The Analgesic and Dissociative Properties of Ketamine are Separate and Correspond to Distinct Neural Mechanisms

Ketamine, a psychoactive medication, exerts both analgesic and dissociative effects. However, whether its analgesic effect stems from its dissociative properties is a topic of debate. Our study aimed to determine whether ketamine’s analgesic and dissociative effects are supported by distinct neural mechanisms. In a within-subject, placebo-controlled study, 37 healthy volunteers were administered ketamine (0.4 mg/kg bolus followed by a continuous drip of 0.4 mg/kg/h) or saline during fMRI sessions where thermal pain was induced. Our results indicate that while ketamine significantly reduced thermal pain ratings and produced robust dissociative effects, these outcomes were not correlated. Neurally, ketamine reduced pain-related brain activations across a network of regions, including the insula and anterior cingulate cortex. Additionally, ketamine significantly diminished functional connectivity between default mode network regions, and this reduction was correlated with the intensity of dissociation. These findings suggest that ketamine’s analgesic and dissociative effects are independent and mediated by distinct neural pathways.