Cannabinoid System

Cannabinoids are a group of related compounds found in the plant Cannabis sativa. The major psychologically active component in marijuana is ∆9-tetrahydrocannabinol (THC). THC acts on mammalian cannabinoid receptors to elicit various responses. Mammals also have endogenous molecules (termed endocannabinoids) that activate the same cannabinoid receptors as THC. The endogenous cannabinoid system in mammals thus includes the cannabinoid receptors, endocannabinoids, and enzymes involved in synthesizing and degrading endocannabinoids.

There are 70 known cannabinoids in Cannabis sativa. Marijuana refers to the dried leaves and flowering tops of the female hemp plant. Marijuana smoking can elicit a variety of psychological and physiological effects. The physiological effect is best exemplified by increased heart rate and increased appetite. The psychological effects are highly subjective experience, and the experience varies enormously depending on many variables such as dose, environmental setting, and prior experience. Common effects include euphoria, diminished psychomotor performance (coordination of cognitive process and motor activity), and impairment of short-term memory. Some people have reported dysphoria and a change in time perception. The most psychologically active component in marijuana is THC. Other cannabinoids may have effects different from those of THC.

The mechanism of action of THC was clarified when a brain receptor was found to be activated by THC in 1990. This brain receptor was termed cannabinoid-1 receptor (CB1R), and is present in the brain of humans, mammals, and vertebrates. A second receptor, cannabinoid-2 receptor (CB2R), was found most predominantly in immune cells. In 1992 and 1995, two molecules with cannabinoid-like activity were identified in mammalian brain and gastrointestinal tract. These endogenous molecules were named anandamide and 2-arachidonyl glycerol, and both activate CB1R and CB2R in a manner analogous to THC.

In the nervous system, endocannabinoids are made from membrane precursors when specific neurons are activated. Anandamide and 2-arachidonyl glycerol are synthesized at the cell body of neurons through two separate biosynthetic pathways, and are degraded by different enzymes, respectively. When endocannabinoids are synthesized, they serve as retrograde neuromodulators, diffuse across the synapse and act on CB1R to inhibit neurotransmission. Thus, endocannabinoids are feedback molecules that dampen both excitatory and inhibitory transmissions if CB1R is expressed in those nerve terminals.

The involvement of the endocannabinoid system in energy balance and feeding control is well supported by the appetite-enhancing effect of marijuana smoking. In addition, endocannabinoid system interacts with other brain mechanisms to exert influence on energy balance. The synthesis of endocannabinoids is inhibited by leptin, indicating that endocannabinoids serve as one of the downstream effectors of leptin action. CB1R is co-expressed with several neuropeptides, [Page 109]such as melanin-concentrating hormone and orexin, which are known to affect food intake and energy expenditure. Furthermore, the endocannabinoid system can also exert its effect in parallel with other systems, leading to an additive or synergistic influence on energy balance.

Several experimental medications are in clinical development. These include inverse agonists such as rimonabant, taranabant, and SLV319 for the treatment of obesity.