This article by Natasha Sumner was originally published on Microdose and appears here with permission.
A growing body of research into the therapeutic use of psychedelics, including — MDMA, psilocybin, LSD, ketamine, and DMT, are delivering promising results to treat a wide range of conditions such as post-traumatic stress disorder (PTSD), depression, end-of-life anxiety, eating disorders, stroke, and chronic pain. Robin Carhart-Harris, head of the Centre for Psychedelic Research at Imperial College London, wrote for The Guardian, “we can no longer ignore the potential of psychedelic drugs…psychedelics appear to increase brain ‘plasticity,’ which, broadly speaking, implies an accelerated ability to change.”
This article provides a brief overview of the Food and Drug Administration’s (FDA) regulatory scheme around drug development, future clinical research of psychedelics, and legal challenges in this emerging area.
Clinical Trials with MDMA and Psilocybin
The FDA regulates all drugs sold in the United States, which includes research pertaining to psychedelics. Typically, once a new molecule has been screened for pharmacological activity and acute toxicity potential in animals, the FDA’s role begins and the legal status of the molecule changes to a “new drug” subject to specific regulatory requirements. The Multidisciplinary Association for Psychedelic Studies (MAPS) conducted Phase 2 clinical trials from 2004 to 2017 studying the effects of MDMA on PTSD.[1] Six randomized, double-blind, controlled clinical trials at five study sites were conducted. Active doses of MDMA (75–125 mg) or placebo/control doses (0–40 mg) were administered to individuals with PTSD during psychotherapy sessions in two or three eight-hour sessions spaced a month apart. Three non-drug 90-minute therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session. After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV[2] total scores from baseline than the control group. Depression symptom improvement was greatest for the active group compared to the control group.
In May 2021, MAPS released the results of its Phase 3 trial.[3] MDMA-assisted therapy reported a significant reduction in PTSD symptoms compared to those who received placebo with therapy. This is the first Phase 3 trial of any psychedelic-assisted therapy. These are incredibly important findings because “although SSRIs are associated with an overall response rate of approximately 60% in patients with PTSD, only 20% to 30% of patients achieve complete remission.”[4]
In a Phase 2 study comparing psilocybin to an SSRI, the psilocybin group did not show a statistically significant difference in Quick Inventory of Depressive Symptomatology-Self-Report scores compared with the SSRI after six weeks. However, the psilocybin group showed significantly larger reductions in suicidality, anhedonia, and standard psychological scores for depression. In November 2021, COMPASS Pathway completed a phase IIb clinical trial on psilocybin and depression that demonstrated “a highly statistically significant and clinically relevant reduction in depressive symptom severity after three weeks, with a rapid and durable treatment response.”
In 2016, Johns Hopkins conducted a small double-blind study looking at the effects of psilocybin on end-of-life anxiety. Researchers reported that a substantial majority of people suffering cancer-related anxiety or depression found considerable relief for up to six months from a single large dose of psilocybin.
The FDA has numerous expedited processes that are designed to speed up the development and review of drugs that are intended to treat a serious condition and psychedelics are no exception to receiving such designations. The first psychedelic drug to gain FDA Breakthrough Therapy designation was Johnson & Johnson’s esketamine nasal spray for treatment-resistant depression in 2013 and then again in 2016. MDMA was designated as Breakthrough Therapy in 2017 for PTSD and psilocybin in 2018 for treatment resistant depression.
In addition to these expedited programs, the FDA has an expanded access program, sometimes called “compassionate use”, which is a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical productfor treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. The Right to Try Act is another way for patients diagnosed with life-threatening diseases who have exhausted all approved treatment options and are unable to participate in a clinical trial to gain access to certain unapproved treatments. However, the Schedule 1 status of psychedelics has been a hurdle to terminally ill patients being provided with these drugs.
The psychedelic arena has also sought orphan drug status. In February 2021, PharmaDrug Inc., a pharmaceutical company focused on the research, development and commercialization of controlled-substances, natural medicines such as psychedelics, cannabis and naturally-derived approved drugs filed an application with the FDA to receive Orphan Drug Designation for N,N-Dimethyltryptamine (DMT) in the treatment of acute ischemic stroke patients presenting for emergency medical assistance within 3-hours of symptom onset and for the prevention of ischemia reperfusion injury in patients undergoing kidney transplantation. An orphan drug designation allows for seven years of market exclusivity, a great incentive to find treatments for rare diseases or conditions.
Current and Future Clinical Trials in The US and Abroad and Future Research
FDA-approved clinical trials are key to psychedelics being approved for use in mental health and other treatments. Below is a list of current and upcoming psychedelic research:
- DMT (dimethyltryptamine) for depression (Yale University)
- Combination MDMA/LSD by Mind Medicine, Inc. assessing subjective and autonomic effects to determine the qualitative emotional differences between a combined MDMA and LSD experience, a pure LSD experience and a pure MDMA experience, versus a placebo. (Phase 1).
- Pacific Neuroscience Institute (PNI) launched its first psychedelic-assisted clinical trial in March 2021. This Phase 2 study will assess feasibility, safety, and efficacy of incorporating Visual Healing® (a nature-themed immersive video experience) to optimize set and setting in psilocybin-assisted therapy for alcohol use disorder.
- The Psychedelics and Health Research Initiative (PHRI) at UC San Diego received a $1.3 million grant in February 2021 to fund a clinical trial investigating the therapeutic potential of psilocybin in treating phantom limb pain.
- Mydecine launched Phase 2A clinical trial on psilocybin-assisted psychotherapy to treat chronic PTSD in veterans and Emergency Medical Services personnel.
- March 2021 drug repurposing company Algernon Pharmaceuticals requested a pre-Investigational New Drug (IND) meeting with regulators to discuss a clinical trial in stroke patients for n,n-dimethyltryptamine (DMT).
