Past and Current Status
Later this year the Food and Drug Administration (FDA) will decide whether MDMA, the drug commonly known as "ecstasy," is a medicine.
Last month, Lykos Therapeutics, which has sponsored multiple positive clinical trials of MDMA-assisted psychotherapy for posttraumatic stress disorder, submitted a New Drug Application for the psychedelic to the FDA. Posttraumatic stress disorder affects 7% of Americans and about a third of patients with this frequently debilitating condition are not helped by existing treatments. The submission of a New Drug Application for MDMA represents the possibility of relief for many patients experiencing immense suffering, while providing the FDA with its first opportunity to evaluate a psychedelic's medicinal potential.
This striking development comes after nearly 40 years of efforts to restore therapists' ability to legally incorporate MDMA into their work. From the late 1970s to mid-1980s, many therapists augmented individual, couples, and group therapy with MDMA, producing promising results, though no randomized controlled trials were conducted then. This work stopped when the Drug Enforcement Administration (DEA) designated MDMA a Schedule I drug with no accepted medical use and a high potential for abuse in 1985, over the objections of many physicians and therapists.
If this history is surprising, you aren't alone — many behavioral health professionals aren't even aware of it. You may also be unaware that other psychedelics, such as LSD, mescaline, and psilocybin, saw clinical use in the 1950s and 1960s, with encouraging findings for conditions like alcohol use disorder and psychological distress in patients with cancer. However, these and most other psychedelics were designated Schedule I drugs in 1970, when the Controlled Substances Act was passed amid growing non-medical use of psychedelics. MDMA was spared at that time, since its psychoactive effects were still unknown.
Because of complex regulations stemming from psychedelics' new Schedule I designation, clinical research into their safety and efficacy was largely curtailed. With significant collective efforts, it was revived in the 1990s and early 2000s by researchers seeking to give the medicinal potential of these compounds a second look.
Now, with only 6 to 10 months before the FDA decides on MDMA's fate, psychiatry could begin reintegrating psychedelic-assisted therapy before year's end. Promising findings in recent industry sponsored phase II clinical trials of other psychedelics, such as psilocybin for depression and treatment resistant depression, as well as LSD for generalized anxiety disorder, suggest MDMA will not be the lone psychedelic in psychiatrists' armamentarium for long if it becomes FDA-approved.
Psychiatrists appear hopeful about psychedelic medicine's potential return. In a recent survey of psychiatrists across the US, 81% believed psychedelics show therapeutic promise, and over half planned to use them upon FDA approval. This optimism, amid an otherwise discouraging time of record-high suicides and overdose-related deaths, stems from the possibility of a new psychiatric treatment paradigm in which some patients may derive months or years of clinically meaningful benefits from a few — or even a single — psychedelic exposures. This approach would obviate the need for some patients with psychiatric conditions to take medications every day, which too often leads to poor adherence and problematic side effects, such as sexual dysfunction. Psychedelics may also offer new hope for patients with treatment resistant psychiatric conditions, which range in prevalence from 20-60% depending on the particular diagnosis.
Considerations to Implementation
At Cleveland Clinic we are conducting clinical trials of psilocybin and LSD, which has provided us with opportunities to better understand obstacles to scaling up safe, effective psychedelic-assisted therapy. We will now elaborate on some of these.
While psychedelics could yield important treatment advances, their return to medicine is likely to be accompanied by unique challenges. Because psychedelics can induce deep mystical states, behavioral health providers may be faced with the unfamiliar proposition of making spirituality a more central part of their work. There are also likely to be a number of implementation hurdles given the training and infrastructure needed to safely treat patients with highly controlled, intensely psychoactive compounds.
Psychedelic-assisted therapy is complex work for both patient and therapist. Dosing sessions typically involve one or two therapists caring for a patient whose consciousness is altered for 6-8 hours. Prior to psychedelic treatment, patients must undergo multiple preparatory sessions during which they become acquainted with their treatment team and learn what to expect from the psychedelic experience. Following their dosing sessions, patients move on to non-drug integration sessions where they learn to incorporate psychedelic insights into daily life to facilitate durable behavioral change.
Due to in-person monitoring needs during psychedelic dosing sessions, we do not foresee providers being able to prescribe psychedelics for home use. Because trained psychedelic-assisted therapists are currently few and our healthcare system has not yet erected the infrastructure to deliver this novel treatment, broad clinical dissemination will likely take years. To ensure safety and maximal efficacy, the FDA is expected to require a Risk Evaluation and Mitigation Strategies (REMS) program and specific training for healthcare professionals wishing to work with psychedelics. While some psychedelic-assisted therapy training programs already exist, whether certificates from these programs would meet future FDA requirements is unknown.
The Multidisciplinary Association for Psychedelic Studies, the non-profit parent organization of Lykos Therapeutics, ambitiously plans to train 25,000 MDMA-assisted therapists by 2030, and some prominent psychedelic research centers are developing their own training programs. However, an initial bottleneck of psychedelic-assisted therapists should be expected if MDMA is FDA-approved. Providers hoping to deliver psychedelic-assisted therapy will also need tailored treatment spaces. Because psychedelic effects are influenced by the physical environment, optimal dosing rooms look like living rooms, with a couch or bed for the patient to lie on, and walls adorned with calming artwork.
In its current form, with two therapists treating a single patient, a round of MDMA-assisted therapy is expected to cost $10,000 to $15,000. This has raised concerns about accessibility, including potential racial disparities in access. To prevent a system dominated by expensive cash only practices, which has occurred with ketamine for depression due to poor payer coverage, sufficient payer reimbursement for this intensive intervention will be essential.
