Cannabinoids
Encyclopedia
Cannabinoids are a class of chemical compounds that include the phytocannabinoids (oxygen-containing C21 aromatic hydrocarbon
compounds found in the cannabis
plant), and chemical compounds that mimic the actions of phytocannabinoids or have a similar structure (e.g., endocannabinoids, found in the nervous
and immune system
s of animals and that activate cannabinoid receptor
s). The most notable of the cannabinoids is ∆9-tetrahydrocannabinol
(THC)—the primary psychoactive compound of cannabis.
Synthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids including the aminoalkylindoles, 1,5-diarylpyrazoles, quinoline
s, and arylsulphonamides, as well as eicosanoid
s related to the endocannabinoids.
s. 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 mammal
s, bird
s, fish
, and reptile
s. At present, there are two known types of cannabinoid receptors, termed CB1 and CB2, with mounting evidence of more.
, to be specific 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 system
s. 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 that can be produced by some drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
, or immune-derived cells with the greatest density in the spleen
. While found only in the peripheral nervous system, a report does 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, 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 trichome
s. In addition to cannabinoids, the resin is rich in terpene
s, which are largely responsible for the odour of the cannabis plant.
Phytocannabinoids are nearly insoluble in water but are soluble in lipid
s, alcohol
s, and other non-polar organic solvents. However, as phenols
, they form more water-soluble phenolate salt
s under strongly alkaline conditions.
All-natural cannabinoids are derived from their respective 2-carboxylic acid
s (2-COOH) by decarboxylation
(catalyzed by heat, light, or alkaline conditions).
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:
) and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors.
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.
, a GPCR expressed in the caudate nucleus
and putamen
. Cannabidiol has also been shown to act as a 5-HT1A receptor
agonist, an action that is involved in its 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.
but still affects the overall effects of Cannabis. It acts as an α2-adrenergic receptor agonist, 5-HT1A receptor
antagonist, and CB1 receptor antagonist. It also binds to the CB2 receptor.
of THC at CB1 receptors and attenuates the psychoactive effects of THC.
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 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.
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.
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.
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.
, 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 metabolite
s 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.
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. CBD is then enzymatically cyclized to THC. For the propyl homologues (THCV, CBDV and CBNV), there is a similar pathway that is based on CBGV. (recent studies show that THC is not cyclized from CBD but rather directly from CBG. no experiment thus far has turned up an enzyme that converts CBD into THC although it is still hypothesized.)
s. Hydrocarbon
s and alcohol
s are often used as solvents. However, these solvents are flammable and many are toxic. Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with carbon dioxide
is an alternative technique. Although this process requires high pressures (73 atmospheres or more), 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.
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.
Endocannabinoids are substances produced from within the body that activate cannabinoid receptor
s. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for an endogenous ligand
for the receptor.
In 1992, in Raphael Mechoulam
's Israeli lab, 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 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.
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-acylethanolamines
, which also includes the noncannabimimetic palmitoylethanolamide
and oleoylethanolamide
, which possess anti-inflammatory
and orexigenic
effects, respectively. Many N-acylethanolamines have also been identified in plant seeds and in molluscs.
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.
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.
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.
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 rat
s, 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.
', 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 neurotransmitter
s, such as acetylcholine
and 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.
The endocannabinoid 2-AG has been found in bovine and human maternal milk.
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.
s, which can affect cells throughout the body.
(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 ischemic, 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
and HIV dementia."
On November 17, 2011, in accordance with 35 U.S.C. 209(c)(1) and 37 CFR part 404.7(a)(1)(i), the National Institutes of Health, Department of Health and Human Services, published in the Federal Register, that it is contemplating the grant of an exclusive patent license to practice the invention embodied in U.S. Patent 6,630,507, entitled “Cannabinoids as antioxidants and neuroprotectants” and PCT Application Serial No. PCT/US99/08769 and foreign equivalents thereof, entitled “Cannabinoids as antioxidants and neuroprotectants” [HHS Ref. No. E-287-1997/2] to KannaLife Sciences Inc., which has offices in New York, U.S. This patent and its foreign counterparts have been assigned to the Government of the United States of America.
The prospective exclusive license territory may be worldwide, and the field of use may be limited to: The development and sale of cannabinoid(s) and cannabidiol(s) based therapeutics as antioxidants and neuroprotectants for use and delivery in humans, for the treatment of hepatic encephalopathy, as claimed in the Licensed Patent Rights.
