Is the U.S. Medical System Ready for Legal Psychedelics?

Updated: August 15, 2024 12:38 PM EDT | Originally published: August 12, 2024 3:09 PM EDT

For a while, MDMA looked poised to make history. After decades of advocacy from impassioned supporters, the party drug best known as ecstasy emerged as the frontrunner to be the first psychedelic approved by the U.S. Food and Drug Administration (FDA). It would have been the first new therapy for post-traumatic stress disorder (PTSD) in two decades.

But the FDA quashed advocates’ dreams on Aug. 9, saying MDMA cannot be approved based on the data currently available and requesting additional research to prove the drug is safe and effective. That decision does more than table the issue for now. It also calls into question whether the U.S. medical system is ready for legal psychedelics at all.

Clinical trials on MDMA’s ability to treat PTSD have turned up promising data. Lykos Therapeutics, the company that applied for MDMA’s FDA approval, has conducted two phase-three trials, finding that many patients treated with a combination of therapy and MDMA see dramatic declines in PTSD symptoms. In one of those trials, the results of which were published in Nature Medicine last fall, 71% of patients no longer met diagnostic criteria for PTSD and almost half were considered in remission—functionally cured—18 weeks after they started MDMA-assisted therapy. Among patients who got therapy along with a placebo, those figures were about 48% and 21%, respectively.

FDA regulators, apparently, weren’t convinced by the results. The agency's decision, which Lykos called "deeply disappointing" and urged regulators to reconsider, suggests the psychedelics industry has more questions to answer before regulators make the jump of allowing these drugs in routine mental health care.

That jump would be a big one. To find their place in the existing U.S. medical system, any psychedelic treatment that ultimately wins approval will have to contend with an overstretched therapeutic workforce, insurance headaches, concerns about safety and illicit use, and logistical issues as seemingly mundane, but potentially seismic, as how to staff, schedule, and oversee intense multi-hour trips within the confines of a system more accustomed to 50-minute sessions.

Getting MDMA in front of FDA regulators was the culmination of decades of advocacy by the Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit founded by psychedelic evangelist Rick Doblin in the 1980s. Doblin and his colleagues have long believed that MDMA’s ability to open the mind and heart puts people in the right headspace to work with a therapist to process, and ultimately move on from, traumas that leave psychological scars. In 2014, MAPS spun out a separate division to direct research and prepare for an eventual FDA application, which it submitted at the end of last year. In early 2024, that offshoot was renamed Lykos Therapeutics.

This was, at one time, widely believed to be MDMA’s year. The data were promising, and there was even bipartisan political momentum to take mental-health treatment into a new era. But in June, an FDA advisory committee overwhelmingly voted against granting Lykos’ application for approval. Committee members raised numerous concerns about how the organization designed its studies, among them that patients and providers could often tell who had gotten MDMA versus a placebo, which raises the chances of data being skewed. They also seemed baffled by how to assess a drug-therapy combination, since the FDA does not regulate talk therapy. A couple months later, the FDA took their side and rejected MDMA.

Some of the committee’s concerns, which Lykos said the FDA echoed in its decision letter, were specific to Lykos. Although the FDA signed off on the company’s study design, Lykos did not gather some data the agency had requested, such as patient experiences of euphoria and other positive feelings that, according to the FDA, could make them more likely to abuse MDMA in the future.

And because the trials were affiliated with MAPS, a pro-MDMA advocacy organization with a vested interest in getting the drug approved, some participants allegedly felt they had to downplay even serious negative side effects, according to a March analysis from the Institute for Clinical and Economic Review, a nonprofit that assesses the value of medical treatments, and various press reports. According to ICER, in at least one case, MAPS trial therapists also apparently committed ethical violations, including having sexual contact with a patient and touching, restraining, and climbing into bed with her—issues that raise serious concerns about study conduct overall, and which reportedly contributed to the recent retraction of some MAPS research. (MAPS has said the therapists "substantially deviated" from treatment protocols.)

Days before the FDA’s decision on MDMA, Lykos CEO Amy Emerson told TIME that “our studies were sound and the data is reliable.” The FDA’s request for data on positive side effects has been implemented in ongoing research, and Lykos thoroughly investigates all patient concerns, Emerson says. In August, the company also announced plans to create an independent expert advisory board and partner with major health care systems on meeting requirements from the FDA and U.S Drug Enforcement Administration—steps that were meant to “help address questions the public has, FDA has…about how we want to do some of this work going forward,” Emerson says.

