FDA Rejects Lykos' MDMA-Assisted Therapy for PTSD

On 9 August 2024, pharmaceutical company Lykos Therapeutics said that the Food and Drug Administration (FDA) had refused to approve its application to use MDMA-assisted therapy to treat post-traumatic stress disorder. The ruling was the first of its kind on an application involving a psychedelic medicine.

Investors and scientists alike have forecast a boom in psychedelics, with MDMA viewed as the first of several psychedelic substances moving through the medicines-development pipeline.

The FDA's ruling disappointed supporters of psychedelic therapy, while shares in leading businesses in the psychedelic sector fell after the announcement. However, the FDA also outlined ways in which the application could be strengthened, potentially allowing MDMA to gain approval at a later date.

A further setback followed within days, when the journal Psychopharmacology withdrew three papers concerning MDMA-assisted therapy. It cited "protocol violations amounting to unethical conduct," especially in one clinical trial.

The Conversation spoke with Benjamin Y. Fong, a drug researcher at Arizona State University, about the implications of the FDA's decision and what it could mean for the future of psychedelic medicines.

What is MDMA, and which conditions might it treat?

MDMA, also called midomafetamine, is commonly known as "molly" or "ecstasy". Technically, it is an amphetamine - as is the substance used in the attention-deficit/hyperactivity disorder medicine Adderall - although MDMA is frequently classed as a psychedelic.

It is thought to produce more pleasure than other amphetamines, which has made it a widely used party drug. Some researchers describe MDMA as an "empathogen", or a "feeling enhancer".

MDMA remains a Schedule I drug, meaning the Drug Enforcement Administration regards it as highly dangerous and without an accepted medical use. Nevertheless, several clinical trials suggest that MDMA combined with talking therapy may benefit people with PTSD.

In 2017, the FDA gave MDMA-assisted therapy "breakthrough therapy" status, accelerating its development and review.

Each year, PTSD affects between 9 million and 13 million people in the US, while no new treatments for the condition have been developed over the past 20 years.

In February 2024, Lykos Therapeutics submitted its application for FDA approval of its MDMA-assisted therapy for PTSD. The treatment combines the medicine with a form of psychotherapy designed to draw out a patient's "inner healing intelligence", defined by Lykos as "a person's innate capacity to heal the wounds of trauma."

Why did the FDA refuse Lykos' MDMA-assisted therapy?

In June 2024, an FDA advisory committee voted by an overwhelming margin against the view that the relevant clinical trials had established MDMA's effectiveness in treating PTSD.

With equal decisiveness, the panel rejected the conclusion that the benefits had been demonstrated to exceed the risks, which include raised blood pressure and the potential for misuse.

At the time, the advisory committee highlighted several concerns in Lykos' submission. First among these was "functional unblinding": because trial participants would generally know whether they had received a powerful psychoactive substance, the findings could be biased.

That issue applies to any psychoactive medicine. Critics of Lykos argue that the company should have followed FDA advice to use an "active placebo" - a placebo that produces psychoactive effects as well - as the comparator in its earlier clinical trials.

The panel also questioned the type of psychotherapy delivered alongside MDMA and raised ethical concerns about several types of misconduct in Lykos' trials. In one company study, a participant alleged sexual misconduct by the therapists involved.

Although the FDA is not required to follow the votes of advisory committees, it usually does so. The Friday decision therefore came as little surprise.

What does the FDA's decision mean for the future of MDMA?

The FDA has called for a further phase 3 study, the clinical-trial stage that rigorously shows a treatment's safety and effectiveness against standard care.

Lykos said it would seek reconsideration of the decision and discuss the FDA's recommendations with the agency, so that it can make sure it is taking the appropriate route forwards.

Lykos chief executive Amy Emerson, who described the decision as "deeply disappointing," said she expects the new trial to take "several years" to complete.

Yet Lykos faces a challenging path, particularly after Psychopharmacology retracted three papers connected to this research.

How could this decision affect approval of other psychedelic drugs?

Compass Pathways, a prominent psychedelics company, is widely regarded as the next likely candidate for FDA approval of a psychedelic medicine. Its phase 3 clinical trials of synthetic psilocybin are already well advanced. Other companies are preparing phase 3 trials for proprietary compounds of their own.

After the advisory panel's June judgement, Compass pointed out that it does not combine its medicine with therapy in the manner used by Lykos. Another firm said that it has a "better trial design that is more in line with FDA guidance."

Other psychedelic companies plainly remain confident that they can achieve success where Lykos has not.

Do psychedelics present distinctive challenges?

The FDA's decision concerned Lykos' particular method rather than representing a blanket rejection of psychedelics as therapeutic treatments.

Even so, developing psychedelic medicines is inherently difficult. These drugs create a profoundly altered state, leaving people vulnerable. Some industry figures I have spoken with think that, because of the nature of the experience, allegations of impropriety are almost impossible to prevent.

Most studies also combine psychedelic medicines with some kind of therapy or facilitation. As the FDA has emphasised, however, its remit is to assess medicines rather than any accompanying psychotherapies.

There is ongoing debate about the relationship between the drugs and the human component of treatment. The shortcomings in Lykos' application highlight some of the distinctive barriers faced by companies developing psychedelic medicines on their route to FDA approval.

Benjamin Y. Fong, Honors Faculty Fellow, Associate Teaching Professor, and Associate Director of the Center for Work & Democracy, Arizona State University

This article is republished from The Conversation under a Creative Commons licence. Read the original article.