Cannabinoids [kuh-nab-uh-noid] are a class of diverse chemical compounds that activate cannabinoid receptors (molecules on the surface of a cells in the brain and throughout the body, which receive chemical signals). After the receptor is engaged, multiple intracellular signal pathways are activated; researchers are still unraveling the precise mechanism at work.

Cannabinoid receptors are activated by endocannabinoids (produced naturally in the body), phytocannabinoids (found in plants), and synthetic cannabinoids (produced chemically in a lab). The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis. However, there are known to exist dozens of other cannabinoids with varied effects. Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors.

The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. At present, there are two known types of cannabinoid receptors, termed CB1 and CB2, with mounting evidence of more. There are three types of transmembrane receptors (Protein, Ion, and Enzyme); cannabinoid receptors are protein based, and the human brain has more cannabinoid receptors than any other protein-coupled receptor type.

CB1 receptors are found primarily in the brain, to be specific in the basal ganglia (associated with movement and motivation) and in the limbic system (the paleomammalian brain), including the hippocampus (important in spacial memory and navigation). They are also found in the cerebellum (works mainly to control balance and coordinate movement) and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. Thus, there is not the risk of respiratory or cardiovascular failure associated with cannabis. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis. CB2 receptors are predominantly found in the immune system, or immune-derived cells, with the greatest density in the spleen. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.

A significant number of cannabinoids are found in both Cannabis and Echinacea plants. In Cannabis, these cannabinoids are concentrated in a viscous resin produced in structures known as glandular trichomes. In Echinacea species, cannabinoids are found throughout the plant structure, but are most concentrated in the roots and stems. Tea leave catechins (antioxidant flavonoids) have an affinity for human cannabinoid receptors. Phytocannabinoids are nearly insoluble in water but are soluble in lipids (fats), alcohols, and other organic solvents.

At least 85 different cannabinoids have been isolated from the Cannabis plant. At least 25 different cannabinoids have been isolated from Echinacea species. Tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study.  Tetrahydrocannabinol (THC) is the primary psychoactive component of the plant. It appears to ease moderate pain (analgesic) and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors. Cannabidiol (CBD) is not particularly psychoactive in and of itself, and was thought not to affect the psychoactivity of THC. However, recent evidence shows that smokers of cannabis with a higher CBD/THC ratio were less likely to experience schizophrenia-like symptoms. This is supported by psychological tests, in which participants experience less intense psychotic-like effects when intravenous THC was co-administered with CBD. Cannabidiol has also been shown to have antidepressant, anxiolytic, and neuroprotective effects. It appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor. CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains. CBD apparently plays a role in preventing the short-term memory loss associated with THC in mammals.

Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant’s cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains that are used as fiber (commonly called hemp) are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for recreational purposes are usually bred for high THC content or for a specific chemical balance.

Because cannabinoid receptors are found throughout the body, cannabinoids can be administered numerous ways such as smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver and some is also stored in fat. Some cannabis metabolites can be detected in the body several weeks after administration. These metabolites are the chemicals recognized by common antibody-based ‘drug tests’; in the case of THC et al., these loads do not represent intoxication (compare to ethanol breath tests that measure instantaneous blood alcohol levels) but an integration of past consumption over an approximately month-long window.

Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. The structure of THC was first determined in 1964. Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant from the precursor CBG. Endocannabinoids are substances produced from within the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for an endogenous ligand (triggering molecule) for the receptor. In 1992, in Raphael Mechoulam’s lab, the first such compound was identified as arachidonoyl ethanolamine and named ‘anandamide,’ a name derived from the Sanskrit word for ‘bliss’ and ‘amide’ (a type of chemical). Anandamide is derived from the essential fatty acid arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to the central (CB1) and, to a lesser extent, peripheral (CB2) cannabinoid receptors, where it acts as a partial agonist (trigger). Anandamide is about as potent as THC at the CB1 receptor. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate.

Endocannabinoids serve as intercellular ‘lipid messengers,’ signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they use retrograde signaling. Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids, on the other hand, are described as retrograde transmitters because they most commonly travel ‘backward’ against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.

Endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized ‘on-demand’ rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research. Because of their hydrophobic nature endocannabinoids cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.

In 2003, a U.S. patent entitled ‘Cannabinoids as Antioxidants and Neuroprotectants’ was awarded to the United States Department of Health and Human Services, based on research done at the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). This patent claims that cannabinoids are ‘useful in the treatment and prophylaxis of wide variety of oxidation associated diseases such as ischemia, age-related, inflammatory, and autoimmune diseases. The cannabinoids are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Epilepsy, and HIV dementia.’

Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids. Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules. Medications containing natural or synthetic cannabinoids or cannabinoid analogs: Dronabinol/ Marinol (THC used as an appetite stimulant, anti-emetic, and analgesic), Nabilone/ Cesamet (an analog of Marinol which is Schedule II unlike Marinol, which is Schedule III), Sativex (a cannabinoid extract oral spray containing THC, CBD, and other cannabinoids used for neuropathic pain and spasticity in 22 countries including England, Canada and Spain), and Rimonabant/ Acomplia (a selective CB1 receptor inverse agonist used as an anti-obesity or for smoking cessation).

Other notable synthetic cannabinoids include: JWH-018, a potent synthetic cannabinoid agonist discovered by Dr. John W. Huffman at Clemson University. It is being increasingly sold in legal smoke blends collectively known as ‘spice.’ Synthetic cannabinoid intoxication is associated with acute psychosis, and several countries and states have moved to ban it legally.

Cannabis indica may have a CBD:THC ratio 4–5 times that of Cannabis sativa. Cannabis strains with relatively high CBD:THC ratios are less likely to induce anxiety than vice versa. This may be due to CBD’s antagonistic effects at the cannabinoid receptors, compared to THC’s partial agonist effect. CBD is also a 5-HT1A receptor agonist, which may also contribute to an anxiolytic (anxiety relieving) effect. This likely means the high concentrations of CBD found in Cannabis indica mitigate the anxiogenic (anxiety causing) effect of THC significantly. The effects of sativa are well known for its cerebral high, hence used daytime as medical cannabis, while indica are well known for its sedative effects and preferred night time as medical cannabis.


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