The pharmacological actions of THC result from its binding to the cannabinoid receptor CB1, located mainly in the central nervous system, and the CB2 receptor, mainly present in cells of the immune system. It acts as a partial agonist on both receptors, i.e., it activates them but not to their full extent. The psychoactive effects of THC are mediated by its activation of the CB1 receptor, which is the most abundant G protein-coupled receptor in the brain.

The presence of these specialized receptors in the brain implied to researchers that endogenous cannabinoids are manufactured by the body, so the search began for a substance normally manufactured in the brain that binds to these receptors, the so-called natural ligand or agonist, leading to the eventual discovery of anandamide, 2-arachidonoyl glyceride (2-AG), and other related compounds known as endocannabinoids. This is similar to the story of the discovery of endogenous opiates (endorphins, enkephalins, and dynorphin), after the realization that morphine and other opiates bind to specific receptors in the brain. In addition, it has been shown that cannabinoids, through an unknown mechanism, activate endogenous opioid pathways involving the μ1 opioid receptor, precipitating a dopamine release in the nucleus accumbens. The effects of the drug can be suppressed by the CB1 cannabinoid receptor antagonist rimonabant (SR141716A) as well as opioid receptor antagonists (opioid blockers) naloxone and naloxonazine.[12]

The mechanism of endocannabinoid synaptic transmission is thought to occur as follows: First, transmission of the excitatory neurotransmitter glutamate causes an influx of calcium ions into the post-synaptic neuron. Through a mechanism not yet fully understood, the presence of post-synaptic calcium induces the production of endocannabinoids in the post-synaptic neuron. These endocannabinoids (such as anandamide), then, are released into the synaptic cleft, where binding occurs at cannabinoid receptors present on pre-synaptic neurons, where they modulate neurotransmission. Thus, this form of neurotransmission is termed retrograde transmission, as the signal is carried in the opposite direction of orthodox propagation, which previously was thought to be exclusively one way.

THC has mild to moderate analgesic effects, and cannabis can be used to treat pain. The mechanism for analgesic effects caused directly by THC or other cannabinoid agonists is not fully understood. Other effects include relaxation; euphoria; altered space-time perception; alteration of visual, auditory, and olfactory senses; loss of anxiety;[13] anxiety in neurotic individuals or individuals unfamilar with effects;[13] disorientation;[13] fatigue; and appetite stimulation (colloquially known as “the munchies”). The mechanism for appetite stimulation in subjects is believed to result from activity in the gastro-hypothalamic axis.[citation needed] CB1 activity in the hunger centers in the hypothalamus increases the palatability of food when levels of a hunger hormone ghrelin increase prior to consuming a meal. After chyme is passed into the duodenum, signaling hormones such as cholecystokinin and leptin are released, causing reduction in gastric emptying and transmission of satiety signals to the hypothalamus. Cannabinoid activity is reduced through the satiety signals induced by leptin release. It also has anti-emetic properties, and also may reduce aggression in certain subjects.

THC has an active metabolite, 11-Hydroxy-THC, which may also play a role in the analgesic and recreational effects of cannabis.

The α7 nicotinic receptor antagonist methyllycaconitine can block self-administration of THC in rats comparable to the effects of varenicline on nicotine administration.[14][15]

Two studies indicate that THC also has an anticholinesterase action [16][17] which may implicate it as a potential treatment for Alzheimer’s and Myasthenia Gravis.

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