Editorial???Behavioural Pharmacology of Cannabinoids

Abstract

The argument for the medicinal application of cannabis products has long been burdened by evidence of their widespread recreational use, which has been associated with cannabis dependence and viewed unfavourably by some segments of Western society. The controversy between proponents and opponents of this argument often has been marked by adamant yet undocumented claims, perhaps best exemplified by the film Reefer Madness (originally entitled Tell Your Children: The Burning Question). This film was produced by a small church group in the USA in 1936, 1 year before possession of marijuana became a federal offense in that country. It was released as an educational message to warn American youth against the lurking dangers of marijuana (i.e. even a single exposure leads to cannabis intoxication, sexual and moral depravity, and inevitably ruined lives). The zealous but unsophisticated creators of this film depended on the blunt instruments of gross overstatement and implausible distortion to forcefully make their points; unintentionally, although perhaps predictably, the resulting film was somewhat comedic and, over the years, Reefer Madness has become a cult classic. Now, some seven decades later, it remains a fine example of both poor cinematography and the wrongheadedness of misinformation-based advocacy of the anti-cannabis perspective. Those who favour the recreational and medicinal use of cannabis products also have been evangelists of a sort, proselytizing for the liberalization, and even removal, of anti-cannabis laws in our societies. Cannabis products have been known for their physiological and psychological effects over a period of nearly 5000 years, perhaps being first used in India and China as antiseptic and analgesic agents. By the late 19th Century, cannabis products were being widely recommended for one malady or another in Western societies. However, their subsequent medical use has declined as the above-mentioned controversy has persisted and other effective therapeutic agents have become available. Presently, the controversy over the use of cannabis products for their psychoactive and medicinal properties continues and, with the emergence of new cannabinoid pharmacology, has been revitalized. It is important to note that, similar to anti-cannabis extremists, the fiercest advocates of the idea that cannabis products are safe and medically beneficial sometimes forward untenable and factually unsupported positions. Whether or not cannabis products are reasonably safe for recreational use and whether or not they have important medicinal value, it is undoubtedly the case that cannabis products, similar to other recreational drugs, can be used to excess and that they, similar to other pharmaceutical products, will not be medicinal panaceas. Against this backdrop of longstanding social, political, and even moral controversy, the science of cannabis has marched briskly forward. The existence in brain receptors for Δ9THC, the principal active ingredient in cannabis, had been presumed since the late 1980s. However, in the first half of the 1990s, a rapid succession of events [i.e. the discovery of the cannabinoid-1 (CB-1) receptor, the isolation and synthesis of its endogenous ligands anandamide and 2-AG, and the development of the CB-1 inverse agonist/antagonist SR 141716A (rimonabant)] have provided the necessary tools for the most recent surge of cannabinoid pharmacology over the last decade. It is an historical irony that the first major cannabinoid medicinal agent likely to emerge from these research efforts is the CB-1 antagonist Acomplia (rimonabant), thereby neatly delaying the thorny issues that may attend the pharmaceutical development and widespread marketing of novel CB-1 agonists. In this regard, it is interesting that recently developed CB-1 agonists, such as HU-210, have been proposed to be medicinally valuable, yet free of undesired effects (including abuse liability) of the traditional benchmark agonist, Δ9THC. It remains to be determined whether such distinctions will stand up under the tests of time and close clinical scrutiny. Notwithstanding such caveats, rapid advances in the medicinal chemistry of CB-1 ligands continue to yield newer, non-cannabinoid ligands for the CB-1 receptor. It is likely that clinically useful compounds with behavioural and pharmacokinetic features that are highly different from those of conventional cannabinergic ligands will emerge from such chemical synthesis programmes. Perhaps, this is enough reason to predict an eventual end to the historical dilemna regarding the medicinal application of recreationally used cannabis products. The purpose of this Special Issue is to provide the reader with a mix of reviews and original investigations that, although not exhaustive, survey several areas of cannabinoid research of current interest for behavioural pharmacology. One such area pertains to the study of antagonists such as rimonabant. The development of rimonabant as an anti-smoking medication has spurred considerable research in the use of CB-1 antagonists to modify the abuse-related effects of other psychoactive drugs. To examine this notion, Beardsley and Thomas provide a careful and methodologically sensitive review of this body of work, with close attention to neurochemical and neuroanatomical points of contact between the endocannabinoid system and other systems mediating the abuse-related effects of drugs. It is striking that, despite the many studies of rimonabant and other CB-1 inverse agonists/antagonists over the past decade, the behavioural pharmacology of these drugs as pharmacological antagonists of CB-1 receptor ligands is not fully understood. In a report of original research, McMahon and colleagues attack this problem by systematically studying the CB-1 antagonistic effects of rimonabant in non-human primates. Another area of research that currently commands