No previous pharmaceutical playbook presents a perfect model for psychedelic medicalization due to the unique combination of 1) their Schedule I placement; 2) their long history of prior and current recreational use; 3) stigma against the drugs as well as mental health conditions; 4) dual/integrated modality of care (both pharmacologic and behavioral components); and 5) contradictory political involvement¹.

Many have used esketamine’s recent approval and commercialization as the closest analog for psychedelic therapies (PT), but this example only contains a few pieces of the PT puzzle. Ketamine is already Schedule III, thereby allowing for off-label use, and SPRAVATO was originally approved as an adjunctive medication to standard of care for a narrowly-defined patient population. Its application was also submitted by Johnson & Johnson, one of the most well-resourced pharmaceutical companies – contrasted to the outsider entities that have led psychedelics’ re-emergence – and presented in the standard pharma fashion: drug alone.

Drugs approved to treat substance use disorders (e.g. Chantix and Suboxone) have also been pointed to as potential comparators, since their Risk Evaluation and Mitigation Strategy (REMS) required that they be delivered in the context of state-of-the-art behavioral interventions (i.e. with use/harm reduction counseling). However, like J&J with SPRAVATO, these developers followed the traditional regulatory model of only getting a drug approved, not any accompanying therapy: the psychological support components were solved for post-approval.      

An overlooked example might be Truvada for HIV pre-exposure prophylaxis (PrEP), another Breakthrough Therapy drug that was 1) first in class; 2) burdened by historical stigma (against disease risk factors and the patient population); 3) fraught with misinformation; 4) brought forward by an unconventional applicant; and, 5) presented for approval alongside a standard of care (SOC) behavioral intervention (i.e. risk reduction counseling).

Background

Truvada’s label expansion (from HIV treatment to preventative) was nothing short of a paradigm shift. Before PrEP’s approval, the most effective methods of preventing HIV transmission were almost exclusively behavioral. The idea of chemoprophylaxis existed – such as anti-malarial drugs taken during periods of travel, or other medications taken as post-exposure preventive measures – but the idea that this approach could be used in everyday sexual health represented a distinct ideological shift toward biomedical science.

This piece will outline some potential lessons learned from the approval of Truvada for PrEP for the psychedelics industry as it navigates the aftermath of Lykos Therapeutics’ MDMA-assisted therapy (MDMA-AT) new drug application (NDA) non-approval, as well as the challenges that undoubtedly lie ahead with future medical psychedelic approvals.

Lesson 1: Overcoming low awareness and slow uptake by non-specialist providers

Because Truvada is an antiretroviral, at the time of PrEP launch most prescribers familiar with the drug were HIV specialists; yet today most scripts are written by non-specialists. Similarly, although located in specialized care now, to achieve the greatest impact, PT may eventually become a primary care intervention – at least as the referral point for compounds with subjective effects, but possibly a full stop for neuroplastogens.

This is due to how patients can access care. For example, specialists may be more difficult to access through an insurance plan, more expensive, or simply out-of-benefit (if mental health benefits or specific pharmaceutical products are not included) or network (due to limited contracted options). Therefore, initiatives to address a patient’s first encounter with the system – primary care providers (PCPs) – should be built to optimize intervention uptake. These include educational programs (on drug class, side effects, clinical management) aimed at this provider type, screening questions/procedures added to clinical forms/intake procedures, Current Procedural Terminology (CPT) codes established by the American Medical Association (AMA), and referral networks stood up in advance (by payors or grassroots efforts).

Optimization could also be achieved by task downshifting. Outsourcing discussion of risks and benefits to Artificial Intelligence (AI) /apps or referring to peer health navigators/counselors or lower-level/ paraprofessionals could be an option before treatment, as has been done with HIV and PrEP. Anticipating what tools will be needed by PCPs to balance psychoeducation and provide appropriate referrals will ease integration for these important first sites in the care continuum.

Lesson 2: Building infrastructure and partnerships for successful rollout

Working with payors to identify appropriate billing practices

Psychedelic therapies – even if delivered with minimal psychological support – require several inputs to the system that will require payor oversight and coordination, the orchestration of which will likely lead to slow adoption of coverage, regardless of which PT modality rolls out first. Similarly, PrEP implementation involved a number of components both preceding and following the writing of a script that took time to gain cohesive traction with payors:

1. Behavioral risk eligibility assessment
2. Risk reduction counseling/education
3. Laboratory eligibility assessment
4. Education on adherence, efficacy, and potential side effects
5. Ongoing laboratory/safety monitoring

These practices span at least three areas of coverage: clinician time, laboratory services, and pharmacy benefits.

