Delta-9-tetrahydrocannabinol intoxication is associated with increased prefrontal activation as assessed with functional near-infrared spectroscopy: A report of a potential biomarker of intoxication

Abstract The primary psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), binds to cannabinoid receptors (CB1) present in high concentrations in the prefrontal cortex (PFC). It is unknown whether the PFC hemodynamic response changes with THC intoxication. We conducted the first double-blind, placebo-controlled, cross-over study of the effect of THC intoxication on functional near infrared spectroscopy (fNIRS) measures of PFC activation. Fifty-four adult, regular (at least weekly) cannabis users received a single oral dose of synthetic THC (dronabinol; 5–50 mg, dose individually tailored to produce intoxication) and identical placebo on two visits at least one week apart. fNIRS recordings were obtained during a working memory task (N-Back) at three timepoints: before THC/placebo, at 100 min (when peak effects were expected), and at 200 min after THC/placebo administration. Functional data were collected using a continuous-wave NIRS device, with 8 sources and 7 detectors arrayed over the forehead, resulting in 20 channels covering PFC regions. Participants also completed frequent heart rate measures and subjective ratings of intoxication. Approximately half of participants reported significant intoxication. Intoxication ratings were not correlated with dose of THC. Increases in heart rate significantly correlated with intoxication ratings after THC dosing. Results indicated that 100 min after THC administration, oxygenated hemoglobin (HbO) response significantly increased from pre-dose HbO levels throughout the PFC in participants who reported significant intoxication. Changes in HbO response significantly correlated with self-reported intoxication at 100 min after THC administration. Among those who reported intoxication, HbO response decreased at 200 min after THC, when intoxication had largely resolved, compared to the peak THC time point. This study demonstrates that THC intoxication causes increased PFC activity, and fNIRS of the PFC can measure this effect. Increased neural activation in PFC represents a potential biomarker for cannabis intoxication.