The mechanism of the hypothermia produced in mice by the naturally occurring cannabinoids, delta9-tetrahydrocannabinol, cannabinol, and cannabidiol, was investigated by evaluating the direct effect of these drugs on the oxygen consumption of tissue homogenates and isolated mitochondria. The tissues studied were brain, liver, skeletal muscle, and heart; the mitochondrial preparations were limited to brain and skeletal muscle. The in-vitro studies included a description of the influence of various cannabinoid vehicles containing Tween 80, ethanol, Pluronic F68, and albumin on the oxygen consumption of tissue preparations. Of these vehicles, only albumin was without effect on all tissues. The other vehicles produced diverse responses, including some that were qualitatively different; the data illustrate that the influence of each vehicle on oxygen consumption must be defined for each tissue employed. In spite of the different vehicle effects, delta9-tetrahydrocannabinol generally reduced oxygen consumption of all tissue preparations; however, the vehicles were capable of modifying the dose-effect relationship. The results of all three drugs prepared in Pluronic F68 on brain and skeletal muscle indicated that the cannabinoids generally cause a dose-related depression of oxygen consumption. The findings demonstrate that the cannabinoids can directly decrease oxidative metabolism of tissue and isolated mitochondria and that a marked response occurs in the concentration range of 1 X 10(-5) to 1 X 10(-4) M. Because these concentrations can exist in tissues following the in-vivo administration of delta9-tetrahydrocannabinol, the results suggest that the depressant effect of the cannabinoids on metabolic rate may contribute to the mechanism of the hypothermia produced by the drugs.