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By Robert G. Bell

Robert BellAs we discussed in Marijuana 103, Cannabinoid Receptors, marijuana and its associated cannabinoids exert their effect by interaction with specific endogenous cannabinoid receptors CB1 and CB2. Cannabinoid receptor CB1 is called the neuronal cannabinoid receptor and has been found in rat, guinea pig, dog, monkey, pig and human brains, and peripheral nerves. CB1 receptors are widely distributed in the cerebral cortex, hippocampus, amygdala, basal ganglia, cerebellum, thalamus, and brainstem. The CB2 receptor was identified in macrophages in the spleen and is also present in other immune cells. The discovery of cannabinoid receptors stimulated research for the endogenous ligand with which the receptors naturally interact. The ligand was found to be a derivative arachidonic acid related to the prostaglandins and the substance was named anandamide after the Sanskrit word for bliss, ananda. Ananamide has a high affinity for CB1 receptors and has most of the actions of THC. Interestingly, as with opium, opioid receptors, and endogenous opioids, this system is now replicated with cannabis, cannabinoid receptors, and anandamides. Similar endogenous fatty acids have since been found, and it now appears that there may be a whole system of multiple cannabinoid receptors and anandamide-related substances whose physiological function has yet to be elucidated.

It appears that both anandamides act as neuromodulators through intracellular G-proteins controlling cyclic adenosine monophosphate formation and Ca2+ and K+ ion transport. This system may have important interactions with other neurotransmitters, including γ -aminobutyric acid, opioid systems, and monoamines. THC has been shown to increase the release of dopamine from the nucleus accumbens and prefrontal cortex. This effect, reversed by naloxone, suggests an opioid link is common to many drugs of abuse such as heroin, cocaine, amphetamine, and nicotine, and may be the basis of its reinforcing properties and its recreational use.

The majority of THC effects are mediated through agonistic actions at cannabinoid receptors. Some non-CB mediated effects of THC and synthetic derivatives have also been described to have some effects on the immune system, neuroprotective effects, and anti-emetic effects. It is possible that several effects previously thought to be non-receptor mediated are mediated by cannabinoid receptor subtypes that have not yet been identified. The mode of action of cannabidiol is not fully understood and several mechanisms have been proposed.

There are many other constituents of marijuana that exert potential pharmacodynamic effects and may have pharmaceutical benefits. These include cannabinol (CBN) for immunosuppressive properties; cannabigerol for anti-inflammatory and analgesic properties; cannabidiol (CBD), which lacks pyschoactivity and does not bind to cannabinoid receptors, as an anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform effects; and tetrahydrocannabivarin (THCV), which has anti-epileptiform /anti-convulsant properties.

On a related matter, marijuana can interact with many drugs. There is an additive effect with alcohol, sedatives, and central nervous system depressants such as barbituates, clonazepam, lorazepam, phenobarbital, zolpidem, and others. Marijuana may interact with theophylline, disulfram, fluoxetine, and cause agitation, trouble sleeping, and irritability. Marijuana may interact with warfarin to increase bruising and bleeding.

Next up, marijuana’s clinical uses and potential recreational abuses.

Robert G. Bell, Ph.D., is president and owner of Drug and Biotechnology Development LLC, a consultancy to the pharmaceutical industry and academia for biological, drug, and device development.