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FDA signage at its headquarters in Maryland iStock, hapabapa In a short statement Friday, Lykos Therapeutics expressed optimism about a recent meeting with the regulator to discuss next steps for the embattled program, following the FDA’s rejection in August 2024. Nine weeks after the FDA rejected Lykos Therapeutics’ MDMA-assisted therapy for post-traumatic stress disorder, the company has taken its first steps forward, announcing a “productive” meeting with the agency. In a statement released Friday, the psychedelic drug developer said the meeting—led by new interim CEO Michael Mullette and new Chief Medical Officer David Hough—“resulted in a path forward” that will include an additional Phase III trial and a potential third-party review of prior Phase III data. The FDA in an Aug. 9 Complete Response Letter said Lykos’ application “could not be approved based on data submitted to date” and requested the company conduct an additional Phase III trial to glean more information on the safety and efficacy of MDMA. At that time, Lykos stated its intention to request a meeting with the regulator to “ask for reconsideration of the decision” and to seek FDA’s recommendations for a resubmission. Former CEO Amy Emerson said that an additional Phase III study “would take several years.” Emerson stepped down from her role in September after 10 years with the company. Along with naming Mullette as interim CEO, Lykos also introduced Hough as the company’s new CMO and said that he would spearhead the efforts to resubmit an FDA application for the MDMA therapy. Less than a week after the FDA rejection, Lykos announced it would lay off around 75% of its staff “with the remaining team focused on its ongoing clinical development, medical affairs, and engagement with the FDA.” On Friday, Lykos said it would “continue to work with the FDA on finalizing a plan” and continue to provide updates “as appropriate.”

iStock/ iQoncept As Massachusetts prepares to vote on a measure that would legalize psilocybin and other plant-based psychedelic substances, researchers raise concerns around safety and a lack of epidemiological data. On Nov. 5, Massachusetts could follow Oregon and Colorado in legalizing certain plant-based psychedelic drugs. However, experts urge caution regarding the safety and purity of such substances. The proposed legislation, Massachusetts’ Question 4: The Natural Psychedelic Substances Act , would establish regulated access to natural psychedelic substances “that show therapeutic potential in increasing well-being and life satisfaction and improving mental health” at licensed therapy centers. If voted into law, Massachusetts residents 21 years and older would be able to legally purchase psilocybin (the active ingredient in so-called magic mushrooms), as well as other plant-based psychedelics, including psilocyn, dimethyltryptamine (DMT), mescaline and ibogaine. A yes vote would set Massachusetts on a similar path to Oregon , which voted to legalize psilocybin in 2020, and Colorado , which in 2022 voted to decriminalize psilocybin, psilocyn, DMT, ibogaine and mescaline. “I admire the sentiment,” Doug Drysdale, CEO of Cybin, a psychedelic drug developer, told BioSpace . “It’s indicative of positive sentiment around use of psychedelic medicines to treat mental health. I think it’s maybe indicative of where the public is leaning as well.” Regulatory efforts going through the FDA have yet to be successful, however. In August, the agency rejected Lykos’ MDMA-assisted therapy for post-traumatic stress disorder (PTSD) and requested that the company conduct an additional Phase III trial to glean more information on the safety and efficacy of MDMA—something former CEO Amy Emerson said at the time “would take several years.” While MDMA is not included in Massachusetts’ proposed legislation, Howard Kornfeld, medical director at Recovery Without Walls, told BioSpace the urgent need for these therapies is the impulse behind such state initiatives. “There’s a sense that the mental health crisis that the country is in, the world is in . . . mandates action now,” he said. Certainly, the need is immense. More than 13 million individuals in the U.S. live with PTSD, 40% to 60% of whom never achieve remission, according to Lykos. Meanwhile, an estimated 21 million American adults had at least one major depressive episode in 2021, and at least 30% of people with major depressive disorder have treatment-resistant depression. PTSD and depression are two of the top indications being pursued by developers of psychedelic therapies. Psychedelics Gaining Momentum With scientific evidence pointing to the therapeutic benefits of psychedelics for these conditions and others, momentum around legalizing—or decriminalizing—these substances is growing. “It’s something that is somewhat happening organically in the United States,” Kornfeld said of efforts to decriminalize psilocybin. For example, in 2022, the San Francisco Board of Supervisors unanimously passed a motion to decriminalize entheogenic, or psychoactive, plants like psilocybin and ayahuasca. The motion calls for San Francisco police to give arrests and investigations