Before the 1980s, it was often speculated that cannabinoids produced their effects through nonspecific interaction with cell membranes, instead of interacting with specific 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 been found in mammals, birds, fish, and reptiles. There are currently two known types of cannabinoid receptors, called CB1 and CB2.
CB1 receptors are found primarily in the Brain, specifically in the Basal ganglia and in the Limbic system, including the Hippocampus. They are also found in the Cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the Medulla oblongata, the part of the brain that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
CB2 receptors are almost exclusively found in the Immune system, with the greatest density in the Spleen. CB2 receptors appear to be responsible for the anti-inflammatory and possible other therapeutic effects of cannabis.
Herbal cannabinoids (sometimes called classical cannabinoids) are nearly insoluble in water but soluble in lipids, alcohols, and other non-polar organic solvents. However, as Phenols they form more water-soluble Phenolate salts under strongly alkaline conditions. All herbal cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by Decarboxylation; that is, catalyzed by heat, light, or alkaline conditions. Herbal cannabinoids occur naturally only in the cannabis plant, and are concentrated in a viscous Resin that is produced in glandular structures known as trichomes. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odor of the cannabis plant.
There are over sixty known herbal cannabinoids. Of these, Tetrahydrocannabinol (THC), Cannabidiol (CBD) and Cannabinol (CBN) are the most prevalent and have received the most study. Other common ones are listed below:
CBG Cannabigerol
CBC Cannabichromene
CBL Cannabicyclol
CBV Cannabivarol
THCV Tetrahydrocannabivarin
CBDV Cannabidivarin
CBCV Cannabichromevarin
CBGV Cannabigerovarin
CBGM Cannabigerol Monoethyl Ether
THC is the primary psychoactive component of the plant. Medically, it appears to moderate pain and to be Neuroprotective. THC has a greater affinity for the CB1 receptor than for the CB2 receptors. Its effects are perceived to be more cerebral.
CBD is not psychoactive, and appears to moderate the euphoric effects of THC. It may decrease the rate of THC clearance from the body, perhaps by interfering with the Metabolism of THC in the Liver. Medically, it appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor. It is perceived to have more effect on the body.
CBN is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive, and is perceived to be sedative or stupefying.
These compounds may be in different forms depending on the position of the double bond in the alicyclic carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called delta-9-THC, while the minor form is called delta-8-THC. Under the alternate Terpene numbering system, these same compounds are called delta-1-THC and delta-6-THC, respectively.
Most herbal cannabinoid compounds are 21 carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side chain attached to the aromatic ring. In THC, CBD, and CBN, this side chain is a pentyl (5 carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3 carbon) chain. Cannabinoids with the propyl side chain are named using the suffix "varin", and are designated, for example, THCV, CBDV, or CBNV. It appears that shorter chains increase the intensity and decrease the duration of the activity of the chemicals.
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, it was originally believed that CBD was a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant. Cannabinoid production starts when an Enzyme causes geranyl-pyrophosphate and olivetolic acid to combine and form CBG. Next, CBG is independently converted to either CBD or CBC by two separate Synthase enzymes. CBC is then enzymatically cyclized to THC. For the propyl homologues (THCV, CBDV and CBNV), there is a similar pathway that is based on CBGV.
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 which 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. Some strains of more than 20% THC have been created.
Quantitative analysis of a plant's cannabinoid profile is usually determined by gas chromatography (GC), or more reliably by gas chromatography combined with Mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, although these are often only semi-quantitative or qualitative. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.
Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the Liver, although some is stored in Fat. Delta-9-THC is metabolized to 11-hydroxy-delta-9-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body after several weeks.
Cannabinoids can be separated from the plant by Extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Supercritical solvent extraction with Carbon dioxide is an alternative technique. Although this process requires high pressures, there is minimal risk of fire or toxicity, solvent removal is simple and efficient, and extract quality can be well-controlled. Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other Distillation techniques. However, to produce high purity cannabinoids, Chemical synthesis or semisynthesis is generally required.
In the early 1990s, the first such compound was identified as arachidonyl ethanolamine and named Anandamide, a name derived from the Sanskrit word for bliss and Amide. Anandamide is a polyunsaturated Fatty acid with pharmacology similar to THC, although its chemical structure is different. Anandamide bonds primarily to the CB1 receptor, and is found in a wide range of animals. It is about half as potent as THC. Two analogs of anandamide, docosatetraenylethanolamide and homo-γ-linoenylethanolamide, have similar Pharmacology.
Another endocannabinoid, 2-arachidonyl glycerol, binds to both the CB1 and CB2 receptors, and is more abundant and less active than anandamide. Little is known about two other discovered endocannabinoids, palmitoyl ethanolamide and oleamide.
Scientific American wrote an article titled "Brain's Own Marijuana" in their Dec. 2004 issue discussing the endogenous cannabinoid system. The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. The cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited to treat so many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, multiple sclerosis, high blood pressure, irritable bowel syndrome, and bladder incontinence.
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.
Other notable synthetic cannabinoids include: