SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF MSD-001 AFTER SINGLE DOSING IN HEALTHY ADULTS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

Background

MSD-001 (5-MeO-MiPT) is an orally bioavailable tryptamine primarily targeting 5-HT1A, 5-HT7, and 5-HT1D receptors. Its selection was guided by AI-based analysis linking biochemical properties to large-scale subjective experience data to select a compound that produces mild psychoactive effects without inducing strongly altered or disorienting experiences. This clinical evaluation aims to support future combination strategies for selectively inducing therapeutically relevant mental states. This single ascending dose study evaluated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of MSD-001 (0.5–10mg) in healthy male and female participants.

Methods

In this randomized, double-blind, placebo-controlled study, healthy participants received a single dose of MSD-001 or placebo. Participants were stratified by cytochrome P450 (CYP) 2D6 activity status: intermediate/extensive metabolizers (IM/EM) received 0.5, 1, 3, 6, or 10 mg MSD-001, while poor metabolizers (PM) received 0.5 or 3 mg MSD-001. Safety was assessed via adverse events (AEs), vital signs, ECGs, laboratory tests, and physical and psychiatric evaluation. Plasma and urine PK were analyzed noncompartmentally. PD outcomes included subjective measures such as the Real-Time Intensity (RTI) scale, the 5-Dimensional Altered States of Consciousness (5D-ASC) questionnaire and a Visual Analogue Scale (VAS), as well as electroencephalography (EEG), functional magnetic resonance imaging (fMRI) and NeuroCart, a validated central nervous system test battery. PD endpoints were analyzed using mixed-effects models and ANOVA.

Results

47 (40 IM/EM, 7 PM) participants were randomized. Single-dose MSD-001 was safe and well tolerated, with no serious AEs. Most AEs were mild, self-limiting and transient. A dose-related increase in AEs was observed. The most common AEs for MSD-001 were sensory processing disorder (e.g., visual effects; 50%), euphoric mood (33.3%), and feeling of relaxation (33%), and for placebo sensory processing disorder (40%), euphoric mood (20%), disturbance in attention (20%), and hyperhidrosis (20%). No clinically meaningful cardiovascular, laboratory, physical, or psychiatric abnormalities were observed. In IM/EM participants, MSD-001 was rapidly absorbed (median Tmax 1–2 h; median t½ ~2–3 h) with generally dose-related exposure, although Cmax and AUC were similar at 6 and 10 mg. In PMs, median Cmax increased ~1.6– 1.8-fold and t½ ~2-fold relative to IM/EMs. MSD-001 produced dose-related PD effects compared with placebo, with minimal changes at 0.5–1 mg and the most consistent effects at 6– 10 mg. Effects typically emerged within 30 min, peaked at 2–3 h, and resolved by 6 h. Subjective effect measures showed visual, bodily, and emotional/metacognitive effects on the RTI, along with increases in total altered state of consciousness, mood and calmness on the 5DASC and VAS, without effects on anxiety or cognitive control. EEG analyses showed reduced delta and theta power and increased gamma power, suggesting a shift toward increased cortical activation and altered information processing, while fMRI changes were minimal. NeuroCart evaluation showed inconsistent effects on saccadic peak velocity, saccadic reaction time, and smooth pursuit.

Conclusions

Single oral doses of MSD-001 up to 10 mg were safe and generally well tolerated in healthy male and female participants, with rapid absorption and dose-related exposure influenced by CYP2D6 activity status. MSD-001 produced dose-dependent subjective drug effects without inducing anxiety. Effects peaked within 2–3 h and resolved by 6 h post-dose. The findings support 6-10 mg as the target dose range in future trials.