MDMA therapy is facing an imminent FDA decision. Here’s what you need to know

A decades-long campaign to legalize MDMA as a mainstream medical treatment will reach a climax as soon as Friday, with the Food and Drug Administration poised to decide whether the psychedelic should be approved as a treatment for post-traumatic stress disorder in conjunction with psychotherapy.

The regulators face an Aug. 11 deadline to decide whether to sign off on the drug or reject it. The agency could also postpone its decision if it needs more time to review data and investigate claims of irregularities in clinical trials run by Lykos Therapeutics.

The push to legalize it has been polarizing. Proponents, including many combat veterans, say MDMA enabled them to overcome disabling PTSD symptoms that didn’t respond to other treatments. Critics call into question the ethics of Lykos and the quality of the data. Those qualms were aired during a contentious June meeting of an FDA scientific advisory panel, which overwhelmingly recommended rejection of MDMA.

For a long while, it was almost a foregone conclusion that regulators would approve the psychedelic — two Phase 3 studies had shown the trial was effective in improving symptoms of PTSD. There’s a tremendous unmet need — there hasn’t been a new therapy for PTSD approved in more than two decades. And the FDA fast-tracked the review process, designating MDMA a “breakthrough therapy” and signing off on Lykos’ study designs.

However, in March, a report from the Institute for Clinical and Economic Review cast doubt on whether Lykos had appropriately tracked serious adverse events during the trials — in particular suicidal ideation.

“If we get an approval, there’s still work to be done. If the FDA delays its decision, there’s work to be done. Regardless of the outcome, we’ll still continue forward,” Blair Clark-Schoeb, Lykos’ chief communications officer, told STAT this week.

Here are answers to common questions about MDMA therapy and psychedelics more broadly:

Where did MDMA come from?

MDMA is a synthetic drug that can act as a stimulant and mild hallucinogen, but is primarily considered an “empathogen”: It can amplify emotional connection and feelings of empathy. A common party drug, it is also known as ecstasy or molly.

It was developed in 1912 by scientists at Merck, who were seeking out a new compound to promote blood clotting. It was considered unremarkable at the time, untested in humans and animals, and described in the patent simply as a “colorless oil, boiling point 155°C at 20 mm pressure, its salt forms white crystals.”

MDMA was largely forgotten for decades. Then, in the 1970s, it was rediscovered by University of California, Berkeley chemist Alexander Shulgin — who synthesized it and introduced the chemical to psychologist Leo Zeff, who explored its use in psychotherapy.

It spread from therapeutic circles to the Dallas party scene, where it was considered a “yuppy drug.” The growing recreational use ultimately led to a crackdown on MDMA: In 1985, the U.S. Drug Enforcement Administration classified it as a Schedule I drug. It was marked illegal, and regulators claimed it held a high potential for abuse and no accepted medical benefit.

If MDMA is approved by the FDA, it would be the first time a criminalized psychedelic has been formally recognized for its medical benefits since the launch of the war on drugs more than a half-century ago.

What’s a psychedelic drug?

Psychedelics are most famous for their mind-bending abilities: They can quickly alter mood, thought processes, and a person’s perception of reality. These substances can trigger visual and auditory hallucinations, and profoundly shift emotion.

Humans have used psychedelic substances for millennia, and they continue to be used medicinally and ritualistically among indigenous communities. Some of the best known include LSD, psilocybin, ketamine, and MDMA.

The term “psychedelic” is a neologism, meaning “mind-manifesting” in Greek. It was coined in 1957 by Humphry Osmond, a psychiatrist at the University of Alabama who studied them. He introduced substances like mescaline and LSD to the author Aldous Huxley, who would later pen books on altered states of consciousness like “The Doors of Perception.”

As Osmond once wrote in a letter to Huxley: “To fathom Hell or soar angelic/ Just take a pinch of psychedelic.”

How does MDMA work in the brain?

MDMA, or 3,4-methylenedioxymethamphetamine, creates a flood of certain neurotransmitters in the brain: It boosts levels of serotonin, dopamine, and norepinephrine. Serotonin helps regulate mood, emotion, and social behavior — so it’s believed the resulting surge can create feelings of emotional closeness, well-being, and empathy.

The boost in dopamine is thought to create feelings of enhanced pleasure, and the norepinephrine increase raises heart rate and blood pressure — boosting alertness and energy. After the drug wears off, neurotransmitter levels plummet, which can cause fatigue, sadness, and irritability.

How does MDMA work in a therapeutic context?

