Anxiolytics, sedatives, and anesthetics
Diazepam is used for treating anxiety, insomnia, muscle spasms, and seizure disorders. Combining diazepam with WIN55212-2 produced a supra-additive anxiolytic effect in the rat elevated plus maze test; combining diazepam with the FAAH inhibitor URB597 also led to a supra-additive effect; coadministration of diazepam with the CB1 antagonist AM251 attenuated diazepam's anxiolytic effect [112]. These findings might be explained by the observation that both chronic and, particularly, acute administration of diazepam to mice is accompanied by strong elevation of brain eCB levels [113].
The anxiolytic and sedative effects of alprazolam were also attenuated by AM251 in mouse behavioral assays (light-dark box test, neurological severity score, and step-down inhibitory avoidance test) [114]. Surprisingly, however, the administration of alprazolam reduced WIN55212-2-stimulated [35S]GTPγS binding in mouse amygdala and hippocampus [114]. CB1 −/− knockout mice showed impaired anxiolytic responses to both buspirone and bromazepam in light/dark box, elevated plus maze, and social interaction tests [115]. N-arachidonoyl-serotonin (AA-5-HT), a dual FAAH/TRPV1 blocker, imparted anxiolytic effects in the mouse elevated plus maze assay [116].
A sub-effective dose of THC given to mice caused catelpsy in the horizontal bar test after sub-effective doses of either flurazepam or baclofen were added [117]. The beta-adrenergic blocking agent propranolol causes mild sedation, but pretreatment with propranolol blocked cannabis-induced cardiovascular effects and learning impairment in a small clinical trial [118].
General anesthesia (midazolam, sufentanil, isoflurane, and sufentanil) resulted in decreased serum AEA in patients stressed by the anticipation of cardiac surgery [119]. The dissociative anesthetic phencyclidine (PCP) impairs rotarod performance and open-field behavior in rats, effects shared by THC; combining the two caused supra-additive results [120]. Low-grade Mexican marijuana was adultered with PCP and marketed as “superweed” in the 1970s [121]. Nitrious oxide and THC both increase pain threshold in the tail-flick and hot-plate test, and their combination caused supra-additive effects [122].