Reading The FDA Tea Leaves On Psychedelics
By Ben Comer, Chief Editor, Life Science Leader
In a candid discussion with members of the media last month, Rick Doblin, founder of the Multidisciplinary Association for Psychedelic Studies (MAPS) — the organization that birthed Lykos Therapeutics as a public benefit corporation to develop and commercialize MDMA — suggested that the FDA had “changed the goal post” following a contentious and emotional FDA Advisory Committee (AdComm) meeting in June 2024.
The FDA explained its reasons for declining to approve Lykos’s midomafetamine- (also known as MDMA, or ecstasy) assisted therapy candidate for PTSD in a Complete Response Letter (CRL) sent to Lykos on August 8, 2024; the CRL was made public for the first time on September 4, 2025. In his comments to reporters, Doblin described the negotiation process between MAPS and FDA that began with an end of Phase 2 meeting on November 29, 2016. “FDA said yes, we can go to Phase 3, but I knew it was very important not to immediately go to Phase 3, but that we engage in discussions with FDA about every single aspect of the protocol design.”
That included discussions around the challenge of double-blind trials with psychedelics, since trial participants would likely deduce which trial arm, active or placebo, they had landed in. “We elected to engage in a Special Protocol Assessment process … which delayed moving into Phase 3 by about eight months,” said Doblin. MAPS received an agreement letter, per Doblin, “which meant that we had successfully negotiated every single aspect of the protocol design, including how we deal with the double-blind.”
Control Arm Complexities
Doblin pointed to a section in the CRL on page four, titled “Minimize potential for bias,” which suggests that Lykos “Consider the inclusion of a low-dose midomafetamine arm as a control” in a future trial. During the Special Protocol Assessment negotiations in 2017, however, the FDA “rejected the idea of a low-dose arm of MDMA, and instead selected therapy with inactive placebo,” said Doblin. “For the FDA to now talk about including a low-dose [MDMA] as a control completely goes back on the decision that the prior group at FDA made when we discussed this in detail. That is an example of shifting the baseline, the evidence, and changing from agreements that were made.”
Additionally, Lykos’s clinical data was found “inadequate to establish [treatment] durability” according to the CRL, an issue that Doblin says hasn’t precluded FDA approval for other drugs. For patients using J&J’s blockbuster drug Spravato, an inhaled esketamine (a more potent derivative of ketamine) treatment for depression, “the results fade pretty quickly,” asserted Doblin, “and you need multiple sessions of Spravato … durability has never been, for any drug, a condition of approval.”
Treatment-Assisted Therapy/Psychological Support
It is unclear how Lykos Therapeutics — which is in the process of changing its name to Resilient Pharmaceuticals, following a $50 million Series B raise last May — plans to proceed with its MDMA candidate in addressing the FDA’s various requests in the CRL. Some have questioned MAPS and Lykos’s decision to pursue treatment-assisted therapy, or administering a drug and psychiatric therapy together, as part of an FDA sanctioned clinical trial and presumably, a drug label; Srinivas Rao, cofounder and CEO at atai Life Sciences, for example, said on an episode of the Business of Biotech that “therapy isn’t the purview of the FDA.”
Doblin, however, said he was relieved that FDA made the Lykos CRL public, in part because it addresses the therapy question. “I think the benefit of the CRL being made public is that I hope the field gets the message that FDA is not saying we want drugs without therapy,” said Doblin. “The FDA is saying we want more understanding of the therapy that is used.”
Joel Latham, President and CEO at Incannex Healthcare, a company developing a synthetic psilocybin treatment administered in combination with psychological support for patients with generalized anxiety disorder, said on the Business of Biotech that “we’re comfortable in what we’re doing.” Latham added that “a lot of our peers steer away from psychological support with the narrative that they push out publicly, because there are a lot of complexities around that component … but we like to attach ourselves to the therapy component of what we’re doing, because we’ve seen real world benefits of how that provides a better outcome to patients.”
Positive Adverse Events?
It may sound like an oxymoron, but feeling too good after taking a prescribed therapeutic also presents a problem for the FDA’s safety evaluation, since it might suggest the potential for abuse. In the Lykos CRL, FDA writes that “not reporting ‘positive’ or ‘favorable’ effects as adverse events raises concerns over the reliability of the safety data,” and that “all adverse events, including ‘positive’ effects, should have been identified and reported.”
I asked Doblin if, during the Special Protocol Assessment negotiations, an agreement was made with FDA about capturing so-called positive adverse events. “My understanding is that this idea of positive adverse events was discussed later on, in discussions between FDA and [Lykos], and we do know that MDMA is also a recreational drug under the name ecstasy,” said Doblin. “There is an enormous amount of information that’s already known about abuse liability, but I would say that the FDA is of the view that they were clearly indicating to the company that they should have gathered these positive adverse events, and the company did not do that, so I think that would be a misunderstanding between the company and the FDA. But this idea that [positive adverse events] is enough to block approval, I think, was never mentioned before.”
Regardless of what Lykos/Resilient does next in its pursuit of FDA approval for MDMA in PTSD, other psychedelic drug developers should read the CRL carefully, to better understand and anticipate FDA’s requirements and standards for psychedelic therapies.