Jacob Bell
New Member
Franjo Grotenhermen
Abstract
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.
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.
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.
CB2 receptors occur principally in immune cells,
among them leukocytes, spleen and tonsils. One of the
functions of CB receptors in the immune system is
modulation of release of cytokines, which are responsible
for inflammation and regulation of the immune
system. Since compounds that selectively activate CB2
receptors (CB2 receptor agonists) do not cause psychological
effects, they have become an increasingly
investigated target for therapeutic uses of cannabinoids,
among them analgesic, anti-inflammatory and anticancer
actions.
There is increasing evidence for the existence of additional
cannabinoid receptor subtypes in the brain and
periphery. One of these receptors may be the orphan Gprotein-
coupled receptor GPR55 [1]. Other receptors
may be only functionally related to the known cannabinoid
receptors than have a similar structure as CB1
and CB2.
Endocannabinoids
The identification of cannabinoid receptors was followed
by the detection of endogenous ligands for these
receptors, named endocannabinoids. In the brain endocannabinoids
serve as neuromodulators. All endocannabinoids
are derivatives of polyunsaturated fatty acids,
thus differing in chemical structure from phytocannabinoids
of the cannabis plant. Among the endocannabinoids
so far identified are anandamide (N-arachidonoylethanolamide,
AEA), 2-arachidonoylglycerol
(2-AG), 2-arachidonylglyceryl ether (noladin ether), Oarachidonoyl-
ethanolamine (virodhamine), and N-arachidonoyl-
dopamine (NADA). Anandamide and
NADA do not only bind to cannabinoid receptors but
also share the ability of capsaicin, a constituent of hot
chilli peppers, to stimulate vanilloid (TRPV1) receptors.
The first two discovered endocannabinoids, anandamide
and 2-AG, have been most studied. In contrast
to other brain chemical signals they are not produced
and stored in the nerve cells but produced "on demand"
(only when necessary) from their precursors and then
released from cells. After release, they are rapidly
deactivated by uptake into cells and metabolized. Metabolism
of anandamide and 2-AG occurs mainly by
enzymatic hydrolysis by fatty acid amide hydrolase
(FAAH) and monoacylglycerol lipase (2-AG only).
Affinity for the Cannabinoid Receptor
Cannabinoids show different affinity to CB1 and CB2
receptors. Synthetic cannabinoids have been developed
that act as highly selective agonists or antagonists at
one or other of these receptor types. Δ9-THC has approximately
equal affinity for the CB1 and CB2 receptor,
while anandamide has marginal selectivity for
CB1 receptors. However, the efficacy of THC and
anandamide is less at CB2 than at CB1 receptors.
Tonic Activity of the Endocannabinoid System
When administered by themselves antagonists at the
cannabinoid receptor may behave as inverse agonists in
several bioassay systems. This means that they do not
only block the effects of endocannabinoids but produce
effects that are opposite in direction from those produced
by cannabinoid receptor agonists, e.g. cause
increased sensitivity to pain or nausea, suggesting that
the cannabinoid system is tonically active. This tonic
activity may be due a constant release of endocannabinoids
or from a portion of cannabinoid receptors that
exist in a constitutively active state.
Tonic activity of the cannabinoid system has been
demonstrated in several conditions. Endocannabinoid
levels have been demonstrated to be increased in a pain
circuit of the brain (periaqueductal grey) following
painful stimuli. Tonic control of spasticity by the endocannabinoid
system has been observed in chronic relapsing
experimental autoimmune encephalomyelitis
(CREAE) in mice, an animal model of multiple sclerosis.
An increase of cannabinoid receptors following
nerve damage was demonstrated in a rat model of
chronic neuropathic pain and in a mouse model of
intestinal inflammation. This may increase the potency
of cannabinoid agonists used for the treatment of these
conditions. Tonic activity has also been demonstrated
with regard to appetite control and with regard to vomiting
in emetic circuits of the brain.
Therapeutic Prospects
Mechanisms of action of cannabinoids are complex,
not only involving activation of and interaction at the
cannabinoid receptor, but also activation of vanilloid
receptors, increase of endocannabinoid concentration,
antioxidant activity, metabolic interaction with other
compounds, and several others. CB receptor antagonists
(blockers) are in clinical use for the treatment of
obesity and under investigation for the treatment of
nicotine and other dependencies.
