Treatment-resistant depression is a global public health concern, leaving a significant portion of the population without effective remedies. To address this issue, innovative strategies are urgently needed. Psilocybin, a non-selective 5-HT2AR agonist, has been found to alleviate depressive mood in individuals with treatment resistant depression (Carhart-Harris et al., 2017) Ketamine exhibits robust and enduring antidepressant properties both in patients and preclinical models. (Krystal et al., 2013). Sleep patterns are often affected by depressive disorders, making wireless EEG a valuable tool for assessing new drugs' impact on sleep and brain activity (Leiser et al., 2011). This study aims to compare the effects of psilocybin and ketamine on the electroencephalogram (EEG) of C57BL/6 mice. Seven adult male C57BL/6 mice were surgically implanted with DSI PhysioTel™ HD-X02 transmitters, which collected continuous EEG, EMG (electromyography), temperature, and activity data. Two biopotential channels were placed in the frontal and parietal cortices for fronto-parietal EEG, and in the neck extensor muscles for EMG. Treatments (vehicle, ketamine at 5&10 mg/kg and psilocybin at 3&10 mg/kg) were administered in a randomized crossover manner, with a 7-day washout period between treatments. Results: ketamine produced a 1-hour increase in waking and non-REM sleep gamma oscillations in C57BL/6 mice, and a 1-hour reduction in sigma-alpha oscillations, but did not significantly affect sleep-wake behaviour. Conversely, psilocybin briefly reduced wakefulness while increasing non-REM sleep, but caused longer-lasting reductions in REM sleep for up to 4 hours. Psilocybin, particularly at 10mg/kg, produced a robust reduction in sigma-alpha oscillations during non-REM sleep.