On the Cannabinoid Receptor: A Study in Molecular Psychiatry

Psychiatric TimesPsychiatric Times Vol 14 No 7
Volume 14
Issue 7

Given that cannabis (marijuana, hashish, ganja, dagga, etc.) is the most widely used illicit substance in the Western world, it behooves us as physicians to understand as much about it as possible. The cannabinoid receptor is a good starting point in such a pursuit. Marijuana is not a single substance, but a collection of substances or compounds which become 2,000 on pyrolysis. Numbered among the 400 constituents of the plant Cannabis sativa are some 60 cannabinoids.

Given that cannabis (marijuana, hashish, ganja, dagga, etc.) is the most widely used illicit substance in the Western world, it behooves us as physicians to understand as much about it as possible. The cannabinoid receptor is a good starting point in such a pursuit.

Marijuana is not a single substance, but a collection of substances or compounds which become 2,000 on pyrolysis. Numbered among the 400 constituents of the plant Cannabis sativa are some 60 cannabinoids, the best-known of which are delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) (Figure) The first of these is psychoactive and is mainly responsible for the "high" its users experience. CBD is a precursor of THC, and CBN is a spin-off product.

The psychoactive constituents of cannabis produce their pharmacological effects by working at specific receptor sites in the brain that were first identified as such in 1988. Opioid receptors had been identified 15 years earlier, but the existence of cannabinoid receptors was not suggested by that discovery.

The Receptor System

It was its enantioselectivity for many of THC's effects that suggested a specific cannabinoid receptor. The naturally occurring (-)-enantiomer (either of a pair of molecules that are mirror images of each other) of trans-delta-9-THC was noted to have up to 100 times more potency than the (+)-enantiomer (Martin). High degrees of enantioselectivity point to a specific mechanism of action, usually involving a receptor. Cannabinoids had already been shown to inhibit adenylate cyclase by interaction with a G1 protein (G proteins are so named because they bind to the nucleotides guanosine diphosphate [GDP] and guanosine triphosphate [GTP]. They are cell-signaling transducers [energy converters]; G proteins help cells in the body communicate with each other). The demonstration of such an associated second messenger system is important when it comes to proving that a binding site is actually a receptor. That the second messenger system most common for neurotransmitters in the brain is inhibited by cannabinoids strengthened the case for an endogenous cannabinoid system.

Autoradiography using labeled congeners demonstrated high concentrations of cannabinoid receptors in the substantia nigra, hippocampus and cerebellum. Appreciable concentrations were also found in the cerebral cortex. Most of the brainstem and pons contain low or minute concentrations. Several researchers have observed that the distribution of cannabinoid receptors in the brain is similar to that of dopamine D1 receptors, suggesting that the cannabinoid receptor system may function indirectly to modulate brain dopaminergic activity. The significance of this is discussed later.

On the heels of uncovering the cannabinoid receptor system came the discovery of an endogenous ligand (usually a small molecule that binds to a receptor) for the cannabinoid receptor in the brain. And here is where our story really begins.

The recognition of the opioid receptor in 1973 led to curiosity as to why the human brain (as well as nerves in the intestine) would have specific receptors for a substance, morphine, which the opium poppy plant produces as a nitrogenous waste product. When the endogenous "opioids" were found, they turned out not to be opiate-like structurally but instead to be peptides. Thus, it can be said that morphine and related opiates merely mimic the actions of endogenous "opioid" peptides at their receptor sites.

An analogous situation exists with the cannabinoids. The natural ligand has been found to be anandamide, structurally unrelated to cannabinoids. Anandamide is the arachidonoyl amide of ethanolamine (Devane and others).

The Cell Membrane

A quick look at a bit of membrane chemistry may be helpful at this point. All cell membranes are composed of lipids, proteins and smaller proportions of carbohydrates. Lipids constitute 40% to 80% of the total membrane content, with phospholipids accounting for a major proportion of the lipid fraction (some 150 to 200 phospholipids have been identified in cell membranes). Phosphatidylcholine (lecithin) is usually the most abundant phospholipid in the membrane, followed by phosphatidylethanolamine. Each phospholipid contains two fatty acid molecules. The most commonly occurring fatty acids are grouped as saturated or mono-unsaturated (palmitic, stearic, oleic) and polyunsaturated (linoleic, linolenic, arachidonic, docosahexaenoic). The fluidity or flexibility of membranes is dependent on the degree of unsaturation of the fatty acids forming the membrane. As the degree of unsaturation increases, the cell membrane becomes more flexible and fluid. Some polyunsaturated fatty acids, such as linoleic acid, cannot be synthesized in the body, and its deficiency in the diet will lead to changes in membrane function. A number of drugs can produce similar effects. One illustration of what can happen is that altering the conformation of a biological membrane would result in the enzymes located in the membrane not functioning effectively.

High lipophilicity with slow clearance from the body is characteristic of the cannabinoids. Cannabinoids accumulate mostly in neutral fat from which they are slowly released. Cannabinoids also deposit on cell membranes, positioning themselves in the lipid portion, where they affect the fluidity and functional state of the membrane. Their presence leads, among other things, to a reversible inhibition of cyclic adenosine monophosphate (cAMP), affecting cell signaling pathways (Howlett and Fleming). Furthermore, arachidonic acid (an omega-6 fatty acid) accumulates on membrane surfaces in brain-slice preparations in response to the presence of cannabinoids. Cannabinoid-induced inhibition of arachidonic acid acylation of membrane lipids leads to the buildup. THC also promotes increased concentrations of arachidonic acid metabolites, which leads to greater susceptibility to opportunistic bacterial pathogens such as Legionella in those already immune-compromised. (Receptors for the endogenous ligand, the arachidonic acid-like anandamide, are present on lymphoid cells-and on sperm, ovary, even on fertilized ova-as well as on brain cells.)

