Phase 1 studies assessing safety, tolerability, pharmacokinetics and pharmacodynamics of SYT-510, a first-in-class selective endocannabinoid reuptake inhibitor in healthy volunteers

Background

SYT-510 is a first-in-class selective endocannabinoid reuptake inhibitor (SERI) designed to restore balance within the endocannabinoid system. This system plays a central neuromodulatory role, regulating neurotransmitter release across key neural circuits, and its dysfunction has been linked to conditions such as anxiety disorders, post-traumatic stress disorder, and obsessive–compulsive disorder. By modulating endocannabinoid tone homeostatically, SYT-510 is intended to offer therapeutic benefit across these conditions, while avoiding the cognitive impairment, sedation, and abuse liability associated with exogenous cannabinoids.

Aims

Supported by strong preclinical data across several animal models of anxiety (see Mader et al., 2026 ECNP abstract), this work evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of SYT-510 in Phase 1 clinical trials.

Methods

A total of 32 healthy adults received a single dose of SYT-510 or placebo, and 16 received repeated dosing of SYT-510 or placebo over 14 consecutive days. To explore target engagement, plasma endocannabinoid levels were quantified using an established LC/MS/MS method of high analytical quality. EEG data was acquired from resting-state EEG with Eyes Closed (EC) and Eyes Open (EO) conditions. Single subject EEG data was then preprocessed and underwent quality control, followed by group-level spectral analysis and data visualization. SYT-510 concentrations were measured in plasma and CSF fluid using a specific, validated, and sensitive LC/MS/MS method. The plasma pharmacokinetic analysis was carried out using WinNonLinâ (Version 8.4 - Pharsight). A model independent method (non-compartmental analysis) was used.

Results

In the Phase 1 single and multiple ascending dose studies, 48 healthy adult participants were enrolled and 36 were exposed to SYT-510. SYT-510 was safe and well tolerated, with no clinically relevant effects in vital signs, ECG and biochemistry​​ and no severe and serious Adverse Events (AEs). All AEs were mild or moderate without any dose related intolerance.

SYT-510 Cmax and AUC increased approximately dose-proportionally across the tested dose range. After multiple doses, steady state was achieved after 9 to 10 days of daily dosing, with an accumulation ratio of approximately 1.6-fold. SYT-510 measurements in CSF demonstrated a time- and dose-dependent increase of SYT-510 in the central compartment, which positively correlated with plasma SYT-510 exposures both after single and multiple drug administrations. A significant increase of 2-AG after 14-days of SYT-510 administration was observed in plasma.

The exploratory EEG analysis revealed a SYT-510 time- and dose-dependent increase in beta power band, with little to no impact on the other spectral bands, suggestive of an anxiolytic profile without eliciting sedative effects.

Conclusions

Taken together, these data show that SYT-510 was safe and well tolerated across all doses tested ​​upon single and multiple administrations, shows a favorable PK profile and influenced PD markers in the brain. Based on these encouraging findings, along with positive pre-clinical data across several animal models of anxiety, SYT-510 is now under Phase 2 investigation for the treatment of anxiety disorders.

References

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