KannaLife Sciences, Inc. ("KannaLife") is a late stage bio-pharmaceutical and phyto-medical technology company focused on the development of natural, phyto-medical products to be used in health and wellness regimens. KannaLife is currently involved in the research and development of novel new therapeutic agents to be used as transport carriers for other compounds seeking to break the blood/brain barrier as well as our own compounds to be used for the treatment and prevention of oxidative and neuro-toxic stresses born from a variety of ailments and illnesses.
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:
Other notable synthetic cannabinoids include:
Aromatic hydrocarbon
An aromatic hydrocarbon or arene is a hydrocarbon with alternating double and single bonds between carbon atoms. The term 'aromatic' was assigned before the physical mechanism determining aromaticity was discovered, and was derived from the fact that many of the compounds have a sweet scent...
compounds found in the cannabis
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
plant), and chemical compounds that mimic the actions of phytocannabinoids or have a similar structure (e.g., endocannabinoids, found in the nervous
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
and immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
s of animals and that activate cannabinoid receptor
Cannabinoid receptor
The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
s). The most notable of the cannabinoids is ∆9-tetrahydrocannabinol
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
(THC)—the primary psychoactive compound of cannabis.
Synthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids including the aminoalkylindoles, 1,5-diarylpyrazoles, quinoline
Quinoline
Quinoline is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown...
s, and arylsulphonamides, as well as eicosanoid
Eicosanoid
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....
s related to the endocannabinoids.
Cannabinoid receptors
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 receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s. 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 mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s, bird
Bird
Birds are feathered, winged, bipedal, endothermic , egg-laying, vertebrate animals. Around 10,000 living species and 188 families makes them the most speciose class of tetrapod vertebrates. They inhabit ecosystems across the globe, from the Arctic to the Antarctic. Extant birds range in size from...
s, fish
Fish
Fish are a paraphyletic group of organisms that consist of all gill-bearing aquatic vertebrate animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish, as well as various extinct related groups...
, and reptile
Reptile
Reptiles are members of a class of air-breathing, ectothermic vertebrates which are characterized by laying shelled eggs , and having skin covered in scales and/or scutes. They are tetrapods, either having four limbs or being descended from four-limbed ancestors...
s. At present, there are 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 brainBrain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, to be specific in the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
and in the limbic system
Limbic system
The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...
, including the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
. They are also found in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
and in both male and female reproductive system
Reproductive system
The reproductive system or genital system is a system of organs within an organism which work together for the purpose of reproduction. Many non-living substances such as fluids, hormones, and pheromones are also important accessories to the reproductive system. Unlike most organ systems, the sexes...
s. CB1 receptors are absent in the medulla oblongata
Medulla oblongata
The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...
, the part of the brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
responsible for respiratory and cardiovascular functions. Thus, there is not the risk of respiratory or cardiovascular failure that can be produced by some drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
Cannabinoid receptor type 2
CB2 receptors are predominantly found in the immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, or immune-derived cells with the greatest density in the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
. While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
in the human cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.
Phytocannabinoids
| Type | Skeleton | Cyclization |
|---|---|---|
| Cannabigerol-type CBG |
 |
 |
| Cannabichromene-type CBC |
 |
 |
| Cannabidiol-type CBD |
 |
 |
| Tetrahydrocannabinol- and Cannabinol-type THC, CBN |
 |
 |
| Cannabielsoin-type CBE |
 |
 |
| iso- Tetrahydrocannabinol- type iso-THC |
 |
 |
| Cannabicyclol-type CBL |
 |
 |
| Cannabicitran-type CBT |
 |
 |
| Main classes of natural cannabinoids | ||
Phytocannabinoids, also called natural cannabinoids, herbal cannabinoids, and classical cannabinoids, are only known to occur naturally in significant quantity in the cannabis
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
plant, and are concentrated in a viscous resin
Resin
Resin in the most specific use of the term is a hydrocarbon secretion of many plants, particularly coniferous trees. Resins are valued for their chemical properties and associated uses, such as the production of varnishes, adhesives, and food glazing agents; as an important source of raw materials...
that is produced in glandular structures known as trichome
Trichome
Trichomes are fine outgrowths or appendages on plants and certain protists. These are of diverse structure and function. Examples are hairs, glandular hairs, scales, and papillae.- Algal trichomes :...
s. In addition to cannabinoids, the resin is rich in terpene
Terpene
Terpenes are a large and diverse class of organic compounds, produced by a variety of plants, particularly conifers, though also by some insects such as termites or swallowtail butterflies, which emit terpenes from their osmeterium. They are often strong smelling and thus may have had a protective...
s, which are largely responsible for the odour of the cannabis plant.
