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). 

Figure: Structures of (endo)cannabinoids

Three years later, 2-arachidonoylglycerol (2-AG), was found as a second endogenous ligand for the cannabinoid receptors. Anandamide and 2-AG are termed endocannabinoids: the body’s own marijuana. The discovery of the endocannabinoids and their receptors, together called the endocannabinoid system, has opened a new road to studying the effects of marijuana and to investigating its physiological role in health and disease. It is thought that the endocannabinoid system is involved in the regulation of a variety of physiological processes, such as pain sensation and appetite, memory, blood pressure and motor coordination. The endocannabinoid system plays a role in several diseases, such as neuropathic pain, cancer, Parkinson’s disease, multiple sclerosis, schizophrenia and obesity. For example, it is well known that smoking marijuana leads to binge eating (i.e. having the ‘munchies’).

Inspired by this observation, researchers have found that increased endocannabinoid levels in the hypothalamus led to chronic cannabinoid CB1 receptor activation, which was associated with weight gain and the metabolic syndrome in obese patients. This raised the interest of pharmaceutical companies to discover potential drug candidates to regulate the activity of the endocannabinoid system. The cannabinoid CB1 receptor blocker rimonabant was shown to be effective in obese patients, but unfortunately caused severe psychiatric side effects, such as depression and suicidal ideation. This led to the withdrawal of this compound from the European market.

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?”

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.

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.