The U.S. Food and Drug Administration expressed concerns Friday about the health effects of MDMA as a treatment for post-traumatic stress disorder, alleging flaws in company studies that could pose a major obstacle to approval of a treatment that hopes to help people suffering from the condition.
The agency said the study was biased because subjects and therapists could easily tell who had been given MDMA and who had been given a placebo, and warned that “significant increases” in blood pressure and pulse rate “may lead to cardiovascular events.”
The staff analysis was conducted for an independent advisory committee that met Tuesday to consider Lykos Therapeutics' application for MDMA-assisted therapeutic use.The agency's concerns highlight the unique and complex issues regulators face in reviewing the therapeutic benefits of an illegal drug better known as ecstasy, which has long been associated with all-night raves and hugs.
The approval would mark a dramatic change in the country's complicated relationship with psychedelics, most of which are classified by the Drug Enforcement Administration as illegal substances with “no currently accepted medical use and a high potential for abuse.”
Studies like the current study on MDMA therapy have garnered support from a wide range of groups and lawmakers in both parties for treating PTSD, a condition that afflicts millions of Americans, especially military veterans who face a significant risk of suicide. No new treatments for PTSD have been approved in more than two decades.
“What's happening right now is really a paradigm shift for psychiatry,” said David Olson, director of the Institute for Psychiatry and Neurotherapeutics at the University of California, Davis. “MDMA is an important step for the field because there are no effective treatments and people need help right now.”
Lycos Therapeutics CEO Amy Emerson said the company is vouching for the data and design of the study, which was developed in consultation with FDA officials.
“These study designs are not simple, they are very complex,” she said.
“Functional unblinding,” in which study participants can tell whether they were given a placebo, often impacts studies of psychotropic drugs because patients are acutely aware of the effects, she said.
A rejection of the application would send a shock wave through the nascent field of psychedelic drugs, which has attracted millions of dollars in private investment, much of that support based on the FDA's Breakthrough Therapy Designation, or fast-track approval, of MDMA therapy in 2017.
The agency has given similar designations to four other psychedelics, including psilocybin, the “magic mushroom” used to treat depression, and an LSD-like substance used to treat generalized anxiety disorder.
The criminalization of hallucinogens, initiated by the Nixon administration in the 1970s, effectively ended research into a range of psychotropic drugs that had previously held great therapeutic promise.
In recent years, MDMA has fascinated scientists, mental health professionals and patients with anecdotes and data suggesting that when combined with talk therapy, it could bring about significant improvements for a range of mental illnesses, including anxiety, depression, substance abuse and eating disorders.
Strictly speaking, the drug is not a classic hallucinogen like LSD or psilocybin. MDMA in its pure form is considered an empathogen or entactogen, meaning it enhances an individual's sense of empathy and social connection. However, illegal versions of the drug purchased for recreational purposes are often mixed with other drugs, increasing the risk of side effects.
Aside from potential risks to the heart, MDMA has an established safety profile and many in the field do not believe it to be addictive.
The FDA generally follows the recommendations of its advisory committees and is expected to make a formal decision by mid-August, but even if approved, the agency could follow the advice of its own staff and outside experts and tightly regulate its use and require additional studies to evaluate its effectiveness as a treatment.
In the final two studies Lycos submitted to the FDA, about 200 patients underwent three eight-hour sessions, with about half receiving MDMA and the other half receiving a placebo, according to a report published in Nature Medicine. In each session, patients receiving MDMA were given 80 to 120 milligrams initially, followed by a half-strength dose about two hours later. The sessions were spaced four weeks apart.
Patients had three consultations to prepare for treatment and nine more to discuss what they had learned.
The latest drug trials found that over 86 percent of subjects given MDMA experienced a measurable reduction in the severity of their symptoms. Approximately 71 percent of subjects improved enough that they no longer met the criteria for a PTSD diagnosis. According to the data presented, 69 percent of subjects given a placebo experienced an improvement in their symptoms, and approximately 48 percent no longer met the criteria for a PTSD diagnosis.
