P225: MM120 (LSD) Demonstrates No Evidence of Abuse Potential in Rodent Preclinical Studies
Poster Presenter
Julie Tripp
Senior Director of Toxicology
Mind Medicine Inc. United States
Objectives
A series of Good Laboratory Practice (GLP) compliant studies evaluated receptor binding activity and abuse potential of MM120 (lysergide D-tartrate), a formulation of lysergic acid diethylamide (LSD) under development as a potential treatment for generalized anxiety disorder (GAD).
Method
Receptor binding activity of MM120 was assessed in vitro using Eurofins CEREP BioPrint. Behavioral studies evaluated short- and long-term effects (single dose) and potential chronic effects (4 weeks, daily dose) in Sprague Dawley rats (oral gavage: vehicle only, 0.5, 2.0, 6.0 mg MM120/kg).
Results
The receptor binding assay showed broad serotonergic agonist activity and hallucinogenic effects driven by agonism at 5-HT2A and 5-HT2C receptors. MM120 also demonstrated agonist activity at 5-HT1A, 5-HT1D, 5-HT5A, 5-HT6, and 5-HT7 receptors and only nanomolar affinity at D2 dopaminergic receptors. In behavioral experiments, short-term effects were evaluated by Modified Irwin at 0.25, 1, 2, and 4 hours post-dosing compared with pre-dose and baseline, with long-term, single-dose neurological effects studied in a functional observation battery (FOB) on the day of dosing and 24 hours post-dose. Single-dose MM120 at 0.5 mg/kg had no effects on behavioral or physiological states. Mild incidences of non-formed feces were recorded in 2 of 6 rats 1 hour post-dose following a single oral administration of 2 mg/kg MM120. Following 6 mg/kg MM120, vocalization was recorded in 1 of 6 rats at hours 2 to 4 post-dose. At the same dose, incidences of mild piloerection in 3 of 6 rats from hour 4 to 24 were recorded and subsided by 3 days post-dose. Additionally, an incidence of decreased grip strength was recorded in 1 of 6 rats 24 hours post-dose. To compare potential chronic MM120 effects, FOB was performed pre-dose, dosing day 27, and day 25 of recovery phase. In these studies, there were no MM120-related changes in basic or fine movements, total ambulation, total rears, or total distance traveled.
Conclusion
Overall, studies confirmed MM120’s neurobiological mechanism of action is mediated by serotonergic activity and suggest no evidence of abuse potential, physical dependence, or withdrawal after sustained administration. The assay of receptor binding activity demonstrated MM120 binds to serotonergic and minimally to dopaminergic receptors. Both receptors are associated with abuse liability, but findings suggest no indication for elements of abuse for MM120. There was no significant interaction observed at other receptors linked to abuse liability. In vivo studies demonstrated minimal transient differences in short- and long-term effects of MM120. MM120 at supratherapeutic doses demonstrated no evidence of physical dependence or withdrawal after sustained, daily administration for 4 weeks. Combined, in vitro and in vivo experiments using MM120 showed no evidence of abuse potential, physical dependence, or withdrawal and support its clinical development profile as a potential novel treatment for GAD. A phase 2b dose-finding study of a single treatment with MM120 suggests a rapid, safe, and durable dose-dependent response in participants with moderate-to-severe GAD. Nonclinical findings suggest that MM120 may at least partially enact its lasting change through serotonergic and minimal dopaminergic agonism. Phase 3 programs are underway to investigate MM120 100µg as a potential treatment for GAD and are planned for major depressive disorder.
