Ketamine and Psilocybin Differentially Impact Sensory Learning During the Mismatch Negativity
OpenAlex – November 07, 2025
Source: OpenAlex
Summary
Ketamine profoundly impacts how the brain processes sensory information, significantly reducing its precision in frontal areas compared to placebo between 207 and 316 milliseconds. Psilocybin, however, showed no such effect. Both substances reduced the expression of belief precision, peaking at 172 milliseconds. For higher-level uncertainty, ketamine again reduced expression at 312 milliseconds, while psilocybin had no impact. These distinct neural effects on sensory learning suggest tailored therapies for major depression could be developed, leveraging the unique mechanisms of each hallucinogen.
Abstract
Abstract Ketamine and psilocybin show potential as therapies for various mental illnesses, including major depressive disorder. However, further investigation into their neural mechanisms is required to understand their effects on the brain. By combining computational modelling with electroencephalography (EEG), we examine the effects of ketamine and psilocybin on hierarchical sensory pwPE learning in the context of the auditory mismatch negativity, an event-related potential consistently shown to be reduced under psychotomimetic interventions. We employed a Bayesian framework and re-analyzed a previously acquired EEG dataset (Schmidt et al., 2012) by modelling single-trial EEG data using the Hierarchical Gaussian Filter. Using a placebo-controlled within-subject crossover design, healthy subjects were administered either S-ketamine or psilocybin during an auditory roving paradigm of pure sinusoidal tones. Our findings elucidate distinct neural impacts of ketamine and psilocybin on sensory learning: ketamine led to a larger reduction in the effect of sensory precision compared to placebo from 207 to 316 ms peaking at 277 ms in the frontal central channels, while psilocybin showed no significant effect. Both drugs reduced the expression of belief precision between 160 to 184 ms, peaking at 172 ms. For higher-level volatility pwPEs, ketamine reduced the expression at 312 ms while psilocybin had a null effect. For perception of elementary imagery, ketamine had a greater effect than psilocybin on sensory and volatility precision, while psilocybin had a greater effect on volatility pwPEs. Our findings suggest hallucinogens have distinct effects on sensory learning that could inform tailored therapies for major depression.