Anticonvulsants
Combining diazepam with WIN55212-2 produced a supra-additive anticonvulsant effect in rats; combining diazepam with the FAAH inhibitor URB597 also led to a synergistic effect; coadministration of diazepam with the CB1 receptor antagonist AM251 attenuated the anticonvulsant effect of diazepam [123]. Chronic administration of valproate in rats increased CB1 binding of the PET scan tracer [18F]MK-9470; this was not seen with levetiracetam [124]. Tiagabine, an anticonvulsant GABA reuptake inhibitor, augmented THC-induced catalepsy [117] but not antinociception or hypothermia [125]. In a human study, tiagabine augmented THC discrimination and enhanced THC effects in other outcomes [126].
Pregabalin is a Ca2+ channel antagonist used for treating epilepsy and neuropathic pain. Isobolographic analysis demonstrated that combining WIN 55,212-2 with pregabalin exerted synergistic antinociceptive effects in the mouse hot-plate test [127]. Vagus nerve stimulation (VNS) is used as an add-on treatment to patients with drug-resistant epilepsy. Implantation of a vagus nerve stimulator in rats significantly decreased AEA and 2-AG in mesenteric adipose tissue, but increased PEA [128]. Chemical VNS by administration of the peptide hormone cholecystokinin 8 to fasted rats decreased expression of CB1 in vagal afferent neurons [129].