, 2025-05-07 12:15:00
A year after the US Food and Drug Administration (FDA) opened the door to clinical use of lysergic acid diethylamide (LSD), US-based MindMed has launched phase 3 trials in the United States and Europe of MM120 (lysergide d-tartrate) for the treatment of generalized anxiety disorder (GAD) and major depressive disorder (MDD).
The trials are testing the company’s 100-mcg orally disintegrating tablet MM120, which received FDA Breakthrough Therapy based on results from a phase 2B trial in GAD. In that study, one dose of the drug was associated with rates of 65% for clinical response and 48% for clinical remission at 12 weeks.
“It’s unprecedented in psychiatry,” investigator Daniel R. Karlin, MD, psychiatrist and chief medical officer of MindMed, said during a presentation at the European Psychiatric Association Congress (EPA) 2025. Compared with traditional psychopharmacologic therapy, the drug’s effect can be measured as early as 1 day after treatment, he added.
Successful phase 3 results could put MM120 in line to become the first FDA-approved psychedelic drug. What does the research show and what hurdles must the drug clear to make it to market?
How Does It Work?
Most experts agree that the mechanism of action of LSD remains somewhat of a mystery. What is known is that all psychedelic drugs bind to the 5-HT2A receptor, a subtype of the serotonin receptor that plays a role in cognition, mood, perception, and other psychological processes.
That binding “seems to start a cascade of events changing how brain networks connect,” Jerrold Rosenbaum, MD, psychiatrist-in-chief emeritus and director of the Center for the Neuroscience of Psychedelics, Massachusetts General Hospital, and professor of psychiatry at Harvard Medical School, both in Boston, told Medscape Medical News.
The resulting surge in synapse and neuronal growth creates neuroplasticity, “potentially reopening critical periods for learning, and then maybe the emotional and spiritual experience,” he said.
Karlin explained it as changing the brain’s filter.
“If I were to tell you that I knew reliably why LSD makes people feel better the way that it does, I’d be making it up,” he said.
“People under the influence of so-called hallucinogens really aren’t hallucinating. What’s happening is the organizing principles that underlie their ability to perceive the world in the usual way are turned down or all the way off, and the world becomes a complicated, confusing mix of lights and colors and sounds, sounds perceived as colors, taste perceived as sound. It’s the loss of organization,” he added.
The result is a rearrangement of an individual’s relationship with anxiety and depression, he noted.
“We have thought for a long time about psychiatric drugs in terms of symptom suppression. What we really haven’t thought about is the potential for psychiatric meds, particularly in anxiety, to enhance the view of the future. It’s not about feeling less overall — therefore, less anxiety — it’s just feeling differently about life and about the prospects of the future,” Karlin said.
Is MM120 Effective?
While none of the clinical research on MM120 to date has been published in peer-reviewed journals, findings have been presented at various scientific congresses.
The phase 2b dose optimization study that prompted the FDA’s Breakthrough Therapy designation included 198 participants with GAD who were randomized to receive either a single administration of MM120 at a dose of 25 mcg (n = 39), 50 mcg (n = 40), 100 mcg (n = 40), or 200 mcg (n = 40) or placebo (n = 39).
The primary endpoint was a change from baseline in the Hamilton Anxiety Rating Scale (HAM-A) scores. MM120 at doses of 100 and 200 mcg demonstrated a statistically significant dose-response relationship at both 4 and 8 weeks.
The estimated minimally efficacious dose to be between 56.7 and 85.1 mcg. At 12 weeks, the 100-mcg dose was associated with a 65% clinical response and a 48% clinical remission based on HAM-A scores compared with 30.8% and 20.5%, respectively, in the placebo group.
Secondary outcomes showed a clinically meaningful change compared with placebo in the Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity, and Patient Global Impression-Severity scores from baseline to weeks 1, 2, 4, 8, and 12.
A separate evaluation of this study also measured the ability of independent clinicians known as “central raters” (CRs) to remain blinded to whether a participant was receiving placebo or active study drug. Findings suggested the majority of CRs remained blinded, demonstrating that study results were protected from functional unblinding.
A third evaluation of the same study looked at functional disability, health-related quality of life, sleep quality, and sexual dysfunction in study participants across the five dosing arms and showed clinically meaningful improvements associated with the two higher doses as early as 1 week post-treatment and through the 12-week follow-up.
Based on these results, MindMed has launched three phase 3 double-blind, randomized clinical trials to study the MM120 efficacy for GAD and MDD.
The two GAD studies, Voyage and Panorama, are expected to enroll approximately 200 US participants and 250 US and European participants, respectively. Voyage will compare the 100-mcg MM120 dose with placebo on a primary endpoint of HAM-A scores at 12 weeks, followed by a 40-week extension phase with the opportunity for four open-label doses looking at safety, as well as time to and response to re-treatment.
Panorama will be identical except for including a third 50 mcg “blinding control” arm, said Karlin.
The MDD trial, Emerge, is expected to enroll approximately 140 US participants and will compare the 100-mcg MM120 dose with placebo. For this trial, the primary endpoint is MADRS scores at 12 weeks, followed by a 40-week extension phase with the opportunity for four open-label doses looking at MADRS scores and the Patient Health Questionnaire for depression.
“Progress in Emerge and additional regulatory discussions will inform the design and timing of a second phase 3 study in MDD,” according to the company website.
What About Safety?
Safety data from early MM120 trials showed no increase in suicidal ideation, and there were minimal side effects, mostly on the day of treatment, said Karlin.
The most frequent adverse events in patients in the therapeutic (100 mcg) dosing arm were illusion, reported by 60% of participants, and nausea, which affected 40%.