In addition to provider education on steps 1-2 and 4, bundled services had to be incorporated into clinical practice guidelines. Similar to how Facebook groups have arisen for peer-to-peer sharing of ketamine billing tricks, a consensus on best billing practices had to be built for PrEP around which CPT codes could provide billing coverage for the varied clinician time and activities (particularly around the diagnosis change: from HIV-positive to “at risk”). Due to the frequency of laboratory procedures specified in the REMS, new benefits schedules needed to be socialized to payors for the drug to be administered within the appropriate safety monitoring timelines. This necessitated the creation of novel workflows for scheduling and coding on-benefit clinic follow-up.

Similarly, guidelines will need to be established governing which types of providers are covered to prescribe PT – e.g. MDs only, or advanced practitioners like Nurse Practitioners (NPs) and Physician Assistants (PAs)? What about PharmDs? To broaden access in rural populations – prescribing psychologists? There is state-specific variation in prescribing permission based on drug schedule and provider scope. In parallel, professional associations may need to weigh in on who can provide accompanying behavioral interventions and to what standards.

As has been raised elsewhere, surgery is another example of coordinated care which includes several different provider types in a room, being billed simultaneously – drugs, providers, and procedures. Will psychedelic products attempt this approach which, while common in other therapeutic areas, lacks real precedent in mental health? Suppose bundled services are not written into benefits. In that case, drug companies will need to decide if they would offer patient assistance programs (PAP) for pharmacy coverage, to augment the respective psychotherapy and lab benefits of insurance plans to increase access.

Generating patient demand and considering the creation of new support roles

About a year after the FDA approval of Truvada for PrEP (2012), The New Yorker ran an article, which gets picked up and recycled every couple of years, with the headline “Why is no one on the first treatment to prevent HIV?”

One can imagine how PT – in its current resource-intensive form, and with such noticeable side effects – could suffer a similar fate. For patients to benefit from a new treatment, they must be educated about it, barriers to access must be removed, and they need to be supported in adhering to it. This is the journey from (clinical trial) efficacy to (real world) effectiveness.

Around 2014, the HIV community became hip to the fact that patients still had many unanswered questions about PrEP. It was difficult to talk to one’s provider (whether for discomfort or lack of knowledge) about PrEP, and complex to get the medication and concomitant labwork covered by insurance. Not to mention how to manage side effects and speak to partners and loved ones about taking PrEP. Experts were baffled that such an effective intervention was going underutilized and sought to bridge the gap between approval and implementation. Thus emerged a class of paraprofessionals, PrEP Navigators.

Peer health navigators usually come from the peer group of at-risk populations and are therefore deemed trustworthy due to shared lived experience. For PrEP, this role grew out of early work funded by the “Be the Bridge” grants Gilead gave to community service organizations (CSOs). By its REMS, Gilead had been precluded from marketing Truvada for the prevention indication directly – and so through educational grants was able to enlist the help of community partners to create videos, educational webinars, community forums, chat lines, and provider pamphlets. Soon the Navigator role proliferated to all major cities and is a staple of HIV organizations today.

Similarities exist for prescription psychedelics – as has been seen with the success of Fireside Project, formation of PsyPAN, and in the development of hybrid models for coverage of off-label generic racemic ketamine infusion therapy via peer-to-peer learning amongst providers. On the patient side, peer health navigators are a cost-effective means of connecting with hard-to-reach-patients, and patient demand can help be a tipping point in any health innovation.

Lesson 3: Utilizing real world reporting structures to capture real time harm

The negative media coverage (post-ICER report) and subsequent polarizing FDA Advisory Committee that Lykos faced are not unique to psychedelics. Fears around viral resistance, risk compensation, and a surge in STIs surfaced in anticipation of PrEP approval, amplified by high profile attacks leading up to and during the PrEP Ad Comm by one of the largest AIDS service providers in the country (who – ironically, is also now one of the largest providers of PrEP prescriptions).

These concerns proved to be unfounded with PrEP rollout. Infectious disease surveillance systems exist to catch such adverse trends, and many current medical practice safeguards could be similarly leveraged for PT. Interventions must establish clinical and laboratory safety, but may not be powered to detect behavioral anomalies before Phase 4/post-marketing review. Indeed, this is part of the intention of any REMS (which may include registries), as well as the oversight of licensing boards and professional associations. Drug companies also maintain complaint hotlines as a rule. It is important to let existing infrastructure function as intended, with shore-ups to account for novel care paradigms and associated challenges.

Lesson 4: Managing expectations (in the era of 24-hour media cycle hype)

Often the narrative around medical breakthroughs elevates them to a level of promise which is in practice untenable. Indeed Dr. Robert Grant (the Principal Investigator of iPrEx – the first PrEP efficacy study) and Rick Doblin, as well as PrEP and MDMA-AT themselves, have all been lauded by TIME magazine as “most influential people” and “important medical breakthroughs”, respectively. This is just one example of overhyped media on both topics – dozens more exist.

When the results of iPrEx were published, they seemed lackluster to insiders – 44% reduction in infections was far below the efficacy proponents wanted or expected. Yet the unmet need was great, and the field was in dire need of innovation. Secondary analyses revealed adherence hugely impacted efficacy, so the researchers pivoted to target adherence strategies to improve effectiveness in later stages of research. Protection, it was found, could be boosted to percentages in the 70s and even 90s, depending on the levels of drug achieved in the body; with perfect adherence, efficacy is estimated to be 99%.

Avoiding language like “cure” or “one-and-done” to describe PT treatments is crucial to managing patient, caregiver, and insurer expectancy before, during, and after the use of these interventions. No medication in history has helped 100% of the disease, 100% of the time. Yet in the face of such life-threatening conditions – it can be seductive to desire innovations to be “slam dunks”. Psychedelics advocates seem most likely to be guilty of using such over-promising language. We need to be careful with our words, as people who have been suffering for a long time are listening, and poised to enter extremely vulnerable experiences.

Most psychedelics proponents – e.g. “healthy normals” seeking the “betterment of the well”, or folks with legitimate psychological diagnoses who became early adopters – did not stop at a single journey, so it’s dangerous to embellish simply in the hopes of gaining mainstream legitimacy. To that end, researchers should now be routinely utilizing expectancy measures (e.g. SETS) and validating new measures, such as the Psychedelic Media Exposure Questionnaire (PMEQ). All good science should strive to avoid publication bias, presenting treatment failure and instances of harm as much as success and benefit (see Lesson 3). Continued investment in the search for biomarkers could also help better target interventions to patients.

Lesson 5: Product differentiation is a patient-centered approach

Today, we have alternate dosing schedules and delivery formulations for PrEP to suit patients’ needs, and more are being developed. There is no one-size-fits-all, we need all the options in our toolkit. One can also look at all the reproductive health methods that people can choose. It’s a basic principle of harm reduction – meet people where they are. Likewise, there will be no compound, delivery method, or therapy style that is suitable for all potential patients seeking PT.

Different formulations, across multiple companies and compounds, are a good thing. This will create the ability to offer patient-centered, tailored solutions. The psychedelic ecosystem – which was reborn by nonprofit/public benefit drug development, has at times decried alternate formulations as patent grabs (and in some cases, they are). But for a wide range of consumer-driven patient preferences, we may actually need pills, oral films, nose sprays, transdermal patches, and intravenous/intramuscular formulations of these medications.

We can also extend this rationale to the ongoing debate in the ecosystem about whether “the trip” is necessary for the efficacy of these treatments. If it works (or is medically necessary) for a patient to bypass the subjective effects, this could create savings for the system and time/burden for patients. Ultimately the goal is many tools, beyond what are available currently, which seem to have garnered a consensus of insufficiency for many people to achieve remission.

Conclusions: New classes of drugs – and scientific revolutions – take time (but industry alignment will be crucial to success)

While PrEP is now a household name in medical practice, it is not for the average consumer. Likewise, psychedelic mainstreaming will be a long process; we are only at the beginning (i.e. somewhere left of infinity on the Gartner curve).

Lykos was always going to have the first-mover disadvantage. PrEP faced skepticism, stigma, low awareness, outsized fear of harm, and care infrastructure challenge. But a cross-functional group of activist scientists, policymakers, and caregivers created an ecosystem to deliver the biggest breakthrough in HIV in 20 years.

Think Pandora, Last FM. Whoever crosses the threshold first always gets bloodied. For second movers, it’s hubris to assume many of the same issues won’t resurface once the next company files their NDA. If it’s true the FDA moved the goalposts, the roaring proliferation of new developments in this field will all but ensure they get moved again. Whether it’s unblinding, abuse potential, contribution of therapy, adverse events, political or public influence, cost-effectiveness, or some TBD thing – the skeptics are waiting, both amongst decision-makers and broader stakeholders. The best solution is a coordinated response.

The industry is still in the process of norming. One only has to read Kuhn² or Gladwell³ to understand that a tipping point, a theoretical saturation, must be reached before scientific innovations take hold. There remain a substantial number of structural, logistical, practical, and legal processes still in need of validating to ensure all needed resources and pathways are appropriately in place – all part of the “forming, storming, norming, performing” cycle. As an inspiration, a recent trial – published 12 years after PrEP’s approval – became the first in history to report zero HIV infections in the active arm. This is a remarkable accomplishment given the endemicity of the virus in the countries where the research was conducted. Imagine what could be possible for psychiatric patient outcomes in the next 10+ years if we take lessons from history, band together, and get this right.

The recent formation of the Association for Prescription Psychedelics is an encouraging advancement for companies currently facing the FDA one-by-one, hoping they alone have figured out the answers to the many methodological questions riddling how to rigorously evaluate the efficacy and safety of these powerful and ineffable compounds. For the prescription psychedelic industry to advance, there must be a collective entity to coordinate action on issues that impact everyone.