Dr. Thomas Insel, who directed the National Institute of Mental Health from 2002 to 2015 and is an advisor to and investor in Compass Pathways, a biotechnology company running clinical trials of psilocybin, the psychoactive component of magic mushrooms, thinks these issues say more about Lykos than the psychedelic field as a whole. “I don’t think that [these problems] are relevant to other companies doing work on other psychedelics, and maybe not even on MDMA,” Insel says.

But other experts aren’t so sure. Although psychedelics have been used in various parts of the world for centuries—and even, at one point, in the U.S.—they are still seen by regulators as “novel treatments and they inevitably raise novel questions,” says Dr. Jonathan Alpert, chair of the department of psychiatry & behavioral sciences at Montefiore Medical Center/Albert Einstein College of Medicine and chair of the American Psychiatric Association’s Council on Research. “That’s positive; it’s a sign of progress. But the questions that were raised [about MDMA] will span most psychedelic applications.”

Concerns about safety issues, side effects, and abuse are likely to pop up for other psychedelics too, says Mason Marks, who leads the Project on Psychedelics Law and Regulation at Harvard Law School. And other psychedelics have also been studied along with psychological support. If future regulatory applications also propose a combination of medication and therapy, the FDA may again be stumped as to if and how it can analyze those requests. (Even before the FDA’s decision on MDMA, executives from Compass Pathways said they plan to avoid that approach. “If and when we get to the point of filing, we will be filing for [only] a drug,” CEO Kabir Nath told TIME.)

Some of the research challenges that plagued Lykos’ studies, like patients guessing whether they’d gotten the active drug, could also apply to other psychoactive substances. “Expectancy bias,” or the tendency for research participants to believe so strongly in a drug that they push for a positive effect, may also be a recurring problem for a class of drugs as hyped as psychedelics. Dr. Walter Dunn, a psychiatrist with the Veterans Administration (VA) Greater Los Angeles Healthcare System and a member of the FDA’s advisory committee on MDMA, calls this “the Michael Pollan effect,” referring to the writer’s popular book and Netflix series on psychedelics, How to Change Your Mind. “Nothing in our field has generated this much enthusiasm and public awareness about a particular treatment,” Dunn says.

And for any psychedelic that follows MDMA, FDA approval would only be the first step. The real test is succeeding in a medical system that was not built for this.

All a typical therapy appointment requires is a patient, a provider, and a conversation. Psychotherapy is so straightforward that it can be conducted over video, phone, or even text message, and appointments typically last just under an hour.

Psychedelic-assisted therapy, if ever approved, would likely be far more involved. Under MAPS’ proposed system, patients would go through several sessions of traditional therapy before embarking on three eight-hour-long MDMA-assisted sessions, each under the supervision of two clinicians. And, because the FDA typically has stricter regulations in place for drugs that come with safety issues or the possibility of abuse, the average therapist’s office probably wouldn’t cut it for these marathon sessions. Appointments would likely need to take place in facilities, like hospitals, where multiple health care providers could monitor patients and respond to potential complications, like cardiac issues in the case of MDMA. But research suggests that the setting in which a person takes a psychedelic trip can influence their experience, so therapy rooms also need to be comfortable and inviting—words not typically associated with U.S. hospitals, where a quiet, empty treatment room of any sort can be rare.

“Seeing somebody in my office, sitting across from a desk—that’s not going to work,” Dunn says.

Emory Healthcare, which has spent years launching a study on MDMA-assisted exposure therapy for people with PTSD, had to build out and decorate a new therapy room just for the trial, says Barbara Rothbaum, who directs Emory Healthcare’s Veterans Program. It’s outfitted with a cozy recliner for patients, plus a pair of comfortable armchairs for the therapists, soothing artwork on cream-colored walls, and light-blocking curtains. The facility also has a safe bolted to the floor for the secure storage of MDMA.

Resource demands may be somewhat lower for other psychedelics. Compass Pathways and MindMed are studying single-dose treatment plans using psilocybin and LSD, respectively. But while those sessions are one-offs, they are still far lengthier than normal talk-therapy appointments. In clinical trials, Compass Pathways’ psilocybin sessions last six to eight hours under the supervision of two therapists. And, although MindMed is testing how a single dose of LSD affects anxiety when given without therapy, monitors still have to sit in the treatment room during a trip that can last hours.

Therapists’ offices, obviously, are not set up for this. Neither are insurers, although Compass Pathways and MAPS worked together to lay the groundwork for creating an insurance billing system for psychedelic care. Experts have estimated that MDMA-assisted therapy could cost about $12,000 or more per patient because of these resource demands. That’s nothing compared to, say, a $2 million gene therapy, but significantly more than insurers are used to paying for mental-health treatment over a short span of time.

