Cannabinoids

Cannabinoid receptors

Before the 1980s, it was often speculated that cannabinoids producedtheir physiological and behavioral effects via nonspecific interactionwith cell membranes, instead of interacting with specificmembrane-bound receptors.The discovery of the first cannabinoid receptors in the 1980s helped toresolve this debate. These receptors are common in animals, and havebeen found in mammals, birds, fish, and reptiles. There are currently two known types of cannabinoid receptors, termed CB1 and CB2, with mounting evidence of more.

Cannabinoid receptor type 1

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 stemthat is responsible for respiratory and cardiovascular functions. Thus,there is not a risk of respiratory or cardiovascular failure as thereis with many other drugs. CB1 receptors appear to be responsible forthe euphoric and anticonvulsive effects of cannabis.

Cannabinoid receptor type 2

• CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen.While generally found only in the peripheral nervous system, a reportdoes indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.

Phytocannabinoids

Phytocannabinoids, also called natural cannabinoids, herbal cannabinoids, and classical cannabinoids, are only known to occur naturally in significant quantity 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 odour of the cannabis plant.

Phytocannabinoids are nearly insoluble in water but are 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 natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).

Types

At least 66 cannabinoids have been isolated from the cannabis plant. To the right the main classes of natural cannabinoids are shown. Allclasses derive from cannabigerol-type compounds and differ mainly inthe way this precursor is cyclized.

Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common cannabinoids are listed below:

• CBG Cannabigerol
• CBC Cannabichromene
• CBL Cannabicyclol
• CBV Cannabivarin
• THCV Tetrahydrocannabivarin
• CBDV Cannabidivarin
• CBCV Cannabichromevarin
• CBGV Cannabigerovarin
• CBGM Cannabigerol Monoethyl Ether

Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is the primary psychoactive component of the plant. Medically, it appears to ease moderate pain (analgetic) and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors. Its effects are perceived to be more cerebral.

delta-9-Tetrahydrocannabinol (Δ⁹-THC, THC) and delta-8-tetrahydrocannabinol (Δ⁸-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. The THCs produce the high associated with cannabis by binding to the CB₁ cannabinoid receptors in the brain.

Cannabidiol

Cannabidiol (CBD) is not psychoactive, and was thought not to affect the psychoactivity of THC. However, recent evidence shows that smokers of cannabis with a higherCBD/THC ratio were less likely to experience schizophrenia-likesymptoms.This is supported by psychological tests, in which participantsexperience less intense psychotic effects when intravenous THC wasco-administered with CBD (as measured with a PANSS test). It has been hypothesized that CBD acts as an allosteric antagonist atthe CB1 receptor and thus alters the psychoactive effects of THC.

Medically, 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.

Cannabinol

Cannabinol (CBN) is the primary product of THC degradation, andthere is usually little of it in a fresh plant. CBN content increasesas THC degrades in storage, and with exposure to light and air. It isonly mildly psychoactive. Its affinity to the CB2 receptor is higherthan for the CB1 receptor.

Tetrahydrocannabivarin

Tetrahydrocannabivarin (THCV) is prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonist of THC at CB₁ receptors and attenuates the psychoactive effects of THC.

Cannabichromene

Cannabichromene (CBC) is non-psychoactive and does not affect the psychoactivity of THC.

Double bond position

In addition, each of the compounds above may be in different forms depending on the position of the double bond in the alicycliccarbon ring. There is potential for confusion because there aredifferent numbering systems used to describe the position of thisdouble bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called Δ⁹-THC, while the minor form is called Δ⁸-THC. Under the alternate terpene numbering system, these same compounds are called Δ¹-THC and Δ⁶-THC, respectively.

