Two are the issues on cannabis addiction that provoke more controversy from a research perspective. The first one is related to the development of tolerance phenomena and, in particular, of a dependence state after chronic cannabinoid consumption, with appearance of withdrawal signs when this is interrupted, that would be (or not) comparable to those observed for other drugs. A second controversial issue is related to the possibility that chronic cannabinoid consumption may increase the risk to consume other drugs of greater addictive power. Since the discovery in the 1990s of the endocannabinoid signaling system as the target for the action of plant-derived cannabinoids, many studies have addressed these two questions in laboratory animals and, although the results have resulted controversial in various aspects, the following conclusions seem evident: (i) prolonged exposure to plant-derived, synthetic or endogenous cannabinoid agonists in laboratory animals is currently associated with the development of tolerance for most of their pharmacological effects, (ii) tolerance is essentially due to adaptative phenomena consisting in pharmacodynamic events (down-regulation/desensitization of cannabinoid receptors), although some evidence exist on additional pharmacokinetic responses, (iii) the discontinuation of chronic cannabinoid treatment does not elicit abstinence responses spontaneously in most of the cases, presumably because the pharmacokinetic characteristics of cannabinoids, but these responses may be elicited after the blockade of cannabinoid CB1 receptors in cannabinoid-tolerant animals, (iv) these abstinent responses include mainly somatic signs and changes in various molecular processes affected during the abstinence to other drugs although the magnitude of these changes was currently lower in the case of cannabinoids, and (v) cannabinoid-tolerant animals do not appear to be more vulnerable to reinforcing properties of morphine, although the manipulation of the endocannabinoid signaling might serve to treat cannabis addiction and, in particular, the addiction to other drugs such as alcohol, nicotine or opioids. The present review article will address all these aspects trying to establish the bases for future research.
Sex differences in the acute behavioral effects of cannabinoids and in the development of tolerance to THC have been reported in rodents. For example, female rats are more sensitive than males to the reinforcing, anxiogenic, antinociceptive, and sedative effects of cannabinoids (Craft et al. 2012; Fattore et al. 2007; Harte-Hargrove and Dow-Edwards 2012; Tseng and Craft 2001). Profound tolerance to THC-induced antinociception occurs in both sexes following repeated THC administration (Wiley et al. 2007), and even when sex differences in acute THC potency are adjusted for, female rats develop greater tolerance than males to the antinociceptive effects of THC (Wakley et al. 2014; 2015). Considering these sex differences in THC’s effects on behavior as well as sex differences in the effect of CBD pretreatment on THC metabolism (Britch et al. 2017), we assessed CBD-THC interactions in both sexes.
Locomotor activity measured after vehicle treatment only (“Control”) and immediately after completion of THC dose-effect curve determinations on pre- vs. post-chronic test days (Days 1 vs. 6), in vehicle+vehicle, CBD+vehicle, vehicle+THC, and CBD+THC tolerance groups. On the pre-chronic test day, all tolerance groups had received a total cumulative dose of up to 18 mg/kg THC, whereas the Control group received vehicle. On the post-chronic test day, vehicle+vehicle and CBD+vehicle groups received a total cumulative dose of 18 mg/kg THC, vehicle+THC and CBD+THC groups received a total cumulative dose of 180 mg/kg, and Control groups received vehicle. Each bar is the mean ± 1 S.E.M. of 8 rats (Control group) or 12 rats (all other groups). +Significant suppression of locomotor activity by THC in the vehicle+vehicle group, compared to Controls that did not receive THC; *Post-chronic day activity significantly higher than pre-chronic day activity, within same sex/treatment group, p<0.05
THC dose-effect curves on tail withdrawal and paw pressure tests were obtained before and after twice-daily treatment with vehicle or CBD (10 mg/kg), plus vehicle or THC (3.6 mg/kg females; 9.3 mg/kg males) for 4 days.