FDA does not approve MDMA therapy in a surprising blow to the psychedelic renaissance

The FDA has decided not to approve MDMA therapy for the treatment of post-traumatic stress disorder, dealing an unexpected blow to the growing movement to raise psychedelics from the underground as a new, strangely powerful type of medicine.

Psychoactive drugs like psilocybin, LSD, and MDMA have been illegal for decades. But academic research looking into how they could be used across various fields, from neuroscience to medicine, resumed in the 1990s, slowly building momentum toward expanding access outside of tightly regulated research organizations. One of the most promising directions has been developing psychedelics as medical treatments for a broad range of hard-to-treat but widespread conditions, from depression and anxiety to chronic pain.

That momentum — which has grown rapidly in recent years — was widely expected to culminate in the FDA’s approval of MDMA therapy this summer, which would have allowed health care professionals to prescribe supervised MDMA therapy sessions to people with PTSD. Until things went sideways.

Instead, the FDA declined to approve the new treatment submitted by Lykos Therapeutics, an organization that develops innovations to “transform mental healthcare,” according to a statement published by Lykos. The FDA is requesting Lykos conduct an additional Phase 3 study, as the agency couldn’t approve the treatment “based on data submitted to date.”

The decision will have far-reaching ripple effects. Some psychedelic advocates will have to put celebrations they’ve been planning for decades on pause; others will rejoice at dodging the bullet of Lykos’s spiritually inflected therapy protocol being the one that breaks the dam of psychedelic treatment. The millions of Americans suffering from PTSD will have to wait for a reformulated attempt at MDMA therapy to pass. And the broader momentum of the psychedelic revival will continue teetering on the edge of mainstream acceptance.

Overall, though, the decision amounts to more of a delay than a death blow to psychedelic therapy.

Lykos Therapeutics received priority review from the FDA back in February, which fast-tracked the potential treatment for a decision within six months. Even the Biden administration was anticipating its approval. If accepted, Lykos’s application would have likely only gained approval for their proprietary formulation of MDMA, not the illicit form of the drug that’s currently considered a Schedule I substance. That means Lykos’s version of MDMA could have been used in prescribed treatment environments, but general MDMA, or “ecstasy,” would remain illegal outside of medical environments.

Still, even approval of a pharmaceutical product including MDMA would solidify the idea that MDMA — a drug that carries federal penalties of up to three years in jail and a $5,000 fine — can be a real medicine, challenging its designation as having “no currently accepted medical use” by the Drug Enforcement Administration. So FDA approval wouldn’t spell the end of the psychedelic prohibition that began in 1970, but it would provide ammunition for broader efforts to reschedule psychedelics and expand access.

But the optimism around approval began to sour in late March, when the Institute for Clinical and Economic Review (ICER), a nonprofit that evaluates evidence for health care interventions, published a report that called Lykos’s clinical trial design into question. They also shared concerns about unreported adverse events and ethical misconduct by therapists during treatment sessions.

Those concerns reached a crescendo during an FDA advisory committee meeting on June 4, where a panel of independent experts convened to review Lykos’s evidence and advise the FDA on its ultimate decision. During the nine-hour meeting, panelists expressed significant misgivings about the clinical trial designs, focusing on how difficult it is to establish placebo controls in psychedelic studies. By “blinding” people as to whether they received the active drug or an inactive placebo, they help prevent people’s expectations from biasing their response to treatment, isolating the effects of the drug. But people tend to know whether or not they’ve taken MDMA or magic mushrooms pretty quickly.

Concerns around failed placebo controls, or “functional unblinding,” are not unique to psychedelic science. But the advisory committee felt these issues cast significant doubt across the positive findings. Beyond the concerns with study design, three members of Psymposia, a non-profit research and media organization that focuses on psychedelic science and harm reduction, went so far as to accuse Lykos of being a “therapy cult” bent on furthering mystical and utopian goals. Ultimately, the advisory committee voted almost unanimously that there was insufficient evidence to support the treatment, and that the benefits do not outweigh the risks.

Despite the criticisms, experts across the psychedelics world felt that the functional unblinding issues that concerned the advisory committee had already been discussed in detail by the FDA and Lykos when they collaborated on the Phase 3 trial design back in 2017. That included the FDA signing off on the methodology to handle placebo controls. The FDA typically follows advisory committee recommendations, but hopes remained that this time would be different.