great interest for behavioural pharmacologists is the involvement of cannabinoid systems in aspects of feeding, including appetite, ingestive behaviour and energy regulation. Kirkham, a leading investigator in this field of research, provides a delightful review that spans these several topics in a scholarly manner. His informative and critical treatment is further supported by research reports on the development of tolerance to CB-1 modulation of feeding behaviour (Jarbe and diPatrizio), CB-1 mediation of the motivation to consume palatable food (Ward and Dykstra) and, in a set of direct comparisons, the dissimilar modulation of food-motivated behaviour and intake by two CB-1 agonists, Δ9THC and HU-210 (Higgs and colleagues). A third focus of this Special Issue is the role of endocannabinoid systems in psychiatric disorders, especially anxiety and depression. Witkin and his colleagues review findings that suggest a role for endocannaboid modulation of anxiety states and, through interactions with monoaminergic systems, depression. However, the data are mixed, and the authors are appropriately guarded in their outlook. Hill and Borzalka also review the involvement of endocannabinoid mechanisms in depression, but these authors take another tack. They note similarities between some attributes of depression and behavioural effects associated with the pharmacological or genetic attenuation of CB receptor activity and observe that both diminished endocannabinoid function and depression may result from chronic exposure to stress. On this basis, they intriguingly propose a formal link between ‘endocannabinoid deficiency’ and melancholic depression. These reviews are bolstered by data from original investigations, one using CB-1 agonists (Hayase and colleagues) and the other using CB-1 inverse agonists/antagonists (Rodgers and colleagues) to explore the involvement of cannabinoid mechanisms in different animal models of anxiety. Furthermore, a re-awakened interest in the role of cannabinoid mechanisms in major psychosis is highlighted in two additional reports. In one, wild-type and CB-1 knockout mice were compared in a phencyclidine-related model of schizophrenia (Haller and colleagues) and, in the second, effects of dopamine D2 agonists were studied during withdrawal from chronic CB-1 agonist treatment (Moreno and colleagues). Both sets of findings point to the involvement of cannabinoid systems in psychosis-related behaviour, suggesting that this area of research will continue to grow in the coming years. Perhaps due to the recognition that behavioural deficits in adults often are rooted in early developmental events, behavioural pharmacology increasingly has turned attention to the effects of early life exposure to drugs on later behaviour. From this perspective, it is not surprising that a great deal of research already has been devoted to studying the effects of early life exposure to cannabinoids. Viveros and colleagues review this literature from a psychoneuroendocrine viewpoint, using data from studies in both human and non-human subjects to focus on the long term consequences of chronic exposure to cannabis and other cannabinoid agonists. In addition to their review, this Special Issue also includes original investigations to address the influence of cannabinoids on aspects of development and maturation. Fride and colleagues who studied the involvement of cannabinoid systems in stress responses, note that cannabinoid mechanisms appear to mediate stress responses from an early age, whereas Moreno and colleagues show that cannabinoid mechanisms play important roles in the ontogeny of psychomotor behaviour. Papers by Schneider and colleagues and by O'Shea and Mallet document concerns regarding, respectively, affectual and cognitive deficits following early life exposure to cannabinoids. It is obvious that this area of research will continue to draw increasing attention because concerns regarding early exposure to cannabis products undoubtedly will continue to be a major issue in Western society. This Special Issue is rounded out with several papers that further illustrate the wide expanse of contemporary cannabinoid research. In elegant electrophysiological experiments, Zhuang and colleagues report on depolarization-induced suppression of GABAergic inhibition, which is thought to involve endocannabinoid mechanisms in hippocampal neurons. There are two papers, by Field and by McLaughlin and colleagues, that report the effects of cannabinoid agonists on stimulus detection in rats and human subjects, respectively. Interestingly, the work by Field reveals an attentional bias for cannabis-related stimuli in cannabis-dependent individuals, whereas McLaughlin and colleagues find that the effects of cannabinoids are dose-related (i.e. low doses of a cannabinoid agonist may actually improve stimulus detection but, as expected, higher doses only impair signal detection processes). Finally, as noted at the outset of these remarks, advances in cannabinoid pharmacology have depended, and will continue to depend, on the development and identification of novel chemicals that act through cannabinoid mechanisms. Thus, it is only appropriate that this special Issue contains two papers reporting, first, on active and inactive ingredients of marijuana in human subjects (Ilan and colleagues) and, second, on the pharmacological profile of a new cannabinomimetic molecule, AMG-3 (Antoniou and colleagues). All in all, advances in cannabinoid pharmacology have occurred at a remarkably rapid pace over the past decade. The reviews and reports in this Special Issue give promise that this pace will continue, and perhaps quicken. It is likely that our understanding of cannabinergic mechanisms of action and endocannabinoid systems will improve and, in turn, will hasten the further development of cannabinoid medicinal products, including CB-1 agonists that are free of the historical controversies that plague cannabis itself.