Phytocannabinoids are nearly insoluble in water but are soluble in lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s, alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
s, and other non-polar organic solvents. However, as phenols
Phenols
In organic chemistry, phenols, sometimes called phenolics, are a class of chemical compounds consisting of a hydroxyl group bonded directly to an aromatic hydrocarbon group...
, they form more water-soluble phenolate salt
Salt
In chemistry, salts are ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of cations and anions so that the product is electrically neutral...
s under strongly alkaline conditions.
All-natural cannabinoids are derived from their respective 2-carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
s (2-COOH) by decarboxylation
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
(catalyzed by heat, light, or alkaline conditions).
Types
At least 85 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.Tetrahydrocannabinol
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
(THC), cannabidiol
Cannabidiol
Cannabidiol is a cannabinoid found in Cannabis. It is a major constituent of the plant, representing up to 40% in its extracts.It has displayed sedative effects in animal tests...
(CBD) and cannabinol
Cannabinol
Cannabinol is a psychoactive substance cannabinoid found in Cannabis sativa and Cannabis indica/afghanica. It is also a metabolite of tetrahydrocannabinol . CBN acts as a weak agonist of the CB1 and CB2 receptors, with lower affinity in comparison to THC.- External links :* Compounds found in...
(CBN) are the most prevalent natural cannabinoids and have received the most study. Other common cannabinoids are listed below:
- CBG CannabigerolCannabigerolCannabigerol is a non-psychoactive cannabinoid found in the Cannabis genus of plants. Cannabigerol is found in higher concentrations in hemp rather than in varieties of Cannabis with high THC content ....
- CBC CannabichromeneCannabichromeneCannabichromene is a cannabinoid found in the cannabis plant. It bears structural similarity to the other natural cannabinoids, including tetrahydrocannabinol, tetrahydrocannabivarin, cannabidiol, and cannabinol, among others...
- CBL CannabicyclolCannabicyclolCannabicyclol is a non-psychotomimetic cannabinoid found in the Cannabis species. CBL is a degradative product like cannabinol. Light converts cannabichromene to CBL.- External links :* from the Comparative Toxicogenomics Database...
- CBV CannabivarinCannabivarinCannabivarin, also known as cannabivarol or CBV, is a non-psychoactive cannabinoid found in minor amounts in the hemp plant Cannabis sativa. It is an analog of cannabinol with the sidechain shortened by two CH2 groups. CBV is an oxidation product of tetrahydrocannabivarin .- External links :* ...
- THCV TetrahydrocannabivarinTetrahydrocannabivarinTetrahydrocannabivarin , also known as tetrahydrocannabivarol, is a non-psychoactive cannabinoid found naturally in Cannabis sativa. It is an analogue of tetrahydrocannabinol...
- CBDV CannabidivarinCannabidivarinCannabidivarine , also known as cannabidivarol, is a non-psychoactive cannabinoid found in low amounts in Cannabis sativa. It is an analog of cannabidiol , with the side-chain shortened by two CH2 groups...
- CBCV Cannabichromevarin
- CBGV Cannabigerovarin
- CBGM Cannabigerol Monoethyl Ether
Tetrahydrocannabinol
Tetrahydrocannabinol (THC) is the primary psychoactive component of the plant. It appears to ease moderate pain (analgesicAnalgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
) and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors.
Delta-9-Tetrahydrocannabinol
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
(Δ9-THC, THC) and delta-8-tetrahydrocannabinol (Δ8-THC), mimic the action of anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
, a neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
produced naturally in the body. The THCs produce the high associated with cannabis
Cannabis (drug)
Cannabis, also known as marijuana among many other names, refers to any number of preparations of the Cannabis plant intended for use as a psychoactive drug or for medicinal purposes. The English term marijuana comes from the Mexican Spanish word marihuana...
by binding to the CB1 cannabinoid receptors in the brain.
Cannabidiol
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 (as measured with a PANSS test). Cannabidiol has no affinity for CB1 and CB2 receptors but acts as an indirect antagonist of cannabinoid agonists. Recently it was found to be an antagonist at the putative new cannabinoid receptor, GPR55GPR55
G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the GPR55 gene.GPR55, along with GPR119 and GPR18, have been implicated as novel cannabinoid receptors.- History :...
, a GPCR expressed in the caudate nucleus
Caudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
and putamen
Putamen
The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...
. Cannabidiol has also been shown to act as a 5-HT1A receptor
5-HT1A receptor
The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
agonist, an action that is involved in its antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
, anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, 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.
