Highlight
This randomized controlled trial (RCT) evaluated the efficacy and safety of MM120 (lysergide D-tartrate) as a single-dose treatment for moderate to severe generalized anxiety disorder (GAD). A dose-response relationship was established, with 100 µg and 200 µg doses producing statistically significant and clinically meaningful reductions in anxiety severity versus placebo at 4 weeks. Adverse events were dose-dependent and consistent with known pharmacological effects of MM120, primarily visual perceptual changes and nausea.
Study Background
Generalized anxiety disorder is a prevalent psychiatric condition characterized by persistent and excessive worry impacting daily functioning. Current pharmacotherapies, including SSRIs, SNRIs, and benzodiazepines, are often limited by delayed onset, side effects, and partial response. Novel agents with better tolerability and rapid anxiety reduction are needed. MM120, a formulation of lysergide, is being investigated for its anxiolytic potential leveraging its serotonergic activity, which may modulate anxiety circuits more effectively. This study aimed to define the dose-response relationship for MM120 in adults with moderate to severe GAD to inform dosing for subsequent trials.
Study Design
This phase 2b, multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled 198 adults aged 18 to 74 years with diagnosed primary GAD and moderate to severe symptom severity, defined as Hamilton Anxiety Rating Scale (HAM-A) scores ≥20. Recruitment spanned 22 US outpatient psychiatric research sites from August 2022 to August 2023. Participants were randomized evenly to receive a single dose of MM120 at one of four doses (25 µg, 50 µg, 100 µg, or 200 µg freebase equivalent) or placebo. Anxiety outcomes were evaluated at baseline and up to 4 weeks post-treatment by independent central raters blinded to treatment allocation. The trial’s primary endpoint was change in HAM-A score at 4 weeks, analyzed using an MCP-Mod dose-response modeling approach.
Key Findings
Out of 198 randomized participants, 194 comprised the full analysis set (mean age 41.3 years; 56.7% female; predominantly White ethnicity). The study demonstrated a clear dose-response relationship favoring MM120 over placebo. The 100-µg dose group showed a least-squares mean difference of -5.0 points (95% CI: -9.6 to -0.4) on HAM-A score relative to placebo, while the 200-µg group achieved -6.0 points (95% CI: -9.8 to -2.0), both exceeding the minimal clinically important difference of 2.5 points. Lower doses (25 µg and 50 µg) showed numerical improvement but did not reach statistical significance compared to placebo.
Safety findings aligned with MM120’s known pharmacodynamics. Visual perceptual changes were the most prevalent adverse event, increasing with dose: 46.2% (25 µg), 75.0% (50 µg), 92.5% (100 µg), 100% (200 µg), versus 10.3% in placebo. Nausea and headaches were also dose-related, with nausea reported up to 60% in the highest dose vs 7.7% placebo, and headache incidences ranging between 12.8% to 35% across dose groups. Overall, adverse events were expected, transient, and manageable, supporting a tolerable safety profile for single-dose administration.
Expert Commentary
The trial’s findings introduce MM120 as a promising candidate for rapid anxiety symptom reduction in GAD, addressing an unmet clinical need. The significant improvements observed at 100 µg and 200 µg doses underscore the importance of adequate dosing to achieve therapeutic benefit. The clear dose-response relationship validated by MCP-Mod reinforces confidence in efficacy estimates. The adverse event profile, dominated by transient visual changes, is consistent with psychedelics’ serotonergic mechanism and warrants careful dose titration and patient monitoring.
Limitations include the single-dose design and relatively short follow-up. Long-term efficacy and safety remain to be established. Moreover, visual perceptual changes, while expected, may affect patient acceptability. Future phase 3 trials should also explore repeated dosing regimens and investigate biological mechanisms underlying anxiolysis via lysergide.
Conclusion
In this rigorously conducted phase 2b RCT, a single administration of MM120 demonstrated dose-dependent reductions in anxiety severity for adults with moderate to severe GAD. The results support further evaluation in phase 3 pivotal trials and provide a foundation for dose selection. MM120 may represent a novel therapeutic avenue with rapid anxiolytic effects, addressing a critical gap in current GAD management, subject to future confirmatory research.
Funding and Clinical Trials Registration
The study was supported by the funding sources detailed in the primary publication. The trial is registered with ClinicalTrials.gov under Identifier NCT05407064.
References
Robison R, Barrow R, Conant C, et al. Single Treatment With MM120 (Lysergide) in Generalized Anxiety Disorder: A Randomized Clinical Trial. JAMA. 2025;334(15):1358-1372. doi:10.1001/jama.2025.13481.
