Phytocannabinoids, also called ''natural cannabinoids'', ''herbal cannabinoids'', and ''classical cannabinoids'', are only known to occur naturally in significant quantity in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes.
In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odor of the cannabis plant.
Phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents. However, as phenols, they form more water-soluble phenolate salts under strongly alkaline conditions.
All-natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).
Types
At least 66 cannabinoids have been isolated from the cannabis plant To the right the main classes of natural cannabinoids are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.
Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common cannabinoids are listed below:
CBG Cannabigerol
CBC Cannabichromene
CBL Cannabicyclol
CBV Cannabivarin
THCV Tetrahydrocannabivarin
CBDV Cannabidivarin
CBCV Cannabichromevarin
CBGV Cannabigerovarin
CBGM Cannabigerol Monoethyl Ether
Tetrahydrocannabinol
Tetrahydrocannabinol (THC) is the primary psychoactive component of the plant. It appears to ease moderate pain (analgetic) and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors. Its effects are perceived to be more cerebral.
''Delta''-9-Tetrahydrocannabinol (Δ9-THC, THC) and ''delta''-8-tetrahydrocannabinol (Δ8-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. The THCs produce the ''high'' associated with cannabis by binding to the CB1 cannabinoid receptors in the brain.
Cannabidiol
Cannabidiol (CBD) is not psychoactive, and was thought not to affect the psychoactivity of THC. However, recent evidence shows that smokers of cannabis with a 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 effects when intravenous THC was co-administered with CBD (as measured with a PANSS test).
It has been hypothesized that CBD acts as an allosteric antagonist at the CB1 receptor and thus alters the psychoactive effects of THC.
It appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor.
Cannabigerol
Cannabigerol (CBG) is non-psychotomimetic 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.
Tetrahydrocannabivarin
Tetrahydrocannabivarin (THCV) is prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonist of THC at CB1 receptors and attenuates the psychoactive effects of THC.
Cannabichromene
Cannabichromene (CBC) is non-psychoactive and does not affect the psychoactivity of THC It is found in nearly all tissues in a wide range of animals.
Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and ''homo''-γ-linolenoylethanolamine, have similar pharmacology.
All of these are members of a family of signalling lipids called ''N''-acylethanolamides, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamine, which possess anti-inflammatory and orexigenic effects, respectively. Many ''N''-acylethanolamines have also been identified in plant seeds and in molluscs.
2-arachidonoyl glycerol (2-AG)
Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both, 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.
Anandamide and 2-AG activate the same receptors as THC, and are found in bovine and human breast milk.
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 (''K''i = 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.
Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.
Virodhamine (OAE)
A fifth endocannabinoid, virodhamine, or ''O''-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1, it behaves as a CB1 antagonist ''in vivo''.
In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.
Function
Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells.
Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they use retrograde signaling.
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.
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 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 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 hormones, which can affect cells throughout the body.
Other thoughts
Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.
''Scientific American'' published an article in December 2004, entitled "The Brain's Own Marijuana" discussing the endogenous cannabinoid system.
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body.