Aside from phytocannabinoids and cannabis preparations,
cannabinoid analogues that do not or only
weakly bind to the CB1 receptor are attractive compounds for clinical research. Additional ideas for the
separation of the desired therapeutic effects from the
psychotropic action comprise the concurrent administration
of THC and CBD, the design of CB1 receptor
agonists that do not cross the blood brain barrier, and
the development of compounds that influence endocannabinoid
levels by inhibition of their membrane
transport (transport inhibitors) or hydrolysis (e.g.FAAH inhibitors). For example, blockers of anandamide
hydrolysis were able to reduce among others,
anxiety, pain, cancer growth, and colitis in animal tests.
Drugs that enhance the response of the CB1 receptor to
endogenously released endocannabinoids by binding to
the so-called allosteric site on this receptor are also
likely to be more selective than compounds that activate
this receptor directly [10].
Modulators of the cannabinoid system in clinical
use and under investigation
Currently two cannabinoid receptor agonists, dronabinol
and nabilone, a cannabis extract (Sativex®), and a
cannabinoid receptor antagonist (rimonabant) are in
medical use. In addition, cannabis herb produced according
to pharmaceutical standards and supervised by
the Office of Medicinal Cannabis of the Dutch Health
Ministry is available in pharmacies of the Netherlands
[4]. In some countries the possession of small amounts
of cannabis either for recreational or medicinal use is
allowed or tolerated, such as in the Netherlands, Spain,
Belgium and some regions of Switzerland. Eleven
states of the USA (Alaska, California, Colorado, Hawaii,
Maine, Montana, Nevada, Oregon, Rhode Island,
Vermont, Washington) have legalized the medical use
of cannabis under state law, while it remains illegal
under federal law. In Canada it is possible to apply for
a certificate of exemption to use otherwise illegal cannabis
for medical purposes, and the Health Ministry
(Health Canada) sells cannabis herb to these patients if
they do not want to grow it themselves.
Dronabinol is the international non-proprietary name
(INN) for Δ9-THC, the main psychoactive compound
of cannabis. In 1985 the Food and Drug Administration
(FDA) of the United States approved Marinol® Capsules,
which contain synthetic dronabinol (2.5 mg, 5
mg or 10 mg), for nausea and vomiting associated with
cancer chemotherapy in patients that had failed to respond
adequately to conventional anti-emetic treatments.
Marinol® is manufactured by Unimed Pharmaceuticals,
a subsidiary of Solvay Pharmaceuticals.
Marinol® has been on the market in the USA since
1987. In 1992 the FDA approved Marinol® Capsules
for the treatment of anorexia associated with weight
loss in patients with AIDS. Marinol is also available on
prescription in several other countries including Canada
and several European countries. In Germany and
Austria dronabinol, which is manufactured by the two
German companies THC Pharm and Delta 9 Pharma,
may be bought by pharmacies to produce dronabinol
capsules or solutions.
In 1985 the FDA also approved Cesamet® Capsules
for the treatment of nausea and vomiting associated
with chemotherapy. Cesamet® made by Eli Lilly and
Company contains nabilone, a synthetic derivative of
dronabinol. However, it was not marketed in the USA
and Lilly discontinued the drug in 1989. Cesamet® is
also available in the United Kingdom marketed by
Cambridge Laboratories and in several other European
countries. In 2006 nabilone (Cesamet®) again got
approval by the FDA as a prescription treatment for
nausea and vomiting associated with chemotherapy. It
is marketed by Valeant Pharmaceuticals International,
which bought the drug from Eli Lilly in 2004 and also
sells it in Canada.
In 2005 Sativex® received approval in Canada for the
symptomatic relief of neuropathic pain in multiple
sclerosis. Sativex® is produced by the British company
GW Pharmaceuticals and marketed in Canada by Bayer
Health Care. Sativex® is a cannabis extract, which is
sprayed in the oromucosal area and contains approximately
equal amounts of dronabinol (THC) and cannabidiol
(CBD). There is also limited access to Sativex
® in the UK and Spain. Sativex is currently under
review for approval as a prescription medication for
treatment of spasticity in multiple sclerosis in the
United Kingdom, Spain, Denmark and the Netherlands.