Cannabinol
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. Its affinity to the CB2 receptor is higher than for the CB1 receptor.Cannabigerol
Cannabigerol (CBG) is non-psychotomimeticPsychotomimetic
A drug with psychotomimetic actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to just hallucinations. Some drugs of the opioid class have psychotomimetic effects, such as pentazocine and butorphanol....
but still affects the overall effects of Cannabis. It acts as an α2-adrenergic receptor agonist, 5-HT1A receptor
5-HT1A receptor
The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
antagonist, and CB1 receptor antagonist. It also binds to the CB2 receptor.
Tetrahydrocannabivarin
Tetrahydrocannabivarin (THCV) is prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonistReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
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 alicyclicAlicyclic compound
An alicyclic compound is an organic compound that is both aliphatic and cyclic. They contain one or more all-carbon rings which may be either saturated or unsaturated, but do not have aromatic character...
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 Δ9-THC, while the minor form is called Δ8-THC. Under the alternate terpene
Terpene
Terpenes are a large and diverse class of organic compounds, produced by a variety of plants, particularly conifers, though also by some insects such as termites or swallowtail butterflies, which emit terpenes from their osmeterium. They are often strong smelling and thus may have had a protective...
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 the length of the side-chain attached to the aromaticAromatic hydrocarbon
An aromatic hydrocarbon or arene is a hydrocarbon with alternating double and single bonds between carbon atoms. The term 'aromatic' was assigned before the physical mechanism determining aromaticity was discovered, and was derived from the fact that many of the compounds have a sweet scent...
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.
Plant profile
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 breedingSelective breeding
Selective breeding is the process of breeding plants and animals for particular genetic traits. Typically, strains that are selectively bred are domesticated, and the breeding is sometimes done by a professional breeder. Bred animals are known as breeds, while bred plants are known as varieties,...
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
Hemp
Hemp is mostly used as a name for low tetrahydrocannabinol strains of the plant Cannabis sativa, of fiber and/or oilseed varieties. In modern times, hemp has been used for industrial purposes including paper, textiles, biodegradable plastics, construction, health food and fuel with modest...
) 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
Recreational drug use
Recreational drug use is the use of a drug, usually psychoactive, with the intention of creating or enhancing recreational experience. Such use is controversial, however, often being considered to be also drug abuse, and it is often illegal...
purposes are usually bred for high THC content or for a specific chemical balance.
Quantitative analysis
Quantitative analysis
Quantitative analysis may refer to:* Quantitative analysis , an analysis technique applying mathematics stochastic calculus to finance...
of a plant's cannabinoid profile is usually determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
(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.
Pharmacology
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 liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, 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
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
in addition to being metabolized in liver. Δ9-THC is metabolized to 11-hydroxy-Δ9-THC
11-Hydroxy-THC
11-Hydroxy-Δ9-tetrahydrocannabinol, abbreviated as 11-OH-THC, is the main active metabolite of THC which is formed in the body after cannabis consumption. 11-Hydroxy-THC has been shown to be active in its own right, but the effects produced are not necessarily identical to those of THC...
, which is then metabolized to 9-carboxy-THC
11-nor-9-Carboxy-THC
11-nor-9-Carboxy-THC, also known as 11-nor-9-carboxy-delta-9-tetrahydrocannabinol, 11-COOH-THC, THC-COOH, and THC-11-oic acid, is the main secondary metabolite of THC which is formed in the body after Cannabis is consumed....
. Some cannabis metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s 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.
Plant synthesis
Cannabinoid production starts when an enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
causes geranyl pyrophosphate
Geranyl pyrophosphate
Geranyl pyrophosphate is an intermediate in the HMG-CoA reductase pathway used by organisms in the biosynthesis of farnesyl pyrophosphate, geranylgeranyl pyrophosphate, cholesterol, terpenes and terpenoids....
and olivetolic acid
Olivetol
Olivetol, also known as 5-pentylresorcinol or 5-pentyl-1,3-benzenediol, is an organic compound found in certain species of lichen; it is also a precursor in various syntheses of tetrahydrocannabinol.- Occurrence :...
to combine and form CBG
Cannabigerol
Cannabigerol is a non-psychoactive cannabinoid found in the Cannabis genus of plants. Cannabigerol is found in higher concentrations in hemp rather than in varieties of Cannabis with high THC content ....
. Next, CBG is independently converted to either CBD or CBC by two separate synthase
Synthase
In biochemistry, a synthase is an enzyme that catalyses a synthesis process.Following the EC number classification, they belong to the group of ligases, with lyases catalysing the reverse reaction....
enzymes. CBD is then enzymatically cyclized to THC. For the propyl homologues (THCV, CBDV and CBNV), there is a similar pathway that is based on CBGV. (recent studies show that THC is not cyclized from CBD but rather directly from CBG. no experiment thus far has turned up an enzyme that converts CBD into THC although it is still hypothesized.)
Separation
Cannabinoids can be separated from the plant by extraction with organic solventSolvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...
s. Hydrocarbon
Hydrocarbon
In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons from which one hydrogen atom has been removed are functional groups, called hydrocarbyls....
s and alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
s are often used as solvents. However, these solvents are flammable and many are toxic. Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
is an alternative technique. Although this process requires high pressures (73 atmospheres or more), 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
Distillation
Distillation is a method of separating mixtures based on differences in volatilities of components in a boiling liquid mixture. Distillation is a unit operation, or a physical separation process, and not a chemical reaction....
techniques. However, to produce high purity cannabinoids, chemical synthesis
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
or semisynthesis is generally required.
History
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.
Endocannabinoids are substances produced from within the body that activate cannabinoid receptor
Cannabinoid receptor
The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
s. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for an endogenous ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
for the receptor.
Types of endocannabinoid ligands
- Arachidonoylethanolamine (Anandamide or AEA)
In 1992, in Raphael Mechoulam
Raphael Mechoulam
Raphael Mechoulam is an Israeli professor of Medicinal Chemistry and Natural Products at the Hebrew University of Jerusalem in Israel...
's Israeli lab, the first such compound was identified as arachidonoyl ethanolamine and named anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
, a name derived from the Sanskrit
Sanskrit
Sanskrit , is a historical Indo-Aryan language and the primary liturgical language of Hinduism, Jainism and Buddhism.Buddhism: besides Pali, see Buddhist Hybrid Sanskrit Today, it is listed as one of the 22 scheduled languages of India and is an official language of the state of Uttarakhand...
word for bliss and -amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
. Anandamide is derived from the essential fatty acid
Essential fatty acid
Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health but cannot synthesize them...
arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
. It has a pharmacology similar to THC
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
, 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.
Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamine, have similar pharmacology
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
. All of these are members of a family of signalling lipids called N-acylethanolamines
N-acylethanolamine
An N-acylethanolamine is a type of compound formed when one of several types of acyl group is linked to the nitrogen atom of ethanolamine. These amides conceptually can be formed from a fatty acid and ethanolamine with the release of a molecule of water, but the known biological synthesis relies...
, which also includes the noncannabimimetic palmitoylethanolamide
Palmitoylethanolamide
Palmitoylethanolamide is an endogenous fatty acid amide, belonging to the class of endocannabinoids. PEA has been demonstrated to bind to a receptor in the cell-nucleus and exerts a great variety of biological functions related to chronic pain and inflammation. The main target is thought to be...
and oleoylethanolamide
Oleoylethanolamide
Oleoylethanolamine is an endogenous peroxisome proliferator-activated receptor alpha agonist. It is a naturally occurring ethanolamide lipid that regulates feeding and body weight in vertebrates ranging from mice to pythons....
, which possess anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
and orexigenic
Orexigenic
An orexigenic is a drug or hormone that increases appetite. This can be a naturally occurring neuropeptide hormone such as ghrelin, orexin or neuropeptide Y, or a medication which increases hunger and therefore enhances food consumption...
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 ether2-Arachidonyl glyceryl ether2-Arachidonyl glyceryl ether is a putative endocannabinoid discovered by Lumír Hanuš and colleagues at the Hebrew University of Jerusalem, Israel. Its isolation from porcine brain and its structural elucidation and synthesis were described in 2001.-Discovery:Lumír Hanuš, Saleh Abu-Lafi, Ester...
(noladin ether)
In 2001, a third, ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "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-dopamineN-arachidonoyl-dopamineN-Arachidonoyl dopamine is an endocannabinoid which acts as an agonist of the CB1 receptor and the transient receptor potential V1 ion channel. Its discovery was described in 2002 by an academic research group from Italy and the USA. It was found in the brain of rats, with especially high...
(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
The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
(TRPV1), a member of the vanilloid receptor family.
- VirodhamineVirodhamineVirodhamine is an endocannabinoid and a nonclassic eicosanoid, derived from arachidonic acid. O-Arachidonoyl ethanolamine is arachidonic acid and ethanolamine joined by an ester linkage, the opposite of the amide linkage found in anandamide...
(OAE)
A fifth endocannabinoid, virodhamine, or O-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
at CB2 and a partial agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
at CB1, it behaves as a CB1 antagonist in vivo. In rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, but 2- to 9-fold higher concentrations peripherally.
Function
Endocannabinoids serve as intercellular 'lipid messengersLipid signaling
Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses...