“It's easy to point out the flaws in the research, but there's no doubt that MDMA helps many people suffering from PTSD,” said Jesse Gould, a former Army Ranger who runs Heroic Hearts, a group that helps veterans access psychedelic treatment, primarily outside the US. “With no other drugs in development and 17 to 22 veterans committing suicide every day, new treatment options are desperately needed.”
The FDA has scheduled about two hours of public comment on Tuesday, likely giving a platform to a vocal group of MDMA study participants and researchers who have complained of ethical violations and pressure to report positive results during clinical trials conducted by MAPS Public Benefit Corporation, which changed its name to Lycos Therapeutics this year.
If approved, it will likely be nuanced. The drug was studied during therapy sessions with a psychotherapist and a second therapist present for safety, given the patient's vulnerability. The FDA staff analysis suggested several limitations to approval, including administering the drug in certain medical settings, monitoring patients, and tracking side effects.
A recent example of such approval is Spravato, a ketamine nasal spray that the FDA requires be administered by a certified provider in a medical setting and monitored for two hours afterward.
In a letter, the American Psychiatric Association urged the FDA to tread carefully. Dr. Jonathan Alpert, chairman of the association's research council, said doctors worry that FDA approval could lead to unorthodox treatments by untrained physicians.
To prevent that, the agency's approval “must be accompanied by rigorous regulation, rigorous prescribing and dispensing controls, comprehensive patient education, and a system of ongoing monitoring and surveillance,” said the letter, signed by Dr. Saul M. Levin, the association's medical director and CEO.
If MDMA is approved, federal health and Justice Department officials would have to take certain steps to downgrade it from a Schedule 1 controlled substance, similar to the process currently in place for marijuana. The DEA could also set production quotas for the drug's ingredients, as it does for stimulants used to treat ADHD.
“Participants appeared to experience rapid, clinically meaningful and durable improvements in PTSD symptoms,” FDA records released Friday said.
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The agency's analysis released Friday echoes concerns raised in recent months. In March, the Institute for Clinical and Economic Review, a nonprofit that studies the costs and effectiveness of medicines, released a 108-page report questioning the Lycos study's results and calling the treatment's effectiveness “inconclusive.”
The report noted that some study participants told ICER that ideology shaped the findings, influenced by the close-knit community of therapists interested in psychedelics who report positive outcomes. Some said they would feel left out if they didn't.
ICER also said the study was small and could be biased because about 40% of participants had taken MDMA before, far more than the general population. Lycos countered the criticism, saying the figures reflect the reality that people with PTSD are desperate for relief and often seek unregulated treatment.
ICER also cited reports of misconduct by an early trial participant, Megan Buisson, whose videotapes of her interactions with two couples therapists suggested inappropriate contact.
“The severe PTSD that led me to this clinical trial was left unaddressed and unresolved,” Buisson said at an ICER advisory meeting on Thursday. “All they did was build a concrete foundation of new trauma on top of it.”
MAPS, the original trial sponsor, said it addressed the issue in 2019 and 2022 and reported the “ethics violations” to the FDA and health authorities in Canada, where the conduct occurred.
In an interview on Thursday, Lycos CEO Emerson acknowledged the pain Buisson had experienced but said there could be greater risks if the company's application was rejected, given the growing number of people taking illegal drugs or seeking MDMA therapy in underground clinics.
“The voices of people who are hurting need to be heard without anyone getting defensive,” she said, “but people are desperate for treatment and removing MDMA from the regulatory framework could create even more harm.”
Whatever the FDA's decision, experts in the field of psychedelics say there's no turning back, given the mounting promising research and broad public and political support that has underpinned their rise.
Robert Jesse, a longtime researcher who helped establish the psilocybin unit at Johns Hopkins University more than 20 years ago, remembers a time when researchers hid their interest in psychedelics for fear of damaging their careers.
“Psychedelics are now starting to pass the laugh test,” he said. “What's remarkable at this point is that while there are people who criticize aspects of this research, you'd be hard pressed to find anyone who would be against the drug because it's a psychedelic. The genie has come out of the lamp.”
