Phytocannabinoids, also called ''natural cannabinoids'', ''herbal
cannabinoids'', and ''classical cannabinoids'', are only known to occur
naturally in significant quantity in the cannabis plant, and are
concentrated in a viscous resin that is produced in glandular
structures known as trichomes.
In addition to cannabinoids, the resin
is rich in terpenes, which are largely responsible for the odour of the
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
All-natural cannabinoids are derived from their respective
2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat,
light, or 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.
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 (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
''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 (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
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
It appears to relieve convulsion, inflammation, anxiety, and nausea.
CBD has a greater affinity for the CB2 receptor than for the
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 (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 (CBC) is non-psychoactive and does not affect the
psychoactivity of THC It is found in nearly all tissues in a wide range
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
- 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.
- 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
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.
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
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 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
The endocannabinoid 2-AG has been found in bovine and human maternal
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
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.
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.
''Scientific American'' published an article in December 2004,
entitled "The Brain's Own Marijuana" discussing the endogenous
The current understanding recognizes the role that endocannabinoids
play in almost every major life function in the human body.
U.S. Patent # 6630507
In 2003 The U.S.A.'s Government as represented by the Department of
Health and Human Services was awarded a patent on cannabinoids as
antioxidants and neuroprotectants. U.S. Patent 6630507.
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