', 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 neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s, such as acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, endocannabinoids differ in numerous ways from them. For instance, they use retrograde signaling
Retrograde signaling
In neuroscience, retrograde signaling is a phenomenon in which a signal travels from a postsynaptic neuron to a presynaptic one. Endocannabinoids are known to play a role in retrograde signaling, with the molecules being synthesized postsynaptically and acting presynaptically...
. 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.
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, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids, on the other hand, are described as retrogradeRetrograde signaling
In neuroscience, retrograde signaling is a phenomenon in which a signal travels from a postsynaptic neuron to a presynaptic one. Endocannabinoids are known to play a role in retrograde signaling, with the molecules being synthesized postsynaptically and acting presynaptically...
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.
Range
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 hormoneHormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s, which can affect cells throughout the body.
U.S. Patent # 6630507
On October 7, 2003, a U.S. patent #6630507 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 HealthNational Institute of Mental Health
The National Institute of Mental Health is one of 27 institutes and centers that make up the National Institutes of Health...
(NIMH), and the National Institute of Neurological Disorders and Stroke
National Institute of Neurological Disorders and Stroke
The National Institute of Neurological Disorders and Stroke is a part of the U.S. National Institutes of Health . It conducts and funds research on brain and nervous system disorders and has a budget of just over US$1.5 billion...
(NINDS). This patent claims that cannabinoids are "useful in the treatment and prophylaxis of wide variety of oxidation associated diseases, such as ischemic, 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
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
and HIV dementia."
On November 17, 2011, in accordance with 35 U.S.C. 209(c)(1) and 37 CFR part 404.7(a)(1)(i), the National Institutes of Health, Department of Health and Human Services, published in the Federal Register, that it is contemplating the grant of an exclusive patent license to practice the invention embodied in U.S. Patent 6,630,507, entitled “Cannabinoids as antioxidants and neuroprotectants” and PCT Application Serial No. PCT/US99/08769 and foreign equivalents thereof, entitled “Cannabinoids as antioxidants and neuroprotectants” [HHS Ref. No. E-287-1997/2] to KannaLife Sciences Inc., which has offices in New York, U.S. This patent and its foreign counterparts have been assigned to the Government of the United States of America.
The prospective exclusive license territory may be worldwide, and the field of use may be limited to: The development and sale of cannabinoid(s) and cannabidiol(s) based therapeutics as antioxidants and neuroprotectants for use and delivery in humans, for the treatment of hepatic encephalopathy, as claimed in the Licensed Patent Rights.
KannaLife Sciences, Inc. ("KannaLife") is a late stage bio-pharmaceutical and phyto-medical technology company focused on the development of natural, phyto-medical products to be used in health and wellness regimens. KannaLife is currently involved in the research and development of novel new therapeutic agents to be used as transport carriers for other compounds seeking to break the blood/brain barrier as well as our own compounds to be used for the treatment and prevention of oxidative and neuro-toxic stresses born from a variety of ailments and illnesses.
Synthetic and patented cannabinoids
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 AdamsRoger Adams
Roger Adams was an American organic chemist. He is best-known for the eponymous Adams' catalyst, and his work did much to determine the composition of naturally occurring substances such as complex vegetable oils and plant alkaloids...
as early as 1941 and later in a group led by Raphael Mechoulam
Raphael Mechoulam
Raphael Mechoulam is an Israeli professor of Medicinal Chemistry and Natural Products at the Hebrew University of Jerusalem in Israel...
. 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), is Δ9-tetrahydrocannabinolTetrahydrocannabinolTetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
(THC), used as an appetite stimulant, anti-emetic, and analgesicAnalgesicAn analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos .... - NabiloneNabiloneNabilone is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It is a synthetic cannabinoid, which mimics the main ingredient of cannabis...
(Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III - SativexSativexNabiximols is a cannabinoid oromucosal mouth spray developed by the UK company GW Pharmaceuticals for multiple sclerosis patients, who can use it to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms. Nabiximols is also being developed in Phase III trials as a...
, a cannabinoid extract oral spray containing THC, CBDCannabidiolCannabidiol is a cannabinoid found in Cannabis. It is a major constituent of the plant, representing up to 40% in its extracts.It has displayed sedative effects in animal tests...
, and other cannabinoids used for neuropathic pain and spasticity in 22 countries including England, Canada and Spain. Sativex develops whole-plant cannabinoid medicines - RimonabantRimonabantRimonabant is an anorectic antiobesity drug that has been withdrawn from the market. It is an inverse agonist for the cannabinoid receptor CB1...
