research. The data is for the most recent fiscal year of each active project (i.e., not lifetime spend).
The letter also addresses specific methodological difficulties with psychedelic research that will be no news to our readers, including the difficulties associated with conducting randomised placebo-controlled clinical trials of psychedelic drugs.
The Institutes’ also point out the lack of participant diversity in clinical trials of psychedelics in terms of both racial and ethnic diversity, but also medical histories with notable exclusions of those with family or personal histories of suicidal thoughts or behaviours, or psychosis.
Ultimately, the NIH favours an experimental therapeutics approach (see Waldman et al., 2009) whereby researchers seek to understand patient response in a high resolution; i.e., they focus on detailed phenotyping of such responses. The Institutes’ ambition is not only to understand the clinical effect of an intervention, but also to “generate information about the mechanisms underlying a disorder or an intervention response.”
This includes a focus on non-hallucinogenic psychedelics, which we expect to only increase among the Institutes.
Another Observational Microdosing Study
Last week a new microdosing article appeared in Scientific Reports. The observational study identifies “improvements in mood and mental health at one month” among microdosers relative to “non-microdosing controls”.
The study also sought to ascertain the additive effect of ‘stacking’, combining psilocybin with substances such as Lion’s Mane.
Remember: these types of studies are purely observational and can make no claims about causality. Refer to our November 2021 Bulletin for discussion of an earlier publication from the same group.
California’s Decrim. Bill (SB-519) is Back on the Agenda
Rolling Stone: “These Mormons Have Found a New Faith — in Magic Mushrooms”
Cassady Rosenblum for Rolling Stone:
Many of the post-Mormons I spoke with see the leap from Joseph Smith to mushrooms as shorter than one might think. “We believe in the gift of tongues, prophecy, revelation, visions, healing, interpretation of tongues, and so forth,” wrote Smith in 1842. The core principle of the faith is revelation, or the idea that God spoke to Joseph Smith, and can speak to you and me, too. According to Tess Huntington, a 29-year-old Divine Assembly member who has emerged as a prominent member due to her personal charisma and extensive experience using psilocybin to heal her own sexual trauma, Latter-day Saints are “already programmed to … seek the divine on the daily.” She quips, “A married [Mormon] couple probably talks to God more every day than they talk to each other.”
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