Length

Most herbal cannabinoid compounds are 21 carbon compounds. However,some do not follow this rule, primarily because of variation in thelength of the side chain attached to the aromaticring. In THC, CBD, and CBN, this side chain is a pentyl (5 carbon)chain. In the most common homologue, the pentyl chain is replaced witha propyl (3 carbon) chain. Cannabinoids with the propyl side chain arenamed using the suffix “varin”, and are designated, for example, THCV,CBDV, or CBNV. It appears that shorter chains increase the intensityand decrease the duration of the activity of the chemicals.

Plant profile

Cannabis plants can exhibit wide variation in the quantity and typeof cannabinoids they produce. The mixture of cannabinoids produced by aplant is known as the plant’s cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify thecannabinoid 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, andstrains used for recreationalpurposes are usually bred for high THC content, or for a specificchemical balance. Some strains of more than 20% THC in their floweringbuds 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 onlysemi-quantitative or qualitative. There have been systematic attemptsto monitor the cannabinoid profile of cannabis over time, but theiraccuracy is impeded by the illegal status of the plant in manycountries.

Pharmacology

Cannabinoids can be administered by smoking, vaporizing, oralingestion, transdermal patch, intravenous injection, sublingualabsorption, or rectal suppository. Once in the body, most cannabinoidsare metabolized in the liver, especially by cytochrome P450 mixed-function oxidases, mainly CYP 2C9. Thus supplementing with CYP 2C9 inhibitors leads to extended intoxication.

Some is also stored in fat in addition to being metabolized in liver. Δ⁹-THC is metabolized to 11-hydroxy-Δ⁹-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body several weeks after administration.

Plant synthesis

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 synthaseenzymes. CBD is then enzymatically cyclized to THC. For the propylhomologues (THCV, CBDV and CBNV), there is a similar pathway that isbased on CBGV.

Separation

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 dioxideis an alternative technique. Although this process requires highpressures (73 atmospheres or more), there is minimal risk of fire ortoxicity, solvent removal is simple and efficient, and extract qualitycan be well-controlled. Once extracted, cannabinoid blends can beseparated 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.

History

Cannabinoids were first discovered in the 1940s, when CBD and CBNwere identified. The structure of THC was first determined in 1964.

Due to molecular similarity and ease of synthetic conversion, it wasoriginally believed that CBD was a natural precursor to THC. However,it is now known that CBD and THC are produced independently in thecannabis plant.

Endocannabinoids

Endocannabinoids are substances produced from within the body which activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for an endogenous ligand for the receptor.

Types of endocannabinoid ligands

• Arachidonoylethanolamine (Anandamide or AEA)

In 1992, the first such compound was identified as arachidonoyl ethanolamine and named anandamide, a name derived from the Sanskrit word for bliss and -amide. 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 thecentral (CB1) and, to a lesser extent, peripheral (CB2) cannabinoidreceptors, where it acts as a partial agonist. Anandamide is about aspotent as THC at the CB1 receptor.It is found in nearly all tissues in a wide range of animals.

Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamine, have similar pharmacology. All of these are members of a family of signalling lipids called N-acylethanolamides, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamine which possess anti-inflammatory and orexigenic effects, respectively. Many N-acylethanolamines have also been identified in plant seeds and in molluscs.

• 2-arachidonoyl glycerol (2-AG)

Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both.2-AG is present at significantly higher concentrations in the brain than anandamide, and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling in vivo. In particular, one in vitro study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.

• 2-arachidonyl glyceryl ether (noladin ether)

In 2001 a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain. Prior to this discovery, it had been synthesized as a stable analog of2-AG; indeed, some controversy remains over its classification as anendocannabinoid, as another group failed to detect the substance at”any appreciable amount” in the brains of several different mammalianspecies. It binds to the CB1 cannabinoid receptor (K_i = 21.2 nmol/L)and causes sedation, hypothermia, intestinal immobility, and mildantinociception in mice. It binds primarily to the CB1 receptor, andonly weakly to the CB2 receptor.

• N-arachidonoyl-dopamine (NADA)

Discovered in 2000, NADA preferentially binds to the CB1 receptor. Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.

• Virodhamine (OAE)

A fifth endocannabinoid, virodhamine, or O-arachidonoyl-ethanolamine (OAE) was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1, it behaves as a CB1 antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.

Function

Endocannabinoids serve as intercellular ‘lipid messengers’,signaling molecules that are released from one cell and activate thecannabinoid receptors present on other nearby cells. Although in thisintercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine or dopamine, endocannabinoids differ in numerous ways from them. For instance, they use retrograde signaling.Furthermore, endocannabinoids are lipophilic molecules that are notvery soluble in water. They are not stored in vesicles, and exist asintegral constituents of the membrane bilayers that make up cells. Theyare believed to be synthesized ‘on-demand’ rather than made and storedfor later use. The mechanisms and enzymes underlying the biosynthesisof endocannabinoids remain elusive and continue to be an area of activeresearch.

The endocannabinoid 2-AG has been found in bovine and human maternal milk.

Retrograde signal

Conventional neurotransmitters are released from a ‘presynaptic’cell and activate appropriate receptors on a ‘postsynaptic’ cell, wherepresynaptic and postsynaptic designate the sending and receiving sidesof a synapse, respectively. Endocannabinoids, on the other hand, aredescribed as retrogradetransmitters because they most commonly travel ‘backwards’ against theusual synaptic transmitter flow. They are in effect released from thepostsynaptic cell and act on the presynaptic cell, where the targetreceptors are densely concentrated on axonal terminals in the zonesfrom which conventional neurotransmitters are released. Activation ofcannabinoid receptors temporarily reduces the amount of conventionalneurotransmitter released. This endocannabinoid mediated system permitsthe postsynaptic cell to control its own incoming synaptic traffic. Theultimate effect on the endocannabinoid releasing cell depends on thenature of the conventional transmitter that is being controlled. Forinstance, when the release of the inhibitory transmitter, GABA, isreduced, the net effect is an increase in the excitability of theendocannabinoid-releasing cell. Conversely, when release of theexcitatory neurotransmitter, glutamate, is reduced, the net effect is adecrease in the excitability of the endocannabinoid-releasing cell.

Range

Endocannabinoids are hydrophobic molecules. They cannot travelunaided for long distances in the aqueous medium surrounding the cellsfrom which they are released, and therefore act locally on nearbytarget cells. Hence, although emanating diffusely from their sourcecells, they have much more restricted spheres of influence than dohormones, which can affect cells throughout the body.

Other thoughts

Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.

Scientific American published an article in December 2004, entitled “The Brain’s Own Marijuana” discussing the endogenous cannabinoid system.

The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body.

In 2003, the U.S. Government as represented by the Department ofHealth and Human Services filed for, and was awarded a patent oncannabinoids as antioxidants and neuroprotectants. U.S. Patent 6630507.

Synthetic and patented cannabinoids

Historically, laboratory synthesis of cannabinoids were often basedon the structure of herbal cannabinoids and a large number of analogshave 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 todetermine the relationship between the structure and activity ofcannabinoid compounds, by making systematic, incremental modificationsof cannabinoid molecules.

Medications containing natural or synthetic cannabinoids or cannabinoid analogs:

• Dronabinol (Marinol), is Δ9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic and analgesic.
• Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It 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 inCanada and Spain. Sativex develops whole plant cannabinoid medicines.
• Rimonabant (SR141716), a selective cannabinoid (CB1) receptor antagonist used as an anti-obesity drug under the proprietary name, Acomplia. It is also used for smoking cessation.

Other notable synthetic cannabinoids include:

• CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC
• Dimethylheptylpyran
• HU-210, about 100 times as potent as THC
• HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II.
• SR144528, a CB2 receptor antagonists
• WIN 55,212-2, a potent cannabinoid receptor agonist
• JWH-133, a potent selective CB2 receptor agonist.
• Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine.

See also

• Cannabinoid receptor antagonist

References | Notes  | External links