Cannabis (drug) - Mechanism of Action

Mechanism of Action

The high lipid-solubility of cannabinoids results in their persisting in the body for long periods of time. Even after a single administration of THC, detectable levels of THC can be found in the body for weeks or longer (depending on the amount administered and the sensitivity of the assessment method). A number of investigators have suggested that this is an important factor in marijuana's effects, perhaps because cannabinoids may accumulate in the body, particularly in the lipid membranes of neurons.

Until recently, little was known about the specific mechanisms of action of THC at the neuronal level. However, researchers have now confirmed that THC exerts its most prominent effects via its actions on two types of cannabinoid receptors, the CB₁ receptor and the CB₂ receptor, both of which are G-Protein coupled receptors. The CB1 receptor is found primarily in the brain as well as in some peripheral tissues, and the CB2 receptor is found primarily in peripheral tissues, but is also expressed in neuroglial cells as well. THC appears to alter mood and cognition through its agonist actions on the CB1 receptors, which inhibit a secondary messenger system (adenylate cyclase) in a dose dependent manner. These actions can be blocked by the selective CB1 receptor antagonist SR141716A (rimonabant), which has been shown in clinical trials to be an effective treatment for smoking cessation, weight loss, and as a means of controlling or reducing metabolic syndrome risk factors. However, due to the dysphoric effect of CB1 antagonists, this drug is often discontinued due to these side effects.

Via CB1 activation, THC indirectly increases dopamine release and produces psychotropic effects. THC, anandamide, and several other cannabinoids also act as allosteric modulators of opioid and glycine receptors. The role of these interactions in the "marijuana high" remains elusive.