Ketamine rapidly reduces depressive symptoms in treatment-resistant depression, but its mechanisms are not fully understood. Recent clinical evidence controversially suggests that ketamine's efficacy may depend on opioid signaling. In rats, blocking opioid receptors suppressed ketamine-induced neurophysiologic changes in brain regions linked to depression and reward, but did not affect changes from a more selective NMDA receptor antagonist. This opioid-dependent response was strongly sex-dependent: absent in females and reversed by removing male gonads. Similar sex-dependent opioid effects appeared in ketamine-evoked structural plasticity and behavioral sensitization. These results indicate that ketamine may induce affective responses via opioid signaling, with subject sex as a strong influence, warranting direct assessment in future clinical trials.
A single dose of the atypical psychedelic ibogaine can be highly effective at treating PTSD in veterans up to twelve months later, according to an observational study of 30 veterans. Using a novel EEG analysis method, researchers found that ibogaine shifted high-beta (24 and 25 Hz) brain networks from frontal areas toward posterior regions, an effect seen both three to four days and one month after treatment. This posterior shift correlated with improvements in PTSD symptoms and was replicated in an independent dataset on ibogaine for opioid use disorder. Neural modeling suggested the shift reflects increased corticocortical, not corticothalamic, connectivity. The reconfiguration of high-beta networks may be a robust biomarker for ibogaine's therapeutic effects.