Other side effects included euphoric mood, headache, visual hallucination, hyperhidrosis, mydriasis, altered state of consciousness, anxiety, increased blood pressure, and abnormal thinking. The frequency of these adverse events ranged from 10% to 27.5%.
“I think the reported effects are quite consistent with what a full dose LSD experience would induce. Illusions, visual hallucinations, and altered state of consciousness for someone choosing an LSD experience would likely be considered desirable, but as a therapeutic for anxiety are registered as adverse effects,” Rosenbaum said.
Additionally, there are a number of known and potential harms associated with LSD use, noted Rosenbaum, who co-authored a recent review on the potential for both healing and harm.
In addition to the uncommon risk for acute or long-term cardiovascular effects, some individuals have reported ongoing perceptual disturbances, including flashbacks and visual trails triggered by moving objects, he noted.
“A small percentage of people who are vulnerable, let’s say, to bipolar, mania, schizophrenia, or other psychotic disorders, may be triggered by psychedelics. Others may have a terrifying and challenging experience which is traumatic itself,” he said.
Hurdles to FDA Approval?
Last year’s FDA rejection of Lykos Therapeutics’ application for midomafetamine with assisted therapy (MDMA-AT) to treat posttraumatic stress disorder was disappointing, but it doesn’t necessarily mean an uphill battle for other psychoactive drugs in the pipeline, said Rosenbaum, who was a consultant for Lykos.
One problem the agency noted was functional unblinding in the trials — the inability to blind participants to whether they were taking a placebo or active drug. MindMed has also made efforts to address this potential barrier with MM120 with its assessment of CRs.
The Panorama trial, which has just launched, includes two LSD arms (a therapeutic dose of 100 mcg and a subtherapeutic dose of 50 mcg) plus placebo.
“The 50 mcg arm isn’t of analytic interest — in the dose range finding study 50 mcg was actually the least active dose,” said Karlin. “But it is to confound the belief of people who got 100 mcg that they got the active dose of drug.”
Although Rosenbaum believes blinding in psychedelic studies is virtually impossible because “a psychedelic experience is pretty obvious,” he and other experts in the field don’t expect this to be a barrier because the FDA has overlooked this in other successful psychotropic drug applications, such as esketamine.
Another problem cited in Lykos’ trials was a lack of evidence to demonstrate the therapy was effective without psychotherapy assistance.
“Pairing the compound with psychotherapy was confusing things, making it harder to study and raising questions, when the FDA said, ‘we don’t regulate therapy,’” Rosenbaum said, referring to Lykos’ MDMA compound.
In early MM120 trials, patients were monitored by clinical staff through an approximately 8-hour treatment session, but there was no psychotherapy component, explained Karlin.
If MindMed is successful in its application for FDA approval, one last hurdle would remain. LSD is currently classified as a schedule 1 drug under the Controlled Substances Act, making its use illegal. The US Drug Enforcement Agency would have to reschedule LSD before MM120 could be prescribed. The rescheduling process is lengthy, and the outcome is uncertain.
Should Psychotherapy Play a Role?
Some experts question the movement toward psychedelics as stand-alone treatment, without accompanying psychotherapy.
“Psychotherapy is as essential as pharmacological treatment in managing mental disorders, particularly in the context of psychedelic therapies,” Gabriella Gobbi, MD, PhD, professor of psychiatry at McGill University, Montreal, Quebec, Canada, told Medscape Medical News.
“The mechanisms of therapeutic action of psychedelics are not entirely dependent on neurobiology, such as receptor interactions and the activation of specific brain circuits, but also rely significantly on psychological, social, and spiritual processes,” noted Gobbi, who also is president-elect of The International College of Neuropsychopharmacology.
“For these reasons, physicians or psychotherapists involved in psychedelic-assisted psychotherapy r equire specialized training to accompany patients through this experience to enhance positive outcomes and address potential side effects.”
Rosenbaum does not dispute that patients need support during their psychedelic treatment session, but in his opinion, psychotherapy is not realistic.
“You can’t do therapy during a psychedelic experience. You can do hand holding, you can do monitoring, you can encourage people to stay within the treatment, and you can rescue them if they’re having a challenging experience. But it’s not therapy,” he said.
Current FDA requirements for clinical trials call for the presence of two monitors when a patient is under the effects of a psychedelic. The lead monitor must be a licensed clinician with graduate-level professional training and clinical experience in psychotherapy. The second monitor must hold a bachelor’s degree and at least 1 year of clinical experience in a licensed mental health care setting.
If the FDA were to approve a psychedelic therapy, it is unclear if the agency would impose similar requirements.
“We don’t think that this is moving in a direction where you don’t need a monitor, but could it be one monitor? That’s something we’ll have to figure out,” Karlin said. “If it can be done safely and effectively, and certainly there’s precedent for that in the Swiss use of the drug. There’s precedent for that in the way that [esketamine] is being used in the US and worldwide.”
Rosenbaum reported holding stock or equity in Atai Life Sciences, Cerebral Inc., Entheos Labs, Psy Therapeutics, Sensorium Therapeutics, Tara Mind Inc., and Terran Biosciences; being a member of the board of directors for Cerebral Inc., Entheos Labs, Psy Therapeutics, and Sensorium Therapeutics; and being an advisor for Tara Mind Inc. and Reunion Neuroscience. Gobbi reported receiving funds from Diamond Therapeutics Inc. and being the inventor of a pending patent on the use of LSD.
Kate Johnson is a Montreal-based journalist with more than 30 years of experience writing about all areas of medicine.