(SR141716), a selective cannabinoid (CB1) receptor inverse agonistInverse agonistIn the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
used as an anti-obesity drugAnti-obesity drugAnti-obesity medication or weight loss drugs are all pharmacological agents that reduce or control weight. These drugs alter one of the fundamental processes of the human body, weight regulation, by either altering appetite, metabolism, or absorption of calories. It is common for them to be tried...
under the proprietary name Acomplia. It is also used for smoking cessationSmoking cessationSmoking cessation is the process of discontinuing the practice of inhaling a smoked substance. This article focuses exclusively on cessation of tobacco smoking; however, the methods described may apply to cessation of smoking other substances that can be difficult to stop using due to the...
Other notable synthetic cannabinoids include:
- JWH-018JWH-018JWH-018 or AM-678 is an analgesic chemical from the naphthoylindole family, which acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2...
, a potent synthetic cannabinoid agonist discovered by Dr. John W. HuffmanJohn W. HuffmanJohn William Huffman is a professor emeritus of organic chemistry at Clemson University who first synthesised many novel cannabinoids, including JWH-007, JWH-015, JWH-018, JWH-019, JWH-030, JWH-051, JWH-073, JWH-081, JWH-122, JWH-133, JWH-147, JWH-171, JWH-182, JWH-203, JWH-210, JWH-250, JWH-307,...
at Clemson UniversityClemson UniversityClemson University is an American public, coeducational, land-grant, sea-grant, research university located in Clemson, South Carolina, United States....
. It is being increasingly sold in legal smoke blends collectively known as "spice"Spice (drug)Synthetic cannabis is a psychoactive herbal and chemical product which, when consumed, mimics the effects of cannabis. It is best known by the brand names K2 and Spice, both of which have largely become genericized trademarks used to refer to any synthetic cannabis product...
. Several countries and states have moved to ban it legally. - CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC.
- DimethylheptylpyranDimethylheptylpyranDimethylheptylpyran is a synthetic analogue of THC, which was invented in 1949 during attempts to elucidate the structure of Δ9-THC, the active component of cannabis...
- HU-210HU-210HU-210 is a synthetic cannabinoid that was first synthesized in 1988 from -Myrtenol by the group led by Professor Raphael Mechoulam at the Hebrew University. HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended duration of action...
, about 100 times as potent as THC - HU-331HU-331HU-331 is a quinone anticarcinogenic drug synthesized from cannabidiol, a cannabinoid in the Cannabis sativa plant. It showed a great efficacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle, cell apoptosis or caspase activation...
a potential anti-cancer drug derived from cannabidiolCannabidiolCannabidiol is a cannabinoid found in Cannabis. It is a major constituent of the plant, representing up to 40% in its extracts.It has displayed sedative effects in animal tests...
that specifically inhibits topoisomerase II. - SR144528, a CB2 receptor antagonist
- WIN 55,212-2WIN 55,212-2WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, that produces effects similar to those of cannabinoid derivatives such as THC but has an entirely different chemical structure....
, a potent cannabinoid receptor agonistAgonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance... - JWH-133JWH-133JWH-133 is a potent selective CB2 receptor agonist, with a Ki of 3.4nM and selectivity of around 200x for CB2 over CB1 receptors. It was discovered by, and named after, John W...
, a potent selective CB2 receptor agonist - LevonantradolLevonantradolLevonantradol is a synthetic cannabinoid analog of dronabinol developed by Pfizer in the 1980s. It is around 30x more potent than THC, and exhibits antiemetic and analgesic effects via activation of CB1 and CB2 cannabinoid receptors...
(Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine - AM-2201AM-2201AM-2201 discovered by Chemist Tyler Merrill, is a drug which acts as a potent but unselective agonist for the cannabinoid receptor CB1, with a Ki of 1.0nM at CB1 and 2.6nM at CB2...
, another synthetic, found to be more potent than THC. found in funky haze.
