Although Jones and Stone (1970) and later MacAvoy and Marks (1975) posited the existence of cross-tolerance between cannabinoid drugs and ethanol based upon their data from humans, preclinical studies in the rat were the first to definitively show a symmetrical cross-tolerance (Newman et al., 1974; Newman et al., 1972). In these studies, rats were trained in a one-way avoidance paradigm where they could escape to an elevated platform to avoid a foot shock. Acute administration of either THC or ethanol impaired avoidance behavior, but after repeated treatment with either THC or ethanol, subjects tested with the other compound (i.e. the one not given during treatment) displayed a marked tolerance where performance was not significantly impaired. Subsequent studies conducted in the 1970’s demonstrate that cross-tolerance also arises between the ataxic effects of cannabinoids and ethanol (Siemens and Doyle, 1979; Sprague and Craigmill, 1976). This cross-tolerance was not due to pharmacokinetic processes because ethanol-tolerant subjects did not metabolize THC more readily, and THC-tolerant rats did not show increased turnover of ethanol (Siemens and Doyle, 1979).