related to these substances “the lowest priority,” according to CNN . “So, churches have popped up that are essentially selling or distributing psilocybin with instructions how to use it, and the law enforcement is leaving them alone and letting it cultivate in that way,” Kornfeld said. The phenomenon isn’t limited to San Francisco. “I think that’s going on in certain cities in Massachusetts that sort of led to this momentum of putting this question on the ballot.” Implementation Obstacles All of the experts who spoke to BioSpace advised caution about state-led legalization initiatives. Drysdale questioned the value of legalizing psilocybin in Massachusetts. “I understand the kind of impatience and the urgency . . . but the timelines and the complexities and all this effort, I’m not sure it’s really going to help many patients. It may even create challenges.” One of these challenges is the cost of the drugs, Drysdale said. In Oregon, “you’re seeing patients being charged $3,500 cash for a session because there’s no insurance coverage. Who would go to a mushroom dealer in some center and pay [$3,500] when they can go their doctor and get a prescription and be reimbursed . . . for something that is synthetic?” He also likened the proposed legislation to compounding pharmacies of GLP-1 medicines—a group which was recently hit with an FDA warning . “This is kind of the same thing, isn’t it, in that it’s a way to get around FDA regulations and they may not be happy about it,” he said. Drysdale suggested that even if Massachusetts’ proposal does pass on Election Day, there could be challenges with its adoption. In Oregon, “about 70% of the counties opted out of implementation, and now what you’re seeing . . . is one specific strain of mushrooms only being available in certain centers with licensed facilitators.” Kornfeld expressed concern around the inclusion of ibogaine in the Massachusetts proposal. “Ibogaine is not a simple drug for the cardiovascular system,” he said, noting that in Mexico, where ibogaine is legal, most centers have a cardiology team in place to monitor patients. “I was surprised that the developers of Question 4 would have put ibogaine in there. I think people will emphasize that the ibogaine is more problematic, medically, physiologically, than the other substances.” Paul Summergrad, a professor of psychiatry and medicine at Tufts University School of Medicine and a scientific advisor to Lykos and fellow psychedelic drug developer MindMed, raised concerns about safety. “We don’t have great data on the risks and harms associated with this in clinical populations. Frankly, we don’t have great data on the risks and harms in general populations,” Summergrad told BioSpace . Psychedelic use can lead to “challenging experiences,” which can be “quite meaningful” in an appropriate clinical setting, he said. However, “It’s not clear that anyone will have enough training to really do this well.” The Massachusetts proposal “kind of runs ahead of where the science is right now in terms of which of [these compounds] are effective for what considerations,” Summergrad added. Potential Impact on Drug Development Ultimately, Drysdale said, the safest path to widespread access to psychedelic therapies is FDA approval of purified, synthetically designed molecules through large, randomized controlled trials that would then trigger Drug Enforcement Agency (DEA) rescheduling and enable reimbursement. Drysdale stressed the importance of having synthetic psychedelic drugs. “The goal is to create an FDA-approved, validated, repeatable manufacturing process that yields highly pure active ingredients, as opposed to the natural, self-grown, highly variable sources proposed in Question 4 of the ballot,” he said. For Summergrad, clinical data are the key to bringing psychedelics to the market. “I think the right way to do it is . . . in a way that lets us get data that will be at least reasonably reliable,” he said. “I think from a clinical standpoint, number one, we would want to have really well-conducted clinical trials in well-defined populations with the best opportunities to manage some of the challenges around placebo effects and functional unblinding.” Functional unblinding, which occurs when trial participants are aware of whether they’ve been given the drug or a placebo because of the drug’s immediate effect, was a key concern for the advisory committee considering Lykos’ application. As for how state initiatives like Massachusetts’ Question 4 will affect psychedelic drug development, Kornfeld contends it isn’t an either/or proposition. “I think these things are going to be happening simultaneously,” he said. Given how readily available these natural substances are, “I think there is probably room in the world for both pharma development and for loosening of the prohibitions against these drugs,” he added. Drysdale said the two arenas are “very separate and different.” “I don’t think FDA is going to be paying attention to the state level changes when it comes to reviewing drugs currently in development,” he said. “Once we have one or two of these substances approved and reimbursed, these other local processes become kind of pointless.”