Psilocybin, a psychedelic compound, may help treat alcohol use disorder (AUD), but its brain effects in AUD are not well understood. In a placebo-controlled crossover study with healthy rats and a rat model of alcohol relapse, psilocybin broadly decreased functional connectivity across the brain while increasing connectivity between serotonin-related core regions and cortical areas. It also reduced connectivity within the default mode network (DMN), mirroring human findings. However, in rats with a history of alcohol relapse, this DMN hypoconnectivity was blunted, and the blunting correlated with relapse intensity. The results suggest that a standard psilocybin dose may be insufficient for severe AUD, a consideration for future clinical trials.
Higher baseline absolute monocyte count (AMC) predicts greater symptom improvement during intravenous ketamine therapy for treatment-resistant depression. In 27 participants receiving six ketamine infusions over three weeks, baseline AMC showed a strong negative correlation with depression severity change after the first infusion and before the last infusion, meaning higher monocyte levels were associated with more symptom reduction. Baseline AMC distinguished responders and partial responders from non-responders but not between partial and full responders. Absolute neutrophil count correlated weakly with early improvement, while C-reactive protein showed no correlation. AMC may serve as a simple clinical marker for predicting ketamine treatment response.
In adults with treatment-resistant depression receiving six intravenous ketamine infusions over three weeks, higher baseline levels of the neuroprotective metabolite kynurenic acid (KYNA) in the kynurenine pathway were associated with greater symptom improvement by day 18. KYNA remained stable over time and did not track with symptom changes, suggesting it acts as a trait-like marker rather than a state-dependent one. Early shifts toward the neurotoxic branch of the pathway (kynurenine and 3-hydroxykynurenine) were linked to reductions in hopelessness and suicidality scores after the first infusion. These exploratory findings indicate that a kynurenine pathway profile biased toward neuroprotective metabolites may inform future biomarker studies of ketamine response, but require validation in larger samples.
Classical and novel antidepressants may share a common mechanism: promoting long-term neuroplasticity and improving negative bias in emotional processing. Extrapharmacological factors—body, environment, and social interaction—appear necessary for these biological changes to produce an antidepressant effect. Rather than dismissing such factors as placebo, the authors argue they should be tested as essential components of treatment and integrated into clinical practice.