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Cannabinoids are a group of terpenophenolic compounds present in Cannabis (Cannabis sativa L). The broader definition of cannabinoids refer to a group of substances that are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoid receptors. The chemical definition encompasses a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and arylsulphonamides and additional compounds that do not fall into these standard classes but bind to cannabinoid receptors. The term cannabinoids also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects. Currently, there are three general types of cannabinoids: phytocannabinoids occur uniquely in the cannabis plant; endogenous cannabinoids are produced in the bodies of humans and other animals; and synthetic cannabinoids are similar compounds produced in a laboratory.
Cannabinoid receptors Edit
- Main article: cannabinoid receptor
Before the 1980's, 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. There are currently two known types of cannabinoid receptors, termed 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 stem 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 possibly other therapeutic effects of cannabis.
Phytocannabinoids, also called natural cannabinoids, herbal cannabinoids, and classical cannabinoids, are only known to occur naturally 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.
At least 66 cannabinoids have been isolated from the cannabis plant To the right the main classes of natural cannabinoids are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.
- CBG Cannabigerol
- CBC Cannabichromene
- CBL Cannabicyclol
- CBV Cannabivarin
- THCV Tetrahydrocannabivarin
- CBDV Cannabidivarin
- CBCV Cannabichromevarin
- CBGV Cannabigerovarin
- CBGM Cannabigerol Monoethyl Ether
- Main article: 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.[How to reference and link to summary or text]
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.
- Main article: cannabidiol
Medically, it appears to relieve convulsion, inflammation, anxiety, and nausea.[How to reference and link to summary or text] CBD has a greater affinity for the CB2 receptor than for the CB1 receptor. It is perceived to have more effect on the body.[How to reference and link to summary or text]
CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains.
- Main article: cannabinol
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.[How to reference and link to summary or text]
- Main article: 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.
- Main article: Cannabichromene
Cannabichromene (CBC) is non-psychoactive and does not affect the psychoactivity of THC, a precursor of CBD and THC.
Double bond positionEdit
In addition, each of the compounds above 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.
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. [How to reference and link to summary or text]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, 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. 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.
Production of cannabinoids include both the synthesis in the plant, and separation of certain types from this material.
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.
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.
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.
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 ligandsEdit
- Arachidonoyl ethanolamide (Anandamide or AEA)
In 1992, the first such compound was identified as arachidonoyl ethanolamide 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 the central (CB1) and, to a lesser extent, peripheral (CB2) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1 receptor. It is found in nearly all tissues in a wide range of animals.[How to reference and link to summary or text]
Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamide, have similar pharmacology. All of these are members of a family of signalling lipids called N-acylethanolamides, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamide which possess anti-inflammatory and orexigenic effects, respectively. Many N-acylethanolamides 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 of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at "any appreciable amount" in the brains of several different mammalian species. It binds to the CB1 cannabinoid receptor (Ki = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1 receptor, and only 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.
Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activate 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, GABA or dopamine, endocannabinoids differ in numerous ways from them. For instance, they use retrograde signaling. Furthermore, 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.
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 ‘backwards’ 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 that is 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. Conversely, 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 hydrophobic molecules. They 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.
Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body.[How to reference and link to summary or text] Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for 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, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence.
Synthetic & Patented Cannabinoids Edit
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), an analog of 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 both THC and CBD used for neuropathic pain and spasticity in Canada and Spain.
- 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
- HU-210, about 100 times as potent as THC.
- 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.
Table of natural cannabinoids Edit
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- ↑ Huffman JW (2000). The search for selective ligands for the CB2 receptor. Curr. Pharm. Des. 6 (13): 1323-37.
- ↑ 4.0 4.1 Behavioural Pharmacology - Abstract: Volume 16(5-6) September 2005 p 487-496 Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids.. URL accessed on 2007-06-24.
- ↑ British Journal of Pharmacology - Abstract of article: Evidence that the plant cannabinoid delta-9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. URL accessed on 2007-06-24.
- ↑ 6.0 6.1 6.2 Grotenhermen F. "Cannabinoids." Current Drug Targets - CNS & Neurological Disorders. 2005 Oct;4(5):507-30. PMID 16266285
- ↑ N-Acylethanolamines in Seeds. Quantification of Molecular Species and Their Degradation upon Imbibition -- Chapman et al. 120 (4): 1157 -- PLANT PHYSIOLOGY. URL accessed on 2007-06-24.
- ↑ ScienceDirect - Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism : Bioactive long chain N-acylethanolamines in five species of edible bivalve molluscs: Possible implications for mollusc physiology and sea food industry. URL accessed on 2007-06-24.
- ↑ Stella N, Schweitzer P, Piomelli D. "A second endogenous cannabinoid that modulates long-term potentiation." Nature. 1997 Aug 21; 388(6644):773-8. PMID 9285589
- ↑ reviewed in Pacher P, Batkai S, Kunos G. "The endocannabinoid system as an emerging target of pharmacotherapy." Pharmacological Reviews. 2006 Sep;58(3):389-462. PMID 16968947
- ↑ Savinainen JR, Jarvinen T, Laine K, Laitinen JT. "Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB(1) receptor-dependent G-protein activation in rat cerebellar membranes." British Journal of Pharmacology. 2001 Oct; 134(3):664-72. PMID 11588122
- ↑ Hanus L, Abu-Lafi S, Fride E, et al (2001). 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci. U.S.A. 98 (7): 3662-5.
- ↑ Oka S, Tsuchie A, Tokumura A, Muramatsu M, Suhara Y, Takayama H, Waku K, Sugiura T. "Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species." Journal of Neurochemistry. 2003 Jun;85(6):1374-81. PMID 12787057
- ↑ Bisogno, T., D. Melck, M. Bobrov, N. M. Gretskaya, V. V. Bezuglov, L. De Petrocellis, V. Di Marzo. "N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo." The Biochemical Journal. 2000 Nov 1;351 Pt 3:817-24. PMID 11042139
- ↑ Bisogno T, Ligresti A, Di Marzo V. "The endocannabinoid signalling system: biochemical aspects." Pharmacology, Biochemistry, and Behavior. 2005 Jun;81(2):224-38. PMID 15935454
- ↑ Ralevic V. (July 2003). Cannabinoid modulation of peripheral autonomic and sensory neurotransmission.. European journal of pharmacology 472 (1-2): 1-21.
- ↑ Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J, Nomikos GG, Carter P, Bymaster FP, Leese AB, Felder CC. (June 2002). Characterization of a Novel Endocannabinoid, Virodhamine, with Antagonist Activity at the CB1 Receptor. The Journal of pharmacology and experimental therapeutics 301 (3): 1020-1024.
- ↑ Fride E, Bregman T, Kirkham TC. (April 2005). Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood.. Experimental Biology and Medicine 230 (4): 225-234. PMID 15792943.
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- Homepage of the ICRS - The International Cannabinoid Research Society
- Homepage of the ECSN - The Endocannabinoid System Network
- The Health and Psychological Effects of Cannabis Use (Australia - Monograph 44) - 2001 at Department of Health and Ageing (Australia)
- Marijuana and Medicine - Assessing the Science Base (Institute of Medicine) - 1999 at National Academies Press
- Overview of the Endocannabinoid Signalling System at Endocannabinoid.net
- Chemical Ecology of Cannabis (J. Intl. Hemp Assn. - 1994) at hempfood.com
- Therapeutic Potential in Spotlight at Cannabinoid Researchers' Meeting at California Cannabis Research Medical Group
- Medicinal marijuana laws, policies and news at cannabishq.com
- Cannabinoids and the Brain - The most recent biomedical book on the endocannabinoid system
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