Advocates argue that investment would pay off. If someone could be cured of PTSD or depression or anxiety in only a few intensive sessions, they wouldn’t need to use the mental-health system as much and for as long as they otherwise would, advocates argue. And that is a compelling line of reasoning, given that typical treatments tend to be long and slow. One 2021 study found that only about 40% of veterans treated for PTSD using traditional methods experienced remission, even if they were in therapy for a year.

But, even if psychedelic-assisted sessions end up being effective, they require high up-front costs, both financial and logistical. A single eight-hour psychedelic appointment staffed by two therapists would essentially take as much time and labor as 16 traditional hour-long, one-on-one therapy appointments—a tough situation to imagine for a system that already can’t meet patient demand. Within health care systems, “resources are finite,” says Rajeev Ramchand, a senior behavioral scientist at the nonpartisan research organization RAND. If a psychedelic were approved and offered, “I don’t see systems just completely creating new wings; they’re borrowing resources from elsewhere.”

Rothbaum can attest to that, even within a research context. “I have to block out times for potential patients weeks or months in advance,” she says of her MDMA study participants. “It means the rest of my week basically gets condensed.” A therapist who already has a full patient load may not be able to squeeze in day-long sessions without the rest of their patient roster suffering—to say nothing of the training programs they would have to go through to offer a psychedelic therapy if and when one is approved.

Safety and illicit use are also likely to be concerns with any psychedelic that gets the FDA’s green light in the future, likely leading to regulatory protocols similar to those initially suggested for MDMA, Marks says. These protocols could include licensing and registration requirements for providers and patients; restrictions around which types of facilities may offer care; and guidelines around how sessions are monitored and when patients are discharged. None of those ideas are inherently unreasonable, Marks says, but together they beg the question, “When does it become excessive and so restrictive that it’s virtually impossible to access” a new therapeutic?

For any psychedelic that eventually gets the FDA's green light, ketamine will likely be an instructive example.

FDA-approved as an anesthetic, ketamine produces a dissociative effect that leads some people to use it as a club drug. (Some people even consider it a psychedelic.) In 2019, the FDA approved Spravato, a nasal spray using a derivative of ketamine, to treat depression.

As would likely be the case with any psychedelic, Spravato was approved with a set of regulatory requirements meant to control its use and ensure safety. Patients, for example, must be monitored for at least two hours after dosing and cannot use the treatment at home. That situation is important proof-of-concept that clinicians and administrators can schedule, staff, and oversee lengthy appointments that are more tightly regulated than average therapy, says Nath from Compass Pathways.

But it's also noteworthy, Insel says, that—even though Spravato is FDA-approved—generic ketamine is still widely used off-label to treat mental-health conditions. Because Spravato's approval came with so many regulatory requirements for providers, it is often easier for clinicians to simply use genetic ketamine, Insel says. Much of this off-label use happens not in regular outpatient medical offices, but in specialty clinics built for the longer appointments and observation periods that ketamine requires.

That's not inherently bad, but the specialty clinic model requires a separate infrastructure. These facilities also often operate outside the traditional insurance system and are subject to the ebbs and flows of the market, Ramchand says. The VA learned that the hard way, he notes: the system partnered with a ketamine chain that abruptly closed last year, leaving many patients without access to care.

As ketamine and Spravato show, “the idea that you’re suddenly going to democratize care by getting [a drug] through the FDA” doesn’t always pan out, Insel says. Neither, as it turns out, does the idea that a psychedelic can get through the FDA at all.

Ultimately, Lykos’ ill-fated MDMA application may be more of a cautionary tale than a death knell for the legal psychedelics movement. Companies following in Lykos’ footsteps are purposely avoiding many of the mistakes their predecessor made, designing their clinical trials and FDA applications to side-step tricky questions about if and how the FDA can regulate therapy and how to interpret biased data about a promising and much-publicized class of drugs.

But the bigger question is what comes after a theoretical approval. A thicket of logistical, infrastructural, and financial obstacles await whichever drug is the first to achieve that outcome—obstacles that are not insurmountable, but that may slow and limit the adoption of substances that advocates claim could revolutionize mental health care as we know it.

“If psychedelics are effective, our patients need us to get ready,” Alpert says. “And we will—but there’s a great deal of thought and effort that will need to go into it.”

The FDA Didn’t Approve MDMA. Is the Medical System Ready for Any Psychedelic?

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