Endocannabinoids in health and disease

Endocannabinoids are signalling molecules formed by the human brain; they activate a protein called the cannabinoid CB1 receptor. This protein can be hijacked by the main component of marijuana (Δ9-THC) and is responsible for a person becoming “high” or “stoned”, and is also linked to binge eating (i.e. having the munchies). Continuous stimulation of the CB1 receptor by the endocannabinoids is associated with nicotine addiction, obesity and metabolic syndrome; these are all major risk factors for illness and death in Europe.

Pharmaceutical companies have, therefore, tried to develop drugs that can block the effect of Δ9-THC and the endocannabinoids. These drugs were effective in obese patients, but unfortunately also had unacceptable psychiatric side effects, such as depression and suicide, in some patients. The drugs were not approved by the FDA and removed from the European market by the European authorities. Thus, there is an unmet medical need for drugs that interfere with endocannabinoid signalling. The new research programme of the Faculty of Science is focused on developing and testing novel molecules, models and methods that can prevent the formation of the endocannabinoids.

Figure 1: Endocannabinoids in health and disease. THC, the psychoactive ingredient from marijuana, activates the cannabinoid CB1 and CB2 receptors. AEA and 2-AG are endocannabinoids produced by the human body that also activate these receptors. The endocannabinoids regulate multiple physiological processes and are associated with several diseases. Rimonabant, a general CB1 receptor blocker, was used for the treatment of obesity and metabolic syndrome, but it was withdrawn from the European market because of severe psychiatric side effects. This indicates that there is a medical need to control the endocannabinoid system in a more specific fashion.

Faculty of Science Profile Programme: “Endocannabinoids”

Recently, the Faculty of Science at the Leiden University has started a program to investigate the role of proteins responsible for the biosynthesis of the Endocannabinoids. In this multi-disciplinary project researchers from the Leiden Institute of Chemistry (LIC), Leiden Academic Center for Drug Research (LACDR) and Institute for Biology Leiden (IBL) will collaborate to address the fundamental questions: “Why does the cannabinoid CB1 receptor use two endogenous ligands in the central nervous system?” and “How does this affect its molecular interaction with the stress pathway?”

Medicinal marijuana

Marijuana is the most widely used illegal drug throughout the world and has aroused great controversies. Nowadays you can buy marijuana (the so-called ‘MediWiet’) on prescription in the drug store. It may help to relieve the symptoms of patients suffering from multiple sclerosis, restore appetite or suppress nausea in cancer patients treated with chemotherapy. Marijuana (bangh, hashish) is an extract from the plant Cannabis Sativa that contains at least 400 chemical components of which 60 belong to the class of cannabinoids.

Endocannabinoids: the body’s own marijuana

The presence of cannabinoid receptors in mammals suggested the existence of endogenous molecules in the brain, which bind and activate these proteins. In 1992, almost 30 years after his discovery of THC, professor Mechoulam isolated the first endogenous compound for these receptors from porcine brain. This component proved to be a lipid: N-arachidonoylethanolamine. The compound was called anandamide ("ananda" is Sanskrit for internal bliss).