The cannabinoid receptor antagonist rimonabant received
a positive recommendation for approval by the
European Medicines Agency in 2006. It is available in
the United Kingdom under the trade name Acomplia®
for the treatment of obesity. Acomplia® tablets contain
20 mg of rimonabant. The drug is manufactured by
Sanofi Aventis.
Preparations under investigation in clinical phase II or
III studies include the capsulated cannabis extract Cannador
®, which contains dronabinol and other cannabinoids
in a ratio of 2 to 1 and is being investigated by
the Institute for Clinical Research in Berlin and the
pharmaceutical company Weleda, ajulemic acid, a
synthetic derivative of THC-COOH, which is also
called CT3 or IP751 and is being investigated by Indevus
Pharmaceuticals, and cannabinor, a synthetic cannabinoid
that binds selectively to the CB2 receptor and
is being investigated by Pharmos Corporation.
References
1. Baker D, Pryce G, Davies WL, Hiley CR. In
silico patent searching reveals a new cannabinoid
receptor. Trends Pharmacol Sci 2006;27(1):1-4.
2. Di Marzo V, De Petrocellis L. Plant, synthetic,
and endogenous cannabinoids in medicine. Annu
Rev Med 2006;57:553-74.
3. ElSohly M. Chemical constituents of cannabis.
In: Grotenhermen F, Russo E, editors. Cannabis
and cannabinoids. Pharmacology, toxicology, and
therapeutic potential. Binghamton/New York:
Haworth Press, 2002. p. 27-36.
4. Grotenhermen F. Cannabinoids. Curr Drug Targets
CNS Neurol Disord 2005;4(5):507-530.
5. Grotenhermen F. Clinical pharmacodynamics of
cannabinoids. In: Russo E, Grotenhermen F, editors.
The Handbook of Cannabis Therapeutics:
From Bench to Bedside. Binghamton/New York:
Haworth Press, 2006. p. 117-170.
6. Hazekamp A. An evaluation of the quality of
medicinal grade cannabis in the Netherlands.
Cannabinoids 2006;1(1):1-9.
7. Howlett AC, Barth F, Bonner TI, Cabral G,
Casellas P, Devane WA, Felder CC, Herkenham
M, Mackie K, Martin BR, Mechoulam R,
Pertwee RG. International Union of Pharmacology.
XXVII. Classification of cannabinoid receptors.
Pharmacol Rev 2002;54(2):161-202.
8. IACM-Bulletin. Bulletin of the International
Association for Cannabis as Medicine. Available
from: 420 MAGAZINE.
org/english/bulletin/iacm.php.
9. Pertwee R. Receptors and pharmacodynamics:
natural and synthetic cannabionoids and endocannabinoids.
In: Guy GW, Whittle B, Robson P,
editors. The Medicinal Uses of Cannabis and
Cannabinoids. London, Chicago: Pharmaceutical
Press; 2004. p. 103-139.
10. Price MR, Baillie GL, Thomas A, Stevenson LA,
Easson M, Goodwin R, McLean A, McIntosh L,
Goodwin G, Walker G, Westwood P, Marrs J,
Thomson F, Cowley P, Christopoulos A, Pertwee
RG, Ross RA. Allosteric modulation of the cannabinoid
CB1 receptor. Mol Pharmacol
2005;68(5):1484-95.
Source: Cannabinoids And The Endocannabinoid System
Abstract
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.
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.
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.
CB2 receptors occur principally in immune cells,
among them leukocytes, spleen and tonsils. One of the
functions of CB receptors in the immune system is
modulation of release of cytokines, which are responsible
for inflammation and regulation of the immune
system. Since compounds that selectively activate CB2
receptors (CB2 receptor agonists) do not cause psychological
effects, they have become an increasingly
investigated target for therapeutic uses of cannabinoids,
among them analgesic, anti-inflammatory and anticancer
actions.
There is increasing evidence for the existence of additional
cannabinoid receptor subtypes in the brain and
periphery. One of these receptors may be the orphan Gprotein-
coupled receptor GPR55 [1]. Other receptors
may be only functionally related to the known cannabinoid
receptors than have a similar structure as CB1
and CB2.
