A family history of alcoholism is linked to differences in how the brain responds to a drug that blocks NMDA glutamate receptors. Healthy young adults with at least two relatives who had ethanol dependence received intravenous infusions of a low or high dose of ketamine, an NMDA receptor antagonist, or a placebo. Compared to those with no family history of alcoholism, individuals with a family history reported fewer perceptual changes and less dysphoric mood during ketamine infusion. These findings suggest that inherited alterations in NMDA receptor function may influence the subjective effects of alcohol and contribute to the risk of developing alcoholism.
A Phase III trial of MDMA combined with psychotherapy for severe PTSD produced a 24.4-point (55.5%) reduction in PTSD severity, compared with 13.9 points (31.5%) for placebo, and 33% of the MDMA group achieved remission versus 5% of the placebo group. The effect size was large (d > 0.9). MDMA also improved depression and social disability. The commentary notes the study was small for a Phase III trial, raises concerns about unblinding due to MDMA's subjective effects, and calls for larger replication trials, active comparators, and better safety monitoring for neurotoxicity and addiction liability.
Post-traumatic stress disorder varies greatly in its clinical and biological features, making treatment difficult. The largest randomized trial of ketamine for PTSD found no overall benefit over placebo, highlighting the need to identify which patients might respond. Using pre-treatment blood DNA methylation profiles and clinical data from that trial, machine learning models predicted treatment response. A model based on 1,208 methylation sites outperformed models using only clinical variables, and combining both data types improved accuracy further. The methylation-derived score identified responders with 92.9% accuracy. Predictive methylation sites were near genes involved in glutamatergic signaling, immune regulation, and known PTSD risk loci, suggesting peripheral DNA methylation patterns can guide precision pharmacotherapy for PTSD.
The balance between excitatory and inhibitory (E/I) activity in the brain is important for normal function, and its disruption is linked to psychiatric disorders. In a randomized, double-blind, placebo-controlled study, healthy volunteers received low doses of ketamine (which shifts E/I balance toward excitation) and thiopental (which shifts it toward inhibition) while their brain activity was recorded with EEG. The drugs altered the aperiodic exponent of the power spectrum in opposite directions, matching computational predictions. Changes in the exponent correlated with subjective and cognitive effects, suggesting that this measure could serve as a noninvasive EEG biomarker for transient shifts in cortical E/I balance.