Prescription Psychedelics: The Road from FDA Approval to Clinical Practice

Abstract

After languishing for decades from legal restrictions and stigma, research into psychedelic drugs is exploding, with the encouragement of the US Food and Drug Administration (FDA). Recent clinical trial successes suggest some long-banned drugs could soon be authorized as treatments for debilitating illnesses. Yet because of these drugs’ history, FDA approval would be just 1 important step in a complex process to transform these compounds into therapies. Incorporating psychedelic drugs into clinical practice will require peeling back multiple layers of legal prohibition, clarifying prescribing guidelines, and developing treatment models that work for drug makers, physicians, and payers. Although psychedelic research yielded promising early results in the mid-20th century, the association of these drugs with the 1960s’ counterculture spurred a legal crackdown against them. The federal Controlled Substances Act of 1970 not only banned the use of many psychedelics, but erected barriers that brought research virtually to a halt. Yet the past decade has seen a resurgence of interest, evidenced by a proliferation of new centers for psychedelic science and numerous clinical trials. The FDA has encouraged this research by granting “Breakthrough Therapy” status, a designation that accelerates the path to drug approval, to the study of multiple psychedelic drugs. In 2019, the FDA approved 1 of these drugs, esketamine, as a therapy for treatment-resistant depression. More recently, researchers published promising results from an FDA-approved phase 2 trial of psilocybin as a treatment for major depressive disorder.1Carhart-Harris R Giribaldi B Watts R et al.Trial of psilocybin versus escitalopram for depression.N Engl J Med. 2021; 384: 1402-1411Crossref PubMed Scopus (163) Google Scholar Perhaps most striking, in June researchers published remarkable results from a phase 3 trial—the final phase before seeking FDA approval—studying 3,4-methyl-enedioxymethamphetamine (MDMA) as a treatment for posttraumatic stress disorder.2Mitchell JM Bogenschutz M Lilienstein A et al.MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.Nature Med. 2021; 27: 1025-1033Crossref PubMed Scopus (112) Google Scholar Two-thirds of study participants who received MDMA-assisted therapy no longer qualified for a PTSD diagnosis 2 months after treatment, compared with 32% who received therapy alone. No serious adverse side effects were reported. If the results of a second phase 3 trial are similarly positive, the FDA could approve the treatment as early as 2022. These successes could pave the way for additional research into potential psychedelic therapies for a range of debilitating conditions, including substance abuse disorders, eating disorders, and end-of-life anxiety. Yet because of the history and distinctive features of psychedelic drugs, it will take more than successful trials, or even FDA approval, to turn them into therapies. As an initial matter, FDA approval would not mean patients could take psychedelic drugs home from the pharmacy. Indeed, the sponsor of the phase 3 MDMA trial, the Multidisciplinary Association for Psychedelic Studies (MAPS), will not seek approval of the drug itself. Rather, it will seek approval for a protocol of drug-assisted therapy in which specially trained professionals administer the drug in clinical settings and conduct guided therapy sessions. Any FDA approval of the drug would almost certainly be conditioned on a stringent set of such safety requirements, which the agency refers to as “elements to assure safe use.”3Marks M. Psychedelic medicine for mental illness and substance use disorders: overcoming social and legal obstacles.NYU J Legislation & Public Policy. 2018; 21: 106-140Google Scholar Even with FDA approval, psychedelic drugs would face additional hurdles from the Drug Enforcement Administration (DEA). Under the Controlled Substances Act, the DEA evaluates drugs to determine if they should be placed in 1 of 5 “schedules,” which are legal categories that place varying levels of restrictions on drugs based on assessments of their risks. Although the DEA normally makes this determination following FDA approval of a new drug, many psychedelic compounds have already been assigned to the most restrictive category, Schedule I. Drugs in this schedule cannot be lawfully prescribed for any purpose because the agency has determined they have no currently accepted medical use in treatment. Although FDA approval of a psychedelic drug would prompt the DEA to reassess that conclusion, doctors still could not prescribe it until the DEA changed the drug's schedule. Moreover, states have their own legal restrictions that would need to be revised before doctors could prescribe a previously banned drug. In some states, a change to a drug's federal schedule automatically triggers a similar change under state law. In others, however, this process can require action by a regulatory agency or even the passage of new legislation. Revising state-level restrictions could delay the introduction of psychedelic therapies in many states. There are also open questions regarding developing business models that will work for drug companies, payers, and physicians. Drug companies typically rely on patents, which grant exclusive rights to sell a drug for a limited time, to generate the revenue necessary to recoup research costs and generate profits. But psilocybin is not eligible for patent protection because it occurs naturally in nature, and the patent for MDMA expired decades ago. Accordingly, several companies are attempting to modify psychedelic drugs in ways that would allow them to claim patents. For example, several companies are working to develop analogs that have a quicker onset and shorter duration. MDMA and psilocybin can take 40 minutes to take effect and can last as long as 6 hours, during which time patients must be monitored by medical professionals. Developing drugs that could produce similar results in less time could help make these treatments more widely accessible. However, any modified drug would have to run the gauntlet of clinical trials, FDA approval, and re-scheduling before reaching clinicians. The search for shorter therapeutic regimens points to another pressing issue: reimbursement. Although these drugs are not expensive to manufacture, some treatments can require dozens of hours of therapy. MAPS estimates its MDMA-assisted PTSD therapy would cost $7543 per patient, more than 90% of which is attributable to therapists’ compensation.4Marseille E Kahn J Yazar-Klosinski B Doblin R. The cost-effectiveness of MDMA-assisted psychotherapy for the treatment of chronic, treatment-resistant PTSD.PLoS One. 2020; 15e0239997Crossref PubMed Scopus (11) Google Scholar Although this exceeds the cost of conventional treatments, MAPS contends the therapy's greater efficacy would save third-party payers money within 3 years. There are also questions regarding how physicians could lawfully prescribe approved psychedelic therapies. Once a drug is approved for a particular indication, doctors generally can prescribe it for other purposes as well—a common practice known as off-label prescribing. Yet under the Controlled Substances Act, physicians can be prosecuted if they prescribe drugs without a “legitimate medical purpose.” Although this prohibition is aimed at preventing doctors from acting as drug traffickers, the DEA has not defined what constitutes a legitimate reason to prescribe psychoactive drugs. Although treating PTSD or depression would clearly qualify, growing research suggests some psychedelic drugs may benefit healthy individuals as well.5Griffiths R Richards W Johnson M McCann U Jesse R Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later.J Psychopharmacol. 2008; 22: 621-632Crossref PubMed Scopus (407) Google Scholar It is not clear whether prescribing MDMA as an adjunct to couples therapy or psilocybin to enhance a healthy person's quality of life would subject physicians to potential prosecution. As drugs that have long been viewed as merely “recreational” gain acceptance as therapies, it will be increasingly important to clarify the law in this area. Although the psychedelic research revival is yielding promising results, challenges remain before these drugs will find their way into clinical practice. Yet this plodding process could enhance the likelihood that these therapies will actually take root. Given the longstanding skepticism toward psychedelic interventions, moving too swiftly might risk a backlash that could further stall research. Proceeding both with caution and openness offers the best hope for harnessing the potential benefits of these drugs while mitigating their risks.