Endocannabinoids
The identification of cannabinoid receptors was followed
by the detection of endogenous ligands for these
receptors, named endocannabinoids. In the brain endocannabinoids
serve as neuromodulators. All endocannabinoids
are derivatives of polyunsaturated fatty acids,
thus differing in chemical structure from phytocannabinoids
of the cannabis plant. Among the endocannabinoids
so far identified are anandamide (N-arachidonoylethanolamide,
AEA), 2-arachidonoylglycerol
(2-AG), 2-arachidonylglyceryl ether (noladin ether), Oarachidonoyl-
ethanolamine (virodhamine), and N-arachidonoyl-
dopamine (NADA). Anandamide and
NADA do not only bind to cannabinoid receptors but
also share the ability of capsaicin, a constituent of hot
chilli peppers, to stimulate vanilloid (TRPV1) receptors.
The first two discovered endocannabinoids, anandamide
and 2-AG, have been most studied. In contrast
to other brain chemical signals they are not produced
and stored in the nerve cells but produced "on demand"
(only when necessary) from their precursors and then
released from cells. After release, they are rapidly
deactivated by uptake into cells and metabolized. Metabolism
of anandamide and 2-AG occurs mainly by
enzymatic hydrolysis by fatty acid amide hydrolase
(FAAH) and monoacylglycerol lipase (2-AG only).
Affinity for the Cannabinoid Receptor
Cannabinoids show different affinity to CB1 and CB2
receptors. Synthetic cannabinoids have been developed
that act as highly selective agonists or antagonists at
one or other of these receptor types. Δ9-THC has approximately
equal affinity for the CB1 and CB2 receptor,
while anandamide has marginal selectivity for
CB1 receptors. However, the efficacy of THC and
anandamide is less at CB2 than at CB1 receptors.
Tonic Activity of the Endocannabinoid System
When administered by themselves antagonists at the
cannabinoid receptor may behave as inverse agonists in
several bioassay systems. This means that they do not
only block the effects of endocannabinoids but produce
effects that are opposite in direction from those produced
by cannabinoid receptor agonists, e.g. cause
increased sensitivity to pain or nausea, suggesting that
the cannabinoid system is tonically active. This tonic
activity may be due a constant release of endocannabinoids
or from a portion of cannabinoid receptors that
exist in a constitutively active state.
Tonic activity of the cannabinoid system has been
demonstrated in several conditions. Endocannabinoid
levels have been demonstrated to be increased in a pain
circuit of the brain (periaqueductal grey) following
painful stimuli. Tonic control of spasticity by the endocannabinoid
system has been observed in chronic relapsing
experimental autoimmune encephalomyelitis
(CREAE) in mice, an animal model of multiple sclerosis.
An increase of cannabinoid receptors following
nerve damage was demonstrated in a rat model of
chronic neuropathic pain and in a mouse model of
intestinal inflammation. This may increase the potency
of cannabinoid agonists used for the treatment of these
conditions. Tonic activity has also been demonstrated
with regard to appetite control and with regard to vomiting
in emetic circuits of the brain.
Therapeutic Prospects
Mechanisms of action of cannabinoids are complex,
not only involving activation of and interaction at the
cannabinoid receptor, but also activation of vanilloid
receptors, increase of endocannabinoid concentration,
antioxidant activity, metabolic interaction with other
compounds, and several others. CB receptor antagonists
(blockers) are in clinical use for the treatment of
obesity and under investigation for the treatment of
nicotine and other dependencies.
Aside from phytocannabinoids and cannabis preparations,
cannabinoid analogues that do not or only
weakly bind to the CB1 receptor are attractive compounds for clinical research. Additional ideas for the
separation of the desired therapeutic effects from the
psychotropic action comprise the concurrent administration
of THC and CBD, the design of CB1 receptor
agonists that do not cross the blood brain barrier, and
the development of compounds that influence endocannabinoid
levels by inhibition of their membrane
transport (transport inhibitors) or hydrolysis (e.g.FAAH inhibitors). For example, blockers of anandamide
hydrolysis were able to reduce among others,
anxiety, pain, cancer growth, and colitis in animal tests.
Drugs that enhance the response of the CB1 receptor to
endogenously released endocannabinoids by binding to
the so-called allosteric site on this receptor are also
likely to be more selective than compounds that activate
this receptor directly [10].
