Cannabinoids and the Endocannabinoid System

The human body possesses specific binding sites on the surface of many cell types for cannabinoids,
and our body produces several endocannabinoids, fatty acid derivatives that bind to these
cannabinoid receptors (CB) and activate them. CB receptors and endocannabinoids together constitute
the endocannabinoid system. Some phytocannabinoids, cannabinoids of the cannabis plant,
and a multitude of synthetic cannabinoids produced in the laboratory mimic the effects of endocannabinoids.
Δ9-THC (dronabinol), the pharmacologically most active cannabinoid of the cannabis
plant, binds to both types of cannabinoid receptors that have been identified so far, the CB1 and
the CB2 receptor. These receptors have been found in the central nervous system (brain and spinal
cord) and many peripheral tissues and organs. Depending on the kind of cells, on dose and state of
the body, activation of CB receptors may cause a multitude of effects including euphoria, anxiety,
dry mouth, muscle relaxation, hunger and pain reduction. Besides activation of CB receptors several
other approaches are under investigation to influence the cannabinoid system with therapeutic
intent, including blockade of CB receptors (antagonism) and modulation of endocannabinoid concentrations
by inhibition of their degradation. Currently, several preparations that stimulate cannabinoid
receptors (dronabinol, nabilone and cannabis) and one compound that blocks the CB1 receptor
(rimonabant) are used medicinally.
Keywords: Cannabis, THC, cannabinoid, cannabinoid receptor, endocannabinoid, therapeutic use.

This article can be downloaded, printed and distributed freely for any non-commercial purposes, provided the original work is properly
cited (see copyright info below). Available online at www.cannabis-med.org
Author's address: Franjo Grotenhermen, franjo-grotenhermen@nova-institut.de

Introduction
Δ9-tetrahydrocannabinol (THC) is thought to be the
pharmacologically most active cannabinoid of the
cannabis plant and its products marijuana (cannabis
herb) and hashish (cannabis resin). The majority of
THC effects are mediated through agonistic actions at
cannabinoid receptors of the human or animal body.
Agonistic action means that receptors are activated in
contrast to antagonistic action, i.e. blockade of receptor
effects.
Cannabinoid receptors and endocannabinoids, compounds
produced by the body that bind to these receptors,
together constitute the endocannabinoid system.
This system is of great importance for the normal function
of the body and is millions of years old. It has been
found in mammals, birds, amphibians, fish, sea urchins,
molluscs and leeches. The mechanism of action
of cannabinoids is best investigated for THC and other
cannabinoids that bind to known cannabinoid receptors,
while the mode of action of other cannabinoids of
therapeutic interest, among them cannabidiol (CBD), is
less well established.
Extended reviews on the issues presented in this short
article are available at [2,4,5,7,9]. Additional and upto-
date information is available from the IACM-Bulletin
[8].
Cannabinoids
Cannabinoids were originally regarded as any of a
class of typical C21 groups of compounds present in
Cannabis sativa L.. The modern definition is termed
with more emphasis on synthetic chemistry and on
pharmacology, and encompasses kindred structures, or
any other compound that affects cannabinoid receptors.



Monoterpenoid numbering Dibenzopyran numberingTHC (dronabinol), the main
cannabinoid in the cannabis
plant, according to the monoterpenoid
system (Δ1-THC) and
dibenzopyran system (Δ9-THC).
This has created several chemical sub-categories that
take into consideration the various forms of natural and
synthetic compounds.
It has been proposed to use the term phytocannabinoid
for the natural plant compounds and endocannabinoids
for the natural animal compounds, the endogenous
ligands of the cannabinoid receptors. Synthetic agonists
of these receptors have been classified according to
their degree of kinship (e.g. "classical" vs. "non-classical")
with phytocannabinoids.
Natural plant cannabinoids are oxygen-containing
aromatic hydrocarbons. In contrast to most other drugs,
including opiates, cocaine, nicotine and caffeine, they
do not contain nitrogen, and hence are not alkaloids.
Phytocannabinoids were originally thought to be only
present in the cannabis plant (Cannabis sativa L.), but
recently some cannabinoid type bibenzyls have also
been found in liverwort (Radula perrottetii and Radula
marginata).
More than 60 cannabinoids have been detected in cannabis,
mainly belonging to one of 10 subclasses or
types [3], of whom the cannabigerol type (CBG), the
cannabichromene type (CBC), the cannabidiol type
(CBD), the Δ9-THC type, and the cannabinol type
(CBN) are the most abundant. Cannabinoid distribution
varies between different cannabis strains and usually
only three or four cannabinoids are found in one plant
in concentrations above 0.1%. Δ9-THC is largely responsible
for the pharmacological effects of cannabis
including its psychoactive properties, though other
compounds of the cannabis plant also contribute to
some of these effects, especially CBD, a non-psychoactive
phytocannabinoid common in some cannabis
strains that has anti-inflammatory, analgesic, anti-anxiety
and anti-psychotic effects.
11-OH-Δ9-tetrahydrocannabinol (11-OH-THC) is the
most important psychotropic metabolite of Δ9-THC
with a similar spectrum of actions and similar kinetic
profiles as the parent molecule. 11-nor-9-carboxy-THC
(THC-COOH) is the most important non-psychotropic
metabolite of Δ9-THC.
Cannabinoid Receptors
To date two cannabinoid receptors have been identified,
the CB1, and the CB2 receptor. They differ in
signaling mechanisms and tissue distribution. Activation
of cannabinoid receptors causes inhibition of adenylat
cyclase, thus inhibiting the conversion of ATP to
cyclic AMP (cAMP). Other mechanisms have also
been observed, e.g. interaction with certain ion channels.
Both CB1 and CB2 receptors belong to the large family
of the G-protein-coupled receptors (GPCR). GPCRs
are the most common receptors, containing 1000-2000
members in vertebrates. Cannabinoid CB1 receptors are
among the most abundant and widely distributed
GPCRs in the brain.
Activation of the CB1 receptor produces effects on
circulation and psyche common to cannabis ingestion,
while activation of the CB2 receptor does not. CB1
receptors are mainly found on nerve cells in the brain,
spinal cord and peripheral nervous system, but are also
present in certain peripheral organs and tissues, among
them endocrine glands, salivary glands, leukocytes,
spleen, heart and parts of the reproductive, urinary and
gastrointestinal tracts. Many CB1 receptors are expressed
at the terminals of central and peripheral
nerves and inhibit the release of other neurotransmitters.
Thus, CB1 receptor activation protects the nervous
system from over-activation or over-inhibition by neurotransmitters.
CB1 receptors are highly expressed in
regions of the brain, which are responsible for movement
(basal ganglia, cerebellum), memory processing
(hippocampus, cerebral cortex) and pain modulation
(certain parts of the spinal cord, periaqueductal grey),
while their expression in the brainstem is low, which
may account for the lack of cannabis-related acute
fatalities. The brainstem controls, among others, respiration
and circulation.

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