Oral pharmaceutical LSD formulation beneficial in generalized anxiety disorder

A single administration of MM120, a semisynthetic pharmaceutical formulation of lysergic acid diethylamide (LSD), helps ease symptoms in patients with moderate to severe generalized anxiety disorder (GAD), as shown in a phase IIB study.

Out of the four doses tested, MM120 at 100 and 200 μg yielded the greatest reduction in Hamilton Anxiety Rating Scale (HAM-A) score at week 4, with a difference of −5 points (95 percent confidence interval [CI], −9.6 to −0.4) and −6 points (95 percent CI, −9.8 to −2), respectively, relative to placebo. [JAMA 2025;doi:10.1001/jama.2025.13481]

The effect observed on HAM-A score with higher MM120 doses were sustained through week 8, with a difference of –2.9 points (95 percent CI, −5.4 to −0.5) with 100 µg and −5.4 points (95 percent CI, −9.5 to −1.4) with 200 µg of MM120. At week 12, scores decreased by 7.7 and 7.4 more with the respective doses vs placebo.

A ≥50-percent improvement in HAM-A score at week 12 was observed in more patients in the 100- and 200-µg dose groups vs the placebo group (65 percent and 62.5 percent vs 30.8 percent, respectively). Remission occurred in 47.5 percent, 45 percent, and 20.5 percent, respectively.

MM120 at 100- and 200-µg doses were also associated with substantial improvements in illness severity (measured using the CGI-S score) on day 2 and at weeks 2 through 12, as well as in depressive symptoms (assessed using the MADRS score) from weeks 1 through 12. These benefits were not seen with the 25- or 50-µg dose or with placebo.

Optimal dose

“This trial was the first to assess the dose-dependent efficacy of MM120 without a co-occurring psychotherapeutic intervention. The 100-µg dose of MM120 was determined to be optimal, demonstrating a statistically significant change in GAD that exceeded the changes seen with lower MM120 doses or with placebo,” according to the investigators.

“Most participants who received 100 µg of MM120 experienced mild to moderate adverse events (AEs), including perceptual changes and nausea. [On the other hand], the 200-µg dose of MM120 was associated with more frequent AEs,” they said.

Overall, treatment-emergent AEs (TEAEs) occurred in 97.5 percent of patients in the 100-µg group, 100 percent in the 200-µg group, 76.9 percent in the 25-µg group, and 90.0 percent in the 50-µg group vs 56.4 percent in the placebo group. The corresponding rates of treatment-related TEAE were 95 percent, 100 percent, 74.4 percent, and 80 percent vs 41 percent.

Most AEs (98.5 percent) occurred on the dosing day and resolved by the end of the dosing session. The most common AEs reported in the 100- and 200-µg dose groups were visual perceptual changes (illusion, pseudo-hallucination, hallucination), nausea, headache, and euphoric mood.

AEs led to treatment withdrawal in two patients each in the 25- and 50-µg dose groups and one in the 100-µg dose group.

There were no reports of suicidal ideation with intent or a plan during the sessions or throughout the trial. Patients with a history of suicidal ideation did not experience an increase in its severity.

Overall, MM120 had an AE profile that was consistent with previous LSD studies, the investigators noted. [Biol Psychiatry 2023;93:215-223; Psychopharmacology (Berl) 2022;239:1893-1905; Neuropsychopharmacology 2021;46:537-544]

“These results support the dose-dependent efficacy of MM120 and inform the dose selection for phase III pivotal trials,” they added.

The study included 198 adult patients with primary GAD who presented with moderate to severe symptoms (HAM-A score ≥20). These patients were randomly assigned to receive a single treatment dose of MM120 at 25 µg (n=39), 50 µg (n=40), 100 µg (n=40), or 200 µg (n=40) or placebo (n=39). A total of 196 patients (mean age 41.3 years, 56.7 percent female, 83 percent White) were included in the full analysis set.

An important first step

“[The current study] has the potential to make significant contributions to the emerging field of psychedelic drug research. It is the first study to evaluate the dose-dependent efficacy of MM120 for anxiety, specifically examining the anxiolytic effects of four different single doses without psychotherapy,” said Dr Claudio Soares of Queen’s University, Kingston, Ontario, Canada, in a linked editorial. [JAMA 2025;doi:10.1001/jama.2025.10869]

“There is ongoing work to clarify the potential connection between hallucinogenic effects and the therapeutic benefits of psychedelic substances. This understanding could have implications for their use in certain conditions (eg, schizophrenia), in which the potential risk of triggering psychedelic-induced psychosis remains a point of concern,” Soares added. [BJPsych Open 2023;9:e134; Mol Psychiatry 2025;30:1223-1255]

He believed that psychedelics could gain broader acceptance if their therapeutic benefits can be achieved with minimal or no hallucinogenic effects.