5-Methoxy-N,N-Dimethyltryptamine: Functional Safety Pharmacology and Video-EEG Assessment of a Short-Acting...

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a serotonin receptor agonist, in clinical development for the treatment of major depression and other psychiatric disorders. A critical safety concern for serotonergic compounds is their potential to induce seizures, as a severe manifestation of serotonin toxicity. The objective of this study was to evaluate the seizure liability of 5-MeO-DMT in a canine model. Beagle dogs (n = 8) were surgically instrumented for continuous telemetric recording of electroencephalography (EEG) and electromyography (EMG), coupled with behavioral video monitoring. Following a baseline period, animals were intranasally administered with control vehicle or escalating doses of 5-MeO-DMT (0.5, 1.0, and 1.5 mg/kg/day), once daily for nine consecutive days. Plasma samples for determination of pharmacokinetic parameters were collected from a satellite group (n = 3). Intranasal administration of 5-MeO-DMT resulted in centrally mediated and dose-dependent behavioral signs, such as head shaking, salivation, repetitive movements, dilated pupils, increased muscle tone, and tremors. A majority of these signs had a rapid onset and offset, which correlated with the peak plasma levels and resolved within 1 hour post-dose, and they were consistent with serotonergic agonism of 5-MeO-DMT. The continuous EEG recording revealed no evidence of seizures or epileptiform discharges at any dose levels throughout the study. In a canine model, considered sensitive to serotonergic drug-induced seizures, daily intranasal administration of escalating doses of 5-MeO-DMT did not induce seizures or epileptiform activity, even at doses causing significant physiological signs of serotonergic stimulation. These results provide robust critical safety information for a low seizure liability of 5-MeO-DMT.