Modulators of the cannabinoid system in clinical
use and under investigation
Currently two cannabinoid receptor agonists, dronabinol
and nabilone, a cannabis extract (Sativex®), and a
cannabinoid receptor antagonist (rimonabant) are in
medical use. In addition, cannabis herb produced according
to pharmaceutical standards and supervised by
the Office of Medicinal Cannabis of the Dutch Health
Ministry is available in pharmacies of the Netherlands
[4]. In some countries the possession of small amounts
of cannabis either for recreational or medicinal use is
allowed or tolerated, such as in the Netherlands, Spain,
Belgium and some regions of Switzerland. Eleven
states of the USA (Alaska, California, Colorado, Hawaii,
Maine, Montana, Nevada, Oregon, Rhode Island,
Vermont, Washington) have legalized the medical use
of cannabis under state law, while it remains illegal
under federal law. In Canada it is possible to apply for
a certificate of exemption to use otherwise illegal cannabis
for medical purposes, and the Health Ministry
(Health Canada) sells cannabis herb to these patients if
they do not want to grow it themselves.
Dronabinol is the international non-proprietary name
(INN) for Δ9-THC, the main psychoactive compound
of cannabis. In 1985 the Food and Drug Administration
(FDA) of the United States approved Marinol® Capsules,
which contain synthetic dronabinol (2.5 mg, 5
mg or 10 mg), for nausea and vomiting associated with
cancer chemotherapy in patients that had failed to respond
adequately to conventional anti-emetic treatments.
Marinol® is manufactured by Unimed Pharmaceuticals,
a subsidiary of Solvay Pharmaceuticals.
Marinol® has been on the market in the USA since
1987. In 1992 the FDA approved Marinol® Capsules
for the treatment of anorexia associated with weight
loss in patients with AIDS. Marinol is also available on
prescription in several other countries including Canada
and several European countries. In Germany and
Austria dronabinol, which is manufactured by the two
German companies THC Pharm and Delta 9 Pharma,
may be bought by pharmacies to produce dronabinol
capsules or solutions.
In 1985 the FDA also approved Cesamet® Capsules
for the treatment of nausea and vomiting associated
with chemotherapy. Cesamet® made by Eli Lilly and
Company contains nabilone, a synthetic derivative of
dronabinol. However, it was not marketed in the USA
and Lilly discontinued the drug in 1989. Cesamet® is
also available in the United Kingdom marketed by
Cambridge Laboratories and in several other European
countries. In 2006 nabilone (Cesamet®) again got
approval by the FDA as a prescription treatment for
nausea and vomiting associated with chemotherapy. It
is marketed by Valeant Pharmaceuticals International,
which bought the drug from Eli Lilly in 2004 and also
sells it in Canada.
In 2005 Sativex® received approval in Canada for the
symptomatic relief of neuropathic pain in multiple
sclerosis. Sativex® is produced by the British company
GW Pharmaceuticals and marketed in Canada by Bayer
Health Care. Sativex® is a cannabis extract, which is
sprayed in the oromucosal area and contains approximately
equal amounts of dronabinol (THC) and cannabidiol
(CBD). There is also limited access to Sativex
® in the UK and Spain. Sativex is currently under
review for approval as a prescription medication for
treatment of spasticity in multiple sclerosis in the
United Kingdom, Spain, Denmark and the Netherlands.
The cannabinoid receptor antagonist rimonabant received
a positive recommendation for approval by the
European Medicines Agency in 2006. It is available in
the United Kingdom under the trade name Acomplia®
for the treatment of obesity. Acomplia® tablets contain
20 mg of rimonabant. The drug is manufactured by
Sanofi Aventis.
Preparations under investigation in clinical phase II or
III studies include the capsulated cannabis extract Cannador
®, which contains dronabinol and other cannabinoids
in a ratio of 2 to 1 and is being investigated by
the Institute for Clinical Research in Berlin and the
pharmaceutical company Weleda, ajulemic acid, a
synthetic derivative of THC-COOH, which is also
called CT3 or IP751 and is being investigated by Indevus
Pharmaceuticals, and cannabinor, a synthetic cannabinoid
that binds selectively to the CB2 receptor and
is being investigated by Pharmos Corporation.
References
1. Baker D, Pryce G, Davies WL, Hiley CR. In
silico patent searching reveals a new cannabinoid
receptor. Trends Pharmacol Sci 2006;27(1