Classical psychedelics like psilocybin and LSD were made illegal by the Controlled Substances Act (CSA) in 1970. MDMA was added to the list in 1985, shortly after it began spreading across the electronic dance music scene. Drug Enforcement Administration (DEA) officials felt that MDMA abuse had become a nationwide problem.

Banning MDMA triggered Rick Doblin, a 32-year-old doing informal psychedelics research, to found MAPS in 1986, the Multidisciplinary Association for Psychedelic Studies. He figured that even though it could take decades, the surest way to undo psychedelic prohibition was through FDA approval.

MAPS began as a non-profit, but launched a separate for-profit arm in 2014, called the MAPS public benefit corporation. The corporation was dedicated to winning FDA approval for MDMA, and eventually, bringing it to market. In early 2024, the MAPS public benefit corporation rebranded itself as Lykos Therapeutics, largely because it was pretty awkward to have the original non-profit that still does drug decriminalization advocacy work share a name with a highly regulated for-profit pharmaceutical company focused only on medical treatments.

Two major aspects of Lykos’s submitted treatment plan — using MDMA rather than other psychedelics, and focusing on PTSD rather than other conditions — were calculated decisions.

Today, PTSD affects about 13 million Americans, or 5 percent of the US population. It’s been 25 years since the last FDA-approved treatments for the disorder: the antidepressants sertraline and paroxetine. But only about 60 percent of patients respond to treatment at all, and just 20 to 30 percent shake the disorder altogether. The current gold-standard treatment is trauma-focused psychotherapy, where dropout rates are high, and many patients still retain their symptoms after treatment. Veteran organizations like the Department of Veterans Affairs have been looking to MDMA therapy to help treat PTSD and stem the growing suicide crisis among veterans, creating an opportunity for politicians across the aisle to work together toward approval.

“We had to choose which psychedelic and which patient population would be most likely to be successful from a political perspective,” Doblin told Boston Magazine in 2019. “We don’t really do science; we do political science.”

While MDMA does pose some physiological risks that classical psychedelics don’t, like raising heart rates and blood pressure, the actual subjective experience of being on MDMA is generally euphoric. MDMA helps release a slew of neurotransmitters, like serotonin (dubbed the “feel-good hormone”) and oxytocin (“the love hormone”). The rush of positive feelings has always made MDMA a popular club drug. But paired with psychotherapy, MDMA can boost tolerance to traumatic memories by dialing down the mind’s tendency to avoid them, opening a window to reconsolidate memories that hold fear.

Meanwhile, tripping on the “classical psychedelics” — psilocybin, LSD, DMT, or mescaline — runs a much wider spectrum of possible experiences. Varieties of euphoria are still common. But slipping into a long and hellish nightmare, like an existential thorn in your grip on the world that never dislodges, can happen too, even if only in rare cases. Bad trips are comparatively less of a concern with MDMA, and therefore can pose less of a public health risk.

By itself, MDMA does not, however, guarantee a good time. Since it can kick up painful memories we normally avoid, MDMA is not immune to bad trips. That’s why Lykos insists on pairing MDMA with therapists who can help support people through difficult experiences, especially in vulnerable populations suffering from depression or PTSD.

Having attending therapists is definitely a good harm-reduction strategy. But they can’t fully eliminate the risks, either. At least one participant in MAPS’s studies reported an increase in suicidal ideation after their treatment sessions, and some controversy has erupted around why that didn’t show up in the published results. And since MDMA can make people more suggestible, the safety and efficacy of the actual therapy protocols are just as important as the drug itself.

But as the former director of the National Institute of Mental Health, Thomas Insel, recently wrote, “the U.S. regulatory system is not optimized for mental health care,” precisely because we lack a federal agency charged with reviewing the safety and efficacy of psychological interventions, like MDMA’s companion therapy. So MAPS developed its own therapy protocol, and held it constant throughout its trials to try and isolate the drug effects, which are technically the only part of this treatment the FDA actually regulates.

MAPS ran two Phase 3 clinical trials, each turning up pretty positive results. The first trial, published in 2021, found that MDMA therapy successfully treated 67 percent of participants, reducing their symptoms to the point where they no longer met the criteria for PTSD. In the placebo group, that number was 32 percent. The second trial, published in 2023, found similar results: 71 percent from the treatment group no longer met PTSD criteria, compared to 48 percent from the placebo group. (Note, however, that even though people likely knew when they were in the placebo group, which just received drug-free psychotherapy, they hit impressive treatment rates.)

While the FDA declined to approve Lykos’s new drug application today, organizations developing similar treatments are close behind. And even among those who’ve advised against approving MDMA therapy, there’s a sentiment that it should eventually get approved. Just not yet, and not like this.

“I don’t think we’re quite there yet,” said Kim Witczak, a consumer representative who voted against MDMA therapy during the advisory committee meeting. In an email to the BBC, she added: “The time to be cautious is now, not afterwards.”

In a press release earlier today, Lykos announced receipt of a complete response letter (CRL) from the FDA, which includes details as to why the agency declined to approve the treatment. The letter isn’t available to the public, but Lykos states that the letter echoes many of the same concerns that were raised in the June 4 advisory meeting, and requests an additional Phase 3 clinical trial to study safety and efficacy. Lykos will request a meeting to ask the agency to reconsider, but if they don’t, another trial “would take several years,” the company writes.

“The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over two decades,” said Amy Emerson, CEO of Lykos. “While conducting another Phase 3 study would take several years, we still maintain that many of the requests that had been previously discussed with the FDA and raised at the Advisory Committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature.”

Whatever happens next with Lykos, other companies are moving toward their own new drug applications. One of the most likely next applicants, the biotech company Compass Pathways, is pairing psilocybin with “psychological support,” which looks like a more hands-off version of Lykos’s approach to therapy. Meanwhile, states can continue passing a variety of legislations, from decriminalization to legalizing supervised adult use models, like Oregon’s approach.

Alongside state legislation, psychedelic research in academia will continue its expansion from medical applications, consciousness science, all the way out to humanities scholars. Religious groups can continue seeking legal exemptions for their use of psychedelics as sacraments. And the psychedelic underground will continue providing access (for both better and worse) to those who manage to find it.

The decision will likely put a dent in the valuation of some psychedelic start-ups, and bring on a wave of skeptical press. But Lykos’s failure may actually increase the odds that subsequent psychedelic treatments pass the FDA approval process. Applicants now know where the FDA is going to focus, and how to strengthen their applications in response.

Both Compass Pathways and the nonprofit Usona Institute have Phase 3 clinical trials — the last step before putting together a new drug application for FDA consideration — underway for psilocybin as a treatment for depression. And a very long list of organizations have Phase 2 trials ongoing for psychedelics ranging from LSD to 5-MeO-DMT (found in the poisonous secretions of a Sonoran Desert toad). More are on the horizon.

So the prospects for psychedelic therapy remain good, if a little frazzled. But at the same time, FDA approval of a pharmaceutical product that can exclusively be used in medical settings will not put an end to the psychedelic prohibition. At least, not in the way that many advocates have been hoping for decades.

When Doblin founded MAPS in 1986, Lykos’s ancestor, the idea wasn’t just to eventually produce a new type of prescribable therapy. As journalist Anna Silman recently reported, Doblin envisioned MAPS as a Trojan horse to rekindle the psychedelic renaissance that crashed and burned in the 1960s by routing it through the FDA. Once approved as a medicine, psychedelics could rise from the underground into mainstream acceptance, opening the door for expanded access outside of a doctor’s office.

But some critics have long been wary of medicalization as the best path toward an equitable psychedelic revival that ever escapes the medical ambit to make the most of their diverse potentials. Psychedelics — used responsibly — can contribute to our perennial search for meaning, scientific innovation, and even expanding our cultural imagination. But those aspects will be undermined if psychedelics get stuck as medicines, and medicines alone.

For a true psychedelic renaissance to kick in, they need to be removed from Schedule I of the Controlled Substances Act. FDA approval is one strategy that could support that process, while treating people in significant need along the way. We’ll see if the next application gets enough escape velocity to not only clear FDA approval, but the medical establishment altogether.

Update, August 9, 6:20 pm: This story has been updated to include details of the FDA’s request to Lykos for further trials.