Table of natural cannabinoids
| Cannabigerol-type (CBG) | ||||
|---|---|---|---|---|
 (E)-CBG-C5 |
 monomethyl ether (E)-CBGM-C5 A |
 (Z)-CBGA-C5 A |
 (E)-CBGV-C3 |
|
 (E)-CBGA-C5 A |
 monomethyl ether (E)-CBGAM-C5 A |
 (E)-CBGVA-C3 A |
||
| Cannabichromene-type (CBC) | ||||
 CBC-C5 |
 CBCA-C5 A |
 (±)-Cannabichromevarin CBCV-C3 |
 acid A CBCVA-C3 A |
|
| Cannabidiol-type (CBD) | ||||
 CBD-C5 |
 momomethyl ether CBDM-C5 |
 CBD-C4 |
 CBDV-C3 |
 CBD-C1 |
 CBDA-C5 |
 CBDVA-C3 |
|||
| Cannabinodiol-type (CBND) | ||||
 CBND-C5 |
 CBND-C3 |
|||
| Tetrahydrocannabinol-type (THC) | ||||
 Δ9-THC-C5 |
 Δ9-THC-C4 |
 Δ9-THCV-C3 |
 Δ9-THCO-C1 |
|
 cannabinolic acid A Δ9-THCA-C5 A |
 cannabinolic acid B Δ9-THCA-C5 B |
 cannabinolic acid-C4 A and/or B Δ9-THCA-C4 A and/or B |
 cannabivarinic acid A Δ9-THCVA-C3 A |
 cannabiorcolic acid A and/or B Δ9-THCOA-C1 A and/or B |
 Δ8-Tetrahydrocannabinol Δ8-THC-C5 |
 Tetrahydrocannabinolic acid A Δ8-THCA-C5 A |
 Tetrahydrocannabinol (−)-cis-Δ9-THC-C5 |
||
| Cannabinol-type (CBN) | ||||
 CBN-C5 |
 CBN-C4 |
 CBN-C3 |
 CBN-C2 |
 CBN-C1 |
 CBNA-C5 A |
 CBNM-C5 |
|||
| Cannabitriol-type (CBT) | ||||
-trans-cannabitriol.png){kind=spacer} Cannabitriol (−)-trans-CBT-C5 |
 (+)-trans-CBT-C5 |
 Cannabitriol (±)-cis-CBT-C5 |
 10-O-Ethyl-cannabitriol (−)-trans-CBT-OEt-C5 |
 Cannabitriol-C3 (±)-trans-CBT-C3 |
-tetrahydrocannabinol.png) tetrahydrocannabinol 8,9-Di-OH-CBT-C5 |
 cannabitriol ester CBDA-C5 9-OH-CBT-C5 ester |
 9,10-Dihydroxy- hexahydrocannabinol, Cannabiripsol Cannabiripsol-C5 |
 Δ9-tetrahydrocannabinol (−)-Cannabitetrol |
-tetrahydrocannabinol.png) tetrahydrocannabinol OTHC |
| Cannabielsoin-type (CBE) | ||||
 Cannabielsoin CBE-C5 |
 C3-Cannabielsoin CBE-C3 |
 Cannabielsoic acid A CBEA-C5 A |
 Cannabielsoic acid B CBEA-C5 B |
 C3-Cannabielsoic acid B CBEA-C3 B |
 OH-iso-HHCV-C3 |
 DCBF-C5 |
 CBF-C5 |
||
| Isocannabinoids | ||||
 Isotetrahydrocannabinol |
 (1R,3R,6S/1S,3S,6R)- Isotetrahydro- cannabivarin |
 Isotetrahydrocannabivarin |
||
| Cannabicyclol-type (CBL) | ||||
 Cannabicyclol CBL-C5 |
 Cannabicyclolic acid A CBLA-C5 A |
 Cannabicyclovarin CBLV-C3 |
||
| Cannabicitran-type (CBT) | ||||
 CBT-C5 |
||||
| Cannabichromanone-type (CBCN) | ||||
 CBCN-C5 |
 CBCN-C3 |
 CBCON-C5 |
||
Cannabinoid information
- Bela Szabo: Pharmacology of Cannabinoid Receptors BIOTREND Reviews No. 02, February 2008
- Marijuana and Medicine - Assessing the Science Base (Institute of Medicine) - 1999 at National Academies PressNational Academies PressNational Academies Press was created by the United States National Academies, to publish the reports issued by the National Academy of Sciences, the National Academy of Engineering, the Institute of Medicine, and the National Research Council. It publishes nearly 200 books a year on a wide range...
- House of Lords Report - Cannabis (United Kingdom) - 1998 at Parliament of the United KingdomParliament of the United KingdomThe Parliament of the United Kingdom of Great Britain and Northern Ireland is the supreme legislative body in the United Kingdom, British Crown dependencies and British overseas territories, located in London...
- Cannabis: A Health Perspective and Research Agenda - 1997 at World Health OrganizationWorld Health OrganizationThe World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
- Chemical Ecology of Cannabis (J. Intl. Hemp Assn. - 1994)
- THC (tetrahydrocannabinol) accumulation in glands of Cannabis (Cannabaceae)
Cannabinoid research organizations
- The International Cannabinoid Research Society
- The Canadian Consortium for the Investigation of Cannabinoids
- Therapeutic Potential in Spotlight at Cannabinoid Researchers' Meeting at California Cannabis Research Medical GroupCalifornia Cannabis Research Medical GroupThe California Cannabis Research Medical Group is a non-profit organization dedicated to educating physicians about the medical use of cannabis....