In 1984, Miles Herkenham and his colleagues at NIMH mapped the brain receptors for THC, using radioactive analogs of THC developed by Pfizer Central Research. They found the most receptors in the hippocampus, where memory consolidation occurs. There we translate the external world into a cognitive and spatial “map”. Receptors also exist in the cortex, where higher cognition is performed. Very few receptors are found in the limbic brainstem, where the automatic life-support systems are controlled. This may explain why it is so difficult to die from an overdose of cannabis. The presence of THC receptors in the nasal ganglia — an area of the brain involved in the coordination of movement — may enable the cannabinoids to relieve spasticity. Some receptors are located in the spinal cord, and may be the site of the analgesic activity of cannabis. A few receptors are found in the testes. These may account for the effects of THC on spermatogenesis and as an aphrodisiac.

S. Munro, et al., located a peripheral CX5 receptor for cannabinoids in the marginal zone of the spleen. The Anandamide/cannabinoid receptor site, a protein on the cell surface, activates G-proteins inside the cell and leads to a cascade of other biochemical reactions which generate euphoria. (26-31)

The brain produces Anandamide (Arachidonylethanolamide), which is the endogenous ligand of the cannabinoid receptor. It was first identified by William Devane and Raphael Mechoulam, et al., in 1992. Anandamide has biological and behavioral effects similar to THC. Devane named the substance after the Sanskrit word Ananda (Bliss). The discovery of Anandamide and its receptor site has unlocked the door to the world of cannabinoid pharmacology. (32-35)

CBD antagonizes THC and competes with THC to fill the cannabinoid receptor site. THC also exerts an inhibitory effect on acetylcholine activity through a GABA-ergic mechanism. It significantly increases the intersynaptic levels of serotonin by blocking its reuptake into the presynaptic neuron. THC also elevates the brain level of 5-hydroxy-tryptamine (5-HT) while antagonizing the peripheral actions of 5-HT. (36-39)

In 1990, Patricia Reggio, et al., developed a molecular reactivity template for the design of cannabinoid analgesics with minimal psychoactivity. The analgesic activity of the template molecule (9-nor-9b-OH-HHC) is attributed to the presence and positions of two regions of negative potential on top of the molecule. The template places all cannabinoid analgesics on a common map, no matter how dissimilar their structures. (40)