Studies suggest MDMA-assisted therapy for PTSD is cost effective, with payers breaking even in less than four years. However, with Americans typically switching health insurance plans every 3 to 4 years, this time horizon may not be appealing to payers. For payers covering MDMA-assisted therapy, prior authorization requirements requiring failure of standard trauma focused therapy and multiple antidepressants may be common initially.
Finally, similar to esketamine providers, psychedelic-assisted therapy providers will need comprehensive administrative support for interfacing with payers, complying with likely FDA REMS patient monitoring mandates, and care coordination. This could present challenges for small private practices. Such practices may also be reluctant to expend capital upfront for MDMA via the Buy and Bill model, which many insurers have required for esketamine. Private practitioners may also be wary of the risk of sizable revenue loss when dosing sessions are canceled on short notice.
Discovery and Prompt Intervention
Psychedelics appear poised to also advance our understanding of neuroscience. As our knowledge of their neurobiological mechanisms accelerates, we may eventually be able to develop new derivative psychiatric medications that meet or exceed the therapeutic efficacy of psychedelics without altering consciousness. Such possibilities have spurred the development of psychedelic research centers around the world. With expanding grant support from the National Institutes of Health after a long period of absence from this research space, psychedelic science is expected to grow significantly in coming years. Neurology may stand to gain as much as psychiatry from these drugs, with preliminary evidence suggesting psychedelics' ability to induce neuroplasticity (the growth and reorganization of neural networks in the brain) could help treat conditions like dementia, chronic pain, traumatic brain injury, and stroke.
Cognizant that most front-line treatment for mood and anxiety orders take time to exert a meaningful effect, whether waiting 1-2 months for an antidepressant to kick in or delivering cognitive behavioral therapy over multiple sessions, the quick onset of psychedelics is of much clinical interest. Where psychedelics fit in the armamentarium of the behavioral medicine specialist remains to be seen, especially as it pertains to treatment resistant mood disorders. Interventional psychiatry, commonly encompassing treatments such as electroconvulsive treatment (ECT) and transcranial magnetic stimulation (TMS), are used for patients who have failed multiple antidepressant trials. Future studies of psychedelics may validate early use of these compounds in the depression trajectory, allowing patients to recover faster and with a sustained response.
To address the intensive time demands of psychedelic dosing sessions, studies are currently evaluating the therapeutic potential of short acting psychedelics such as dimethyltryptamine (DMT) and 5-MeO-DMT. While requiring dosing sessions of less than 2 hours in duration, the subjective effects of these psychedelics are typically much more intense than those of longer acting psychedelics, so tolerability must be closely investigated. Conducting preparation and integration sessions in group therapy formats appears a likely means of reducing costs and maximizing access. Researchers are also exploring dosing sessions led by a single therapist rather than two, with favorable results thus far. There is also considerable debate within psychiatry about how much psychological support is required for safe and effective psychedelic treatments. Important work remains to be undertaken on bringing a personalized medicine approach to psychedelic-assisted therapy by identifying patients most likely to benefit from it and tolerate it well. We also have much to learn about the optimal positioning of psychedelics in behavioral health treatment algorithms to optimize cost-effective deployment.
The Role of Comprehensive Treatment Centers and Education
Since behavioral health patient populations in academic medical centers often have severe psychiatric conditions with high levels of medical comorbidity, comorbid substance use disorders, and suicidality, we suspect these facilities will play an important role in delivering psychedelic-assisted therapy to higher risk populations. While academic medical centers can more easily handle some of the hurdles to clinical uptake facing private practices, they face implementation barriers of their own, including complex bureaucracies and internal competition for space and other resources.
Growing data for psychedelics in rapidly treating cancer-related distress makes their integration by cancer treatment centers likely, a possibility Sunstone Therapies is pursuing. Notably, psychedelic biotechnology companies are collaborating with behavioral healthcare chains specializing in the delivery of TMS, esketamine, and other advanced therapeutics. Cybin and Compass Pathways have both announced collaborations with Greenbrook TMS to explore delivery models of psychedelics in their clinics.
As we await the anticipated FDA approval of the first psychedelic, behavioral health providers are increasingly contending with how to counsel patients with psychiatric conditions considering self-treatment with psychedelics or attending psychedelic retreats. We must navigate the difficult, but important, task of educating patients that psychedelics are not safe for everyone, particularly outside of clinical settings. This issue is now particularly salient with the recent decriminalization of naturally occurring psychedelics in multiple cities, as well as the legalization of facilitated, non-medical psychedelic administration in Colorado and Oregon. Unfortunately, many patients are reluctant to discuss psychedelic use with their providers due to concerns about stigma and other issues.
Many are also unaware that people with cardiac conditions, seizure disorders, personality disorders, and personal or family histories of bipolar disorder or psychotic disorders are typically excluded from psychedelic clinical trials for safety reasons. As psychiatrists we have seen the rare but serious consequences of non-medical use of psychedelics gone wrong, such as mania in people with bipolar disorder and psychosis in people with a family history of psychotic disorders. With so little education on psychedelics delivered in behavioral health training, there is an urgent need for incorporating psychedelic harm reduction courses into these programs and continuing education programs for practicing providers. This will help providers competently counsel patients on the psychological and physical risks of non-medical psychedelic use, as well as potential interactions between psychedelics and other psychiatric medications.
With psychedelic medicine's resurrection a possibility later this year, it is clear that optimizing psychedelics' public health impact will require significant forethought and concerted scale up efforts. To reap the most from these powerful compounds for our patients, we should begin planning for their return to medicine now.
Disclosure: Dr. Barnett has financial relationships with the following companies developing psychedelic treatments: CB Therapeutics, Compass Pathways, and MindMed. Dr. Pozuelo has no such relationships to report.