Cannabinoid tolerance and dependence: A review of studies in laboratory animals

Abstract

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.

Introduction

Cannabis sativa derivatives, such as marijuana and hashish, are among the drugs of abuse whose consumption has higher prevalence, particularly among young people (Budney et al., 1999, Ashton, 2001). Marijuana has always been considered as a “soft drug” in part due to its lower impact on human health compared to opioids, alcohol or psychostimulants, and in part due to the late discovery of mechanisms of action in the brain of its psychoactive constituents. Due to these two considerations, various aspects of cannabis addiction have resulted to recent controversies with some being clarified only very recently, among them: (i) whether cannabis is addictive as what happens with other recreational substances consumed by humans; (ii) whether a prolonged exposure to cannabinoids develops tolerance due to similar responses operating for other drugs, i.e., down-regulation/desensitization of specific receptors, changes in bioavailability, or neuronal adaptation; this point is also important considering the possible regular therapeutic use of cannabinoids in specific diseases; (iii) whether there exists an abstinence syndrome equivalent to that occurring in the case of other habit-forming drugs of recognized greater addictive power; and (iv) whether cannabis might play a gateway effect by increasing the risk to consume these more strongly addictive drugs. With the exception of the first of these four issues, which has been addressed in the review article written by Elliot Gardner in this special issue (Gardner, 2005), the present review will address all literature published, mainly in laboratory animals, on the remaining three issues of this purported addiction to cannabis.