Dose-related reductions in prefrontal recruitment during cognitive reappraisal following oral delta-9-tetrahydrocannabinol in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is characterized by difficulties in emotion regulation and altered recruitment of prefrontal control systems during cognitive reappraisal. Cannabinoid signaling has been implicated in stress and affect regulation, yet dose-dependent effects of acute delta-9-tetrahydrocannabinol (THC) on the neural mechanisms supporting reappraisal in PTSD remain unclear. In a randomized, double-blind, placebo-controlled design, adults with PTSD received a single oral dose of placebo (N = 12), 5 mg dronabinol (synthetic THC; N = 12), or 10 mg dronabinol (N = 13) prior to fMRI during a validated cognitive reappraisal task. Relative to placebo, both THC doses were associated with reduced activation during reappraisal of negative images (Reappraise-Negative > Maintain-Negative) across prefrontal and parietal regions implicated in top-down control, with broader and stronger attenuation at 10 mg. In contrast, in-scanner negative affect ratings were robustly sensitive to task conditions but did not differ by dose. Post-scan valence and arousal ratings confirmed expected stimulus effects without reliable dose effects. Exploratory analyses revealed limited correspondence between regional activation and subjective affect. These findings indicate that acute oral THC is associated with dose-dependent reductions in recruitment of prefrontal control circuitry during cognitive reappraisal in PTSD without detectable changes in self-reported affect, consistent with a potential neural-subjective dissociation, although smaller behavioral effects may not have been detectable in the current sample.