During the past 15 years, the biology of the endocannabinoid system has become one of the hottest fields of biomedical research. These recently discovered lipid mediators have been implicated in a growing number of physiological functions, both in the CNS and in the periphery, and many of these have the promise to become targets for pharmacotherapy. Our review surveyed endocannabinoid research with special emphasis on its potential therapeutic implications.

“Our review surveyed endocannabinoid research with special emphasis on its potential therapeutic implications.”

Although our review is far from being comprehensive, given the recent explosive growth of this field, the more than 1,400 references listed in it are a clear indication of the level of interest in these mediators and their impact on drug development. We have also attempted to give a balanced overview of the mechanisms underlying the potential therapeutic effects of cannabinoid-based treatment strategies in a large number of human disease conditions, and provided extensive background information on the biology of endocannabinoid signaling, which may be the reasons why the paper is being highly cited.

As a review, the emphasis was on synthesizing recently emerging knowledge and highlighting potential therapeutic implications.

Marijuana being the most widely used "recreational" drug in Western societies, its effects on the mind and body are well known to the general public. The recent discovery of specific receptor molecules that mediate these effects, and the subsequent discovery of the body’s own marijuana-like substances, which can activate these receptors, opened new possibilities to exploit these effects for the treatment of disease. For example, smoking marijuana is known to increase appetite, causing the "munchies."

This has triggered the development of synthetic compounds that can block the receptor mediating this effect. The results of recent clinical trials indicate that such compounds are effective in reducing weight and also improving metabolic abnormalities in people with obesity/metabolic syndrome. In other cases, it is the activation of these receptors that may produce a beneficial effect, such as suppression of nausea, pain, or relieving anxiety (e.g., in some cancer patients).

Although smoking marijuana may produce such beneficial effects, its addictive, psychoactive properties limit its usefulness. However, novel synthetic compounds have been developed that block an enzyme responsible for the degradation of endogenous cannabinoids and thus can elevate their levels in tissues. Such a compound was found to reduce anxiety without causing other, marijuana-like psychological effects.

I have long been interested in blood pressure regulation, and my interest in endocannabinoids started with observations that these substances can effectively lower blood pressure, which has led us to discover that they contribute to the low blood pressure that accompany various forms of shock or advanced liver cirrhosis. Later we became interested in the role of endocannabinoids in the regulation of appetite and fat metabolism, and identified some of the cellular mechanisms involved in these effects.

Dr. Pal Pacher, who recently set up his own independent laboratory within our Institute, is interested in the mechanisms involved in inflammation, immune responses, and oxidative/nitrosative stress-mediated tissue injuries, and his recent work highlighted the role of endocannabinoids in these processes as well.

My own laboratory focuses on the metabolic effects of endocannabinoids, and on the role of the liver in these effects, with recent emphasis on both alcoholic and non-alcoholic fatty liver. We are also exploring the mechanisms by which endocannabinoids influence the contractile function of the heart. Dr. Pacher is interested in the role of the endocannabinoid system in various forms of tissue injury associated with oxidative/nitrosative stress and inflammation. Of course, we continue to collaborate in many of these projects.

Marijuana and its active ingredient have significant abuse potential, which makes their therapeutic use socially unacceptable in contemporary society. One important aspect of research into the endocannabinoids and their functions will be to separate the therapeutically desirable effects from socially unacceptable addictive psychological effects through the development of novel compounds with selectivity to specific molecular targets.