BACKGROUND:Serotonergic psychedelics, such as N,N-dimethyltryptamine (DMT), have shown therapeutic potential in various psychiatric disorders. However, DMT demonstrates pharmacokinetic (PK) variability and a short half-life. AIMS:This exploratory study investigated the PK, pharmacodynamic (PD), and safety profile of CYB004, a deuterated DMT analogue, following intravenous administration in healthy volunteers. METHODS:CYB004, a deuterated DMT analogue, was evaluated in a randomized, double-blind, placebo-controlled, two-part study in healthy participants. Part 1 was a single-dose cohort, in which participants received a 5-minute intravenous 12.7 mg CYB004 bolus, followed by a 30-minute 15.41 mg infusion. Part 2 was a three-way crossover, during which two separate 5-minute 12.7 mg CYB004 boluses were administered. Outcome measures included PK of CYB004 and subjective, autonomic, neurophysiological, and adverse effects. RESULTS:Although high CYB004 doses led to intense psychedelic experiences and participant withdrawals, lower doses achieving plasma concentrations similar to those in previous DMT studies demonstrated an acceptable safety profile. CYB004 demonstrated a PD profile that was similar to DMT at comparable plasma concentrations. PD effects consisted of subjective psychedelic effects, electroencephalography power band reductions, and autonomic nervous system activation. CYB004's half-life was approximately two-fold longer than DMT, prolonging the duration of psychedelic effects to ~40-60 minutes following brief intravenous administration. However, deuteration did not improve PK variability, with IV-administered CYB004 demonstrating moderate to high variability, largely driven by interindividual differences. CONCLUSION:CYB004 demonstrated PD effects comparable to DMT. However, CYB004 demonstrated an extended duration of these effects due to reduced clearance, while maintaining an acceptable safety profile at clinically relevant exposures despite PK variability.
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