- Havn Life, a Canadian biotechnology company pursuing standardized extraction of psychoactive compounds, announced the first preclinical study to focus on the effects of psilocybin on the immune system.
Challenges and Legal Issues
There are numerous issues that have and will arise in the context of clinical research and drug development of psychedelics such as finding a source of a Schedule 1 drug that will pass regulatory muster. In addition to regulating importation of drugs, the Drug Enforcement Agency (DEA) restricts who and how a researcher can study Schedule 1 drugs. Furthermore, there are difficulties in using a placebo for bias control in a psychedelic trial because of the strong physical and psychological effects these drugs have; in other words, both the participant and the researcher would know whether or not the participant was given the active compound versus the placebo.
Because clinical trials are showing high efficacy and safety, at least in certain settings, some of the psychedelic drugs may be rescheduled in the near future. That may create issues with exclusivity periods. When the DEA seeks to schedule a new drug under the Controlled Substances Act, it must request recommendations from the FDA. Because the FDA requires applicants for approval of new drugs to commit not to market those drugs until after the DEA makes its scheduling determination, the scheduling process can delay the entry of new drugs into the market, sometimes by more than a year after their FDA approval. The central issue in Eisai, Inc. v. United States Food and Drug Administration (US Dist. Ct, D.C., 2015) was whether and under what circumstances the period of time drug manufacturers spend waiting for a final DEA scheduling determination counts against the five-year exclusivity period.[5]
Because many psychedelic research companies are located outside of the Unites States, John Doe v. DEA (2017) is an interesting and relevant case addressing importation and bioequivalence in the context of generic drug approval. A drug manufacturer wanted to market a generic version of the drug Marinol, an FDA-approved drug containing the same active ingredient as marijuana and used to treat nausea and loss of appetite in cancer and AIDS patients. To get approval to market its generic alternative, the plaintiff was required to successfully complete “bioequivalency” studies. Id. At 563. The FDA, after extensive testing and research, approved Marinol describing it as “ [d]ronabinol (synthetic) in sesame oil and encapsulated in a soft gelatin capsule”—for treatment of nausea associated with cancer patients and anorexia associated with weight loss in AIDS patients. Id. At 564. The DEA eventually assigned “dronabinol (synthetic) in sesame oil and encapsulated in a soft gelatin capsule in a U.S. Food and Drug Administration approved product ” to schedule III. Ibid. All other “mixtures, compounds and preparations” containing dronabinol “remain[ed] in Schedule I.” Ibid. In practical effect, only the brand name drug Marinol was rescheduled. Ibid.
The plaintiff sought to import over half a million capsules of its drug from its overseas manufacturing partner. Id. at 563. When the DEA learned that the substance plaintiff sought to import was not Marinol, the DEA denied plaintiff’s permit application. Id. At 564. Because plaintiff’s drug containing dronabinol has not been approved for marketing by the FDA, the DEA classified the drug as falling within the general category of “dronabinol” in schedule I, not schedule III’s narrow description of “[d]ronabinol … in a U.S. Food and Drug Administration approved product.” 21 C.F.R. § 1308.13(g)(1) (emphasis added). Ibid. Thus, the plaintiff found itself in a catch–22: while it sought to import its drug under schedule III so it could conduct testing necessary to obtain FDA approval, the DEA’s interpretation of its regulatory provision effectively prohibits importation of a drug containing dronabinol under schedule III until the drug is FDA approved. Ibid. The DEA interpreted its schedule III regulatory language—“Dronabinol (synthetic) in sesame oil and encapsulated in a soft gelatin capsule in a U.S. Food and Drug Administration approved product,” 21 C.F.R. § 1308.13(g)(1)—as not encompassing Doe’s dronabinol drug, because plaintiff’s drug is not FDA “approved” for marketing. Id. at 570-71. The plaintiff argued that this interpretation was contrary to law, arbitrary and capricious, and violated the due process clause of the Fifth Amendment. Ibid. In disagreeing with plaintiff, the court noted that plaintiff had options: (1) petition to have its dronabinol drug rescheduled, or (2) obtaining schedule I registration. Id. at 573. The court also noted that it was not “unsympathetic to plaintiff’s predicament. The DEA’s interpretation obviously does make it harder (and costlier) for plaintiff to obtain final FDA approval to market its generic drug. As plaintiff has pointed out, this result runs counter to Congress’s purpose manifested in the so-called Hatch–Waxman Amendments, Pub. L. No. 98–417, 98 Stat. 1585 (1984), ‘to make available more low cost generic drugs.’” Ibid. (citations omitted). The court concluded by noting that “to the extent the DEA’s interpretation is bad policy, that must be addressed by the agency or Congress.” Ibid
A sign that the federal government is changing its purview of psychedelics is the May 2021 DEA decision to allow Wake Network to legally import psilocybin for research. Furthermore, the DEA recently increased the legal production quotas of MDMA, DMT, and psilocybin for use in research.
The importance of these cases and recent DEA actions to the area of medicinal use of psychedelics is manifold. The court’s decision in John Doe effectively meant that Marinol would have a much longer hold on the market absent any competition from a generic version. Additionally, the cases referenced above illustrate the importance of where the DEA places a drug on the schedule and how the FDA describes the approved drug in terms of importation, research, and ultimately commercial viability of a drug.
Conclusion
Psychedelic research is here to stay. How that research progresses largely depends on whether psychedelic drugs get rescheduled, whether and how patents are issued, and state laws. In the next article, I will further discuss paths to drug development specific to psychedelics and some of the legal issues that will likely arise including whether the drug is “novel” that would dictate the pathway to approval and ultimately the length of time to potential commercial availability.
