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DEVELOPMENT OF TOLERANCE TO THE PROLONGATION OF HEXOBARBITONE SLEEPING TIME CAUSED BY CANNABIDIOL

1 The effects of acute and subacute cannabidiol (CBD) administration on hexobarbitone sleeping time and on some constituents of the hepatic microsomal drug‐metabolizing system were assessed in the mouse. 2 Acutely administered CBD prolonged sleeping time; but with subacute treatment, tolerance to the effect rapidly developed. 3 Brain hexobarbitone concentration upon awakening was unchanged by either acute or subacute CBD treatment, which suggests that neither the prolongation of sleeping time nor the tolerance is the result of a change in sensitivity of the central nervous system to the barbiturate. 4 Acute CBD treatment increased the half‐time of hexobarbitone in the brain, which returned toward normal with the development of tolerance. 5 Acutely, CBD caused a 30% decrease in hepatic cytochrome P‐450 level; with tolerance, the cytochrome concentration returned to normal. 6 The evidence suggests that the CBD‐induced prolongation of barbiturate sleeping time and the tolerance to this effect are the result of changes in the rate of drug metabolism, which are related to changes in the amount of cytochrome P‐450. 7 The effects of CBD on the hepatic microsomal drug‐metabolizing enzyme system are different from those attributed to SKF 525‐A and piperonyl butoxide because the cannabinoid does not decrease cytochrome P‐450 quantitatively by complex formation, it does not produce a recovery overshoot in the cytochrome concentration and, finally, it does not cause an induction of the hexobarbitone‐metabolizing enzymes.