A single dose of an investigational lysergic acid diethylamide (LSD)-based medication known as MM120 (lysergide D-tartrate, Mind Medicine Inc [MindMed]) was associated with a rapid and significant reduction in both anxiety and depressive symptoms in adults with generalized anxiety disorder (GAD), a new phase 2b trial showed.

Participants with moderate-to-severe GAD who received MM120 at a dose of either 100 or 200 µg showed greater symptom improvement at week 4 than those who received matching placebo, meeting its primary endpoint.

Additionally, the 100-µg dose was associated with a 65% clinical response rate and a 48% remission rate at 12 weeks, along with a significant reduction in depression symptoms, compared with placebo.

The active treatment also worked quickly, with a significant reduction in anxiety symptoms observed within the first week.

“People had a rapid effect, starting as soon as day 1 that persisted through week 12,” co-investigator Daniel R. Karlin, MD, chief medical officer at MindMed, told Medscape Medical News.

The response and remission rates were also “truly remarkable and give us great confidence to move forward into phase 3,” added Karlin, who is also on staff at Tufts University School of Medicine, Boston.

Preliminary findings were presented at the American Psychiatric Association Annual Meeting last year, and full results were published online on September 4 in JAMA.

Dose-Finding Investigation

The past-year prevalence of GAD in US adults is about 10%. However, the FDA hasn’t approved any new medications for this common psychiatric condition since 2007.

LSD has been the focus of a number of previous studies for a range of psychiatric disorders, including posttraumatic stress disorder. Although past research has shown promise for LSD plus psychotherapy for anxiety disorders, the current investigators wanted to assess the contribution of an LSD-based product as monotherapy.

MM120, which received FDA Breakthrough designation last year for GAD, is a pharmaceutical formulation of LSD in the form of an orally disintegrating tablet, which is designed for more rapid absorption.

In a multicenter, randomized, placebo-controlled, double-blind, phase 2b study conducted from 2022 to 2023, nearly 200 adults with GAD (mean age, 41 years; 57% women; 83% White) received a single treatment of placebo or MM120 at a dose of 25 µg (n = 39), 50 µg (n = 40), 100 µg (n = 40), or 200 µg (n = 40).

“We thought one of the most important questions we could answer was: What is the right dose to bring forward into confirmatory clinical trials?” Karlin said. “No one in the modern psychedelic era had done this sort of dose-range finding.”

All participants had moderate-to-severe symptoms of GAD, defined by a score ≥ 20 on the Hamilton Anxiety Rating Scale (HAM-A).

The primary outcome was a dose-response relationship, as measured by change from baseline to week 4 on the HAM-A. Secondary outcomes included this change at week 8 and change in Montgomery-Åsberg Depression Rating Scale (MADRS) depressive symptom scores.

Response rates, defined as a 50% reduction in the HAM-A total score, and remission rates, defined as a HAM-A score ≤ 7, were also determined at 12 weeks.

Significant Improvements

The dose-response relationship for HAM-A score change at 4 weeks was significant for MM120 at both 100- and 200-µg doses compared with placebo (least-squares mean difference [LSMD], -5 points and -6 points, respectively). There was no significant difference on this measure between placebo and the lower doses of MM120.

At week 8, the dose-response change in the HAM-A score was also significantly greater for the 100 and 200 µg groups than for the placebo group (LSMD, -2.9 and -5.4 points, respectively).

Further analyses showed significant adjusted HAM-A score reductions for the 100 µg group compared with the placebo group at week 4 (LSMD, -7.6 points; P < .001) and at week 12 (LSMD, -7.7 points; P = .003).

At 12 weeks, there was a response rate of 65% in the 100 µg group vs 30.8% in the placebo group, with remission rates of 47.5% vs 20.5%.

MADRS depression scores were also significantly improved after 12 weeks for those receiving the 100-µg dose compared with those receiving placebo (P = .02). The improved scores were observed from weeks 1 through 12.

Additionally, illness severity improvements, as measured with Clinical Global Impression-Severity scores, were observed on day 2 and at weeks 2-12 in participants receiving either of the active treatment’s higher doses.

Optimal Dose

The rate for at least one treatment-emergent adverse events (AEs) was 97.5% in the 100 µg group and 100% in the 200 µg group vs 56% in the placebo group.

In addition, 93% of participants receiving the100-µg dose had visual perception changes on dosing day, including illusions and visual hallucinations, compared with 10% of those receiving placebo. Other common AEs included nausea (40% vs 8%) and headache (35% vs 23%).

Karlin said the AEs in this study were consistent with the expected effects of the drug and noted that there were no signals of suicidality.

“Although both the 100 and 200 showed efficacy, the 100 showed efficacy a bit earlier and with a bit more durability, and it had a lower AE burden,” Karlin added.

That led the researchers to conclude that the 100-µg dose was “the optimal dose” for treatment.

Two phase 3 trials of MM120, named Voyage and Panorama, are already recruiting patients for the treatment of GAD. A third phase 3 trial, Emerge, will assess the therapy for major depressive disorder.

Karlin noted that topline results for Voyage are expected to be released in the first half of 2026, with topline results for the other two trials to be released in the second half of the year.

Encouraging…With Caveats

In an accompanying editorial, Claudio N. Soares, MD, PhD, Center for Psychedelic Health and Research at Queen’s University, Kingston, Ontario, Canada, applauded the investigators while also noting study limitations, including its short duration and high dropout rates.

“This work has the potential to make significant contributions to the emerging field of psychedelic drug research,” he wrote.

However, more research is needed into the “sustainability of the clinical benefits, the long-term efficacy of these agents after a single-dose administration, and the risks associated with potential misuse or abuse of these substances,” Soares added.

Commenting for Medscape Medical News, Jerrold F. Rosenbaum, MD, director of the Center for the Neuroscience of Psychedelics at Massachusetts General Hospital, Boston, noted that although the effects “were meaningful” for the higher doses, the study had a small number of participants — and a much larger study is needed.

Rosenbaum, who was not involved with the research, noted that the process of receiving therapeutic LSD takes about 12 hours and includes an observer in a clinical setting.

In addition, MM120’s effects might not be unique in the future. “I think most psychedelics, and maybe all, will prove efficacious. And then the question will be what is easiest for patients to use or prescribers to prescribe,” Rosenbaum said.

“The issue with LSD is going to be how long it takes to administer and how long until the patient is really safe to go back to his or her business again,” he noted.

“Also, how durable is the response? There’s no question you can get acute relief that lasts for a while. But will [long-term benefit] be a differentiator among the various products that are going to come to market?” Rosenbaum asked.

Also commenting for Medscape Medical News, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale School of Medicine, Yale University, New Haven, Connecticut, called the current study “exciting” but also noted a few caveats as the investigators move forward with further trials.

“The findings are quite encouraging in terms of efficacy of the medication and demonstrated nice separation from placebo,” said Sanacora, who was not involved in the current study.

“They also made good attempts to minimize the impact of expectations on unblinding,” he said.

“There’s room for improvement, but definitely this study is improved over some previous studies that have been done in the psychedelic space,” he added.

The study was funded by MindMed. Karlin and several of the other investigators reported employment with MindMed. Rosenbaum reported having no relevant financial relationships. Sanacora reported receiving personal fees and grants, holding equity, and/or holding patents from various companies, including Biohaven Pharmaceuticals, Biogen, Axsome Therapeutics, and Freedom Biosciences — but not from MindMed.