Arachidonic acid, in addition to being a membrane component, is the biological precursor of the eicosanoids. These physiologically active substances derived from arachidonic acid-the prostaglandins, leukotrienes and thromboxanes-are products of what is referred to as the arachidonic acid cascade. Ethanolamine, a part of the phosphatidylethanolamine molecule, another cell-membrane component, is available for other cellular activity. And the endogenous ligand anandamide, mentioned previously, is the arachidonoyl amide of ethanolamine, a condensation product of arachidonic acid and ethanolamine.Nature is indeed parsimonious. William of Occam (14th century) grasped that in his day. Occam's razor (also known as the principle of parsimony) stipulates that "entities should not be multiplied unncessarily." Rather than create one more molecule from scratch, nature took two molecules already involved in the cell's economy and blended them into anandamide, to do whatever it is anandamide does-perhaps functioning indirectly in some manner to modulate brain dopaminergic activity, as several researchers have suggested.

A Labeling Change

The fact that the cannabinoids fix themselves to receptor sites created for anandamide is incidental in the greater scheme of things, although not inconsequential. What has so facilely come to be called cannabinoid receptors should now be relabeled anandamide receptors. The cannabinoids are strictly chemical interlopers, hitching themselves to spaces reserved for the endogenous ligand anandamide. In displacing anandamide, the cannabinoids not only produce their own effects but also deprive anandamide of its function(s).

THC binds to anandamide receptors with only moderate affinity. Various synthetic molecules with higher affinities have been developed in recent years. When measured against THC, anandamide has a somewhat lower degree of affinity for its receptor. The concentration of THC required to activate the anandamide receptor is on the order of a nanogram. The concentration needed to initiate the process leading to a "high" would depend upon the degree of tolerance developed by the user, so no such precise figure can be given. The distribution in the brain of the anandamide receptor system has already been touched upon. The highest concentration of receptors, in the outflow nuclei of the basal ganglia (substantia nigra, pars reticulata, globus pallidus and regions of the caudate putamen) and the molecular layer of the cerebellum, helps explain the well-known effects of cannabinoids on motor coordination. Intermediate binding levels are found in parts of the hippocampus (CA pyramidal cells and dentate gyrus) and cortical levels I and VI, accounting for the disruptive effects on short-term memory associated with THC. The clogging by cannabinoids of anandamide receptors (competition for the sites) in the ventromedial striatum and nucleus accumbens, areas which play a key role in mediating brain reward, suggests once again that the endogenous ligand anandamide has an association with dopamine neurons. The observation that cannabis lacks acute lethal effects is probably related to the low levels of receptors in the brainstem areas controlling cardiovascular and respiratory functions.

Encapsulating what is key, it is thought that the various serious adverse effects associated with the chronic use of cannabinoids result from their interaction with cell membranes. But the drug's pharmacology is mediated by a specific receptor, which consists of an aggregate of protein molecules surrounding a central channel traversing the lipid layer of the membrane.

The cannabinoids are good substrates for cytochrome P450 and are extensively metabolized, THC alone giving rise to more than 100 metabolites (and nearly as many are found for several other cannabinoids.) This area of research is still embryonic, and there is a need to further explore the specific cytochrome P450 enzymes responsible for cannabinoid metabolism. It has already been ascertained that cytochrome P450 2C9 catalyzes the formation of the 11-hydroxy metabolite from THC, a compound even more psychoactive than the parent cannabinoid (Bornheim and others). Various isoforms of P450 figure in the hydroxylation process occurring at other sites on the molecule. Oxidation of 11-hydroxy-delta-9-THC yields delta-9-THC-11-oic acid, the major excretory product of THC in humans (conjugated with glucuronic acid). Thus, both phase I and phase II reactions are involved in the biotransformation of this xenobiotic. Delta-9-THC-11-oic acid, as the conjugate, is the most abundant metabolite found in urine and is the compound targeted by tests for cannabis abuse (Williams and Moffat).

When cannabinoids are tested in a variety of cell types-amoebas, lymphocytes, neuroblastoma cells, testicular cells-the results reveal decreased incorporation of nucleic acids and proteins into these cells, with a slowing of cell renewal. That alone should caution the public about cannabis. For when you create a slowdown in DNA/RNA/protein replacement within cells, cellular activity must also decelerate. Thus it is not surprising that marijuana depresses body functioning-energy level, thinking, sperm counts, testosterone production, ovulation, time itself. Rephrased, cannabinoids act as dysregulators of cellular regulation. Ultimately, molecular psychiatry will pinpoint the cannabinoid-induced alterations in brain DNA which lead to cognitive, imaginative, feeling and personality changes.




Bornheim LM, Lasker JM, Raucy JL. Human hepatic microsomal metabolism of delta-9-tetrahydrocannabinol. Drug Metab Dispos. 1992;20:241.


Devane WA, Dysarz FA, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605-613.


Howlett AC, Fleming RM. Cannabinoid inhibition of adenylate cyclase; pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol. 1984;26:532-538.


Martin BR. The THC receptor and its antagonists. In Nahas GG, Burks TF, eds. Drug Abuse in the Decade of the Brain. Amsterdam, Netherlands: IOS Press; 1997.


Williams PL, Moffat AC. Identification in human urine of delta-9-tetrahydrocannabinol-11-oic acid glucuronide, a tetrahydrocannabinol metabolite. J Pharm Pharmacol. 1970;32:445.

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