In a rat model of depression (Flinders Sensitive Line), depressive behavior was negatively correlated with levels of the endocannabinoid 2-AG. A single dose of S-ketamine restored 2-AG levels and increased endocannabinoid signaling in the prefrontal cortex. Although S-ketamine decreased gene expression of the CB1 receptor and the enzyme FAAH, protein levels did not change significantly. S-ketamine increased CB1 receptor binding, and computer modeling suggested it may bind to CB1, CB2, GPR55, and FAAH. However, blocking CB1 receptors with rimonabant did not prevent S-ketamine's behavioral effects, indicating a complex interaction with the endocannabinoid system that requires further study.
The dissociative effects of ketamine and psychedelics may be linked to their rapid antidepressant properties, but it is unclear whether these effects are necessary for therapeutic action. Because patients can often tell whether they received an active drug or placebo based on the dissociative experience, clinical trial results may be biased. The authors propose a novel approach: administering these drugs to patients during sleep to separate the subjective dissociative experience from the drug's biological effects, potentially allowing for better-controlled studies.