Psilocybin-induced default mode network hypoconnectivity is blunted in alcohol-dependent rats.

Alcohol Use Disorder (AUD) adversely affects the lives of millions of people, but still lacks effective treatment options. Recent advancements in psychedelic research suggest psilocybin to be potentially efficacious for AUD. However, major knowledge gaps remain regarding (1) psilocybin's general mode of action and (2) AUD-specific alterations of responsivity to psilocybin treatment in the brain that are crucial for treatment development. Here, we conducted a randomized, placebo-controlled crossover pharmaco-fMRI study on psilocybin effects using a translational approach with healthy rats and a rat model of alcohol relapse. Psilocybin effects were quantified with resting-state functional connectivity using data-driven whole-brain global brain connectivity, network-based statistics, graph theory, hypothesis-driven Default Mode Network (DMN)-specific connectivity, and entropy analyses. Results demonstrate that psilocybin induced an acute wide-spread decrease in different functional connectivity domains together with a distinct increase of connectivity between serotonergic core regions and cortical areas. We could further provide translational evidence for psilocybin-induced DMN hypoconnectivity reported in humans. Psilocybin showed an AUD-specific blunting of DMN hypoconnectivity, which strongly correlated to the alcohol relapse intensity and was mainly driven by medial prefrontal regions. In conclusion, our results provide translational validity for acute psilocybin-induced neural effects in the rodent brain. Furthermore, alcohol relapse severity was negatively correlated with neural responsivity to psilocybin treatment. Our data suggest that a clinical standard dose of psilocybin may not be sufficient to treat severe AUD cases; a finding that should be considered for future clinical trials.

Molecular Imaging of Dopamine Partial Agonists in Humans: Implications for Clinical Practice.

Positron emission tomography (PET) has been used since the late 1980s for the assessment of relationships between occupancy of D2/3 receptors by antipsychotic drugs in the human brain and the clinical effects and side effects of these compounds in patients. It is now well established for most D2/3 antagonists, both of the first and the second generation, that the ideal occupancy of their target receptors is between approximately 65 and 80%. If the occupancy is below 65%, the probability of treatment response is reduced, if the occupancy is higher than 80%, the risk for extrapyramidal side-effects increases substantially. However, partial agonist antipsychotics behave different from these rules. It has been shown for all three available drugs of this class (aripiprazole, brexpiprazole, cariprazine) that, due to their special pharmacology, a very high target engagement (>90%) not only is not harmful but represents a prerequisite for antipsychotic efficacy. The available PET studies for these drugs are reviewed in this work. It is demonstrated that optimal plasma levels for partial agonist antipsychotics can be derived from these studies, which can guide individual treatment in routine patient care.