It’s not known how the drug might affect symptoms of PTSD or other mental illnesses. The neurochemical storm prompted by MDMA is thought by some researchers to create a sense of trust, self-love, and empathy — making it much easier to revisit and process traumatic memories during talk therapy. Patients with PTSD tend to struggle deeply with confronting past turmoil, so proponents say the drug helps soften the entryway into discussing old psychological wounds.

The approach championed by Lykos is for MDMA to be administered in a therapist’s office, under the supervision of two mental health professionals. Patients would undergo non-psychedelic psychotherapy before the MDMA sessions, and then again after.

How did MDMA make it to the FDA?

Rick Doblin — now a central figure in psychedelic research — and many other champions of psychedelia attempted to lobby regulators to keep MDMA legal before the DEA’s 1985 decision. The following year, Doblin created the Multidisciplinary Association for Psychedelic Studies, or MAPS — a nonprofit aimed at advocating for the medical and therapeutic benefits of psychedelics, particularly MDMA.

Funded largely by donations from psychedelics enthusiasts, MAPS conducted early safety studies on MDMA and pressed for it to be reclassified. The work was slow-going, but it laid the groundwork for subsequent psychedelic research, which by that point had largely been shut down.

In 2004, MAPS began Phase 2 trials for MDMA-assisted psychotherapy for PTSD. In 2017, the FDA granted MDMA a “breakthrough therapy” designation for the treatment of PTSD. This set the stage for a Phase 3 trial, which kicked off in 2018 and underpins Lykos’ efforts to seek approval from the FDA.

In 2014, MAPS created a public benefit corporation, MAPS PBC, to push MDMA-assisted therapy toward approval. This past January, it changed its name to Lykos Therapeutics.

What’s the case for MDMA’s approval for PTSD?

There’s a tremendous unmet need for PTSD therapies: There haven’t been any new treatments for the disorder in more than two decades. And the results from the MDMA-assisted therapy studies show that it can be incredibly effective: Some people say that just three sessions cured their PTSD.

Earlier this week, more than 60 bipartisan lawmakers in the House and Senate urged President Biden in a letter to approve MDMA-assisted therapy. And 19 senators wrote a similar letter to FDA Commissioner Robert Califf, asking the same.

Veterans groups in particular are vocal in their advocacy for MDMA — saying that the treatment could prevent many thousands of military vets with PTSD from taking their lives.

Lykos’ two Phase 3 trials that are being evaluated by the FDA generated some compelling data: The studies found that 67% and 71% of patients who took MDMA, respectively, no longer met the diagnostic criteria for PTSD. This compares to 32% and 48% in the placebo groups.

What are the arguments against MDMA’s approval?

Much of the MDMA research leading up to the drug’s potential approval has been conducted by evangelists for psychedelics — which can undermine the results.

There are concerns from ICER, the FDA advisory committee, and patient testimony that Lykos didn’t accurately report patient suicidality. If that’s true, then the trial data doesn’t encapsulate the risks involved — and there’s a chance that MDMA could actually worsen mental health symptoms in a vulnerable patient population.

Other concerns include risks of sexual abuse of patients, given how vulnerable and dissociated they can be while undergoing the therapy; and the small size of the trials and expectancy bias. There were fewer than 200 people in the studies, and most patients could guess whether or not they’d been given MDMA.

How does Lykos plan to allay the risks of MDMA-assisted therapy?

If it’s approved, the FDA will outline a REMS for Lykos — that is, a series of risk evaluation and mitigation strategies to make sure the drug is administered safely.

In advance of that, Lykos recently announced it’s launching an independent advisory board to help plan a potential commercial launch — and to help inform therapy training. Lykos said it would only roll out the treatment in health care centers that have several layers of oversight for therapists — such as Emory University, Sheppard Pratt, and Pacific Neuroscience Institute.

Have any other psychedelic drugs been approved?

Ketamine, an anesthetic first approved by the FDA in 1970, was used off-label for many years to treat major depressive disorder, treatment-resistant depression, and suicidal ideation. And in 2019, the FDA approved Spravato, or esketamine, a molecule that’s structurally similar to ketamine, from Johnson & Johnson.

Spravato’s on its way to $1 billion in sales this year, suggesting that other psychedelic drugs could also be commercially viable.

Are other psychedelics in the pipeline?

Compass Pathways is close on Lykos’ heels, with Phase 3 trials underway for psilocybin therapy that target treatment-resistant depression.

There’s been a groundswell of companies in the psychedelics space — with research underway for LSD, ibogaine, DMT, psilocybin, ayahuasca, and others. Several startups are now focusing on second-generation modified psychedelics, and some are actually working to remove the psychedelic component entirely — creating drugs that can spur neuroplasticity but have minimal psychoactive effect.

These are being studied in just about every mental health condition, including addiction, anorexia, anxiety, depression, and others.