The endogenous cannabinoid system and drug addiction: 20 years after the discovery of the CB1 receptor

Cannabis sativa preparations (hashish, marijuana) have been used by humans for the last 5000 years. But being one of the oldest recreational drugs with abuse potential, its neurobiological mechanisms remained obscure until the isolation and identification in 1964 of Dtetrahydrocannabinol (THC), its main psychoactive constituent, by the group of Ralph Mechoulam (Gaoni & Mechoulam 1964). THC was the first of a series of a new class of drugs termed cannabinoids, but despite this finding, the brain targets of THC remained unidentified for another long period. It was in November 1988, 20 years ago, when a seminal paper by the group of Allyn Howlet (Devane et al. 1988) identified pharmacologically the presence in the brain of a G protein-coupled receptor as the target of natural cannabinoids. It was followed immediately by the molecular cloning of the cannabinoid receptor (Matsuda et al. 1990) and by the identification by the group of Raphael Mechoulam of the first endogenous ligand of the cannabinoid receptor, an arachidonic acid derivative termed anandamide (Devane et al. 1992). This discovery completely changed the research on cannabinoids and marijuana and led to one of the most active fields of research in neuropharmacology. As an example, 2924 cannabis-related papers were published until 1988. From 1988 to-date, 7183 scientific communications can be found in biomedical databases. In 20 years, the cannabinoid field has generated three times more documents than in the whole anterior period. Table 1 summarizes the most important hints on cannabinoid research since the discovery of the first cannabinoid receptor. Why is the discovery of the cannabinoid receptor so important? And why a special issue in Addiction Biology? The identification of a specific receptor for THC opened not only the gate to an active research on the neurobiology of cannabis abuse, it also allowed the scientific community to identify an evolution-preserved, widely distributed modulatory system that participates in multiple physiological processes such as motivated behaviours, emotional homeostasis, memory storage or motor control (Fig. 1). In fact, the potentiality of the endogenous cannabinoid system as a target for the development of new medicines can be envisioned by simply paying attention to the multiple inventions surrounding its discovery. Table 2 shows the patents filed in the last 15 years, most of them by major pharmaceutical companies, protecting the utility of methods and compounds related to the endogenous cannabinoid system for applications on multiple disorders. Few fields on science can show such an explosion of technology. We can expect a reasonable pay-off from these patents in the next 10 years. In fact, a first medicine based on the cannabinoid CB1 receptor, the antagonist rimonabant, is already in the market for complicated obesity, and many others are already on clinical trials. Regarding addiction, many different approaches identified how natural cannabinoids modulated reward systems and induced tolerance. But only with the identification of the cannabinoid CB1 receptor did we come to understand why cannabinoids did so and how the endocannabinoid system participated in cannabis addiction (Table 1). Research has demonstrated how animals self-administer cannabinoid CB1 receptor agonists and how cannabinoid receptor antagonist suppresses cannabinoid-induced positive reinforcement. Moreover, cannabinoid withdrawal in animal models and in humans was identified and explained on the basis of the presence of the CB1 receptor in specific brain circuits. But the real surprise came from the discovery of the role of the endogenous cannabinoid system in general reward process and in the neurobiology of addiction. Both the endocannabinoids and the cannabinoid receptor appear to be crucial in opioid, alcohol, psychostimulant and nicotine addiction. Its presence in reward circuits allows a clear modulation not only of reward, but also of relapse processes, a key issue on drug abuse therapy. This is the justification for the present issue on cannabinoids in Addiction Biology. The intense work developed for the past 20 years by researchers throughout the world has placed the CB1 receptor and the endogenous cannabinoid system in the center of the search for new therapies on addiction. This issue also wants to pay homage to the seminal work of those who devoted their scientific career to this field, specially to Dr. Miguel Navarro, who passed away recently. His essential contribution to the understanding of opioid–cannabinoid interactions, to the role of endocannabinoids on alcoholism and to the cannabinoid CB1 receptor modulation of anxiety merits our recognition. We have put together a wide overview of the endogenous cannabinoid system on addiction. The first article of the invited reviews, by Roger Pertwee, gives a detailed GUEST EDITORIAL doi:10.1111/j.1369-1600.2008.00116.x