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):

1. 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.
   
   
2. 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.
   
   
3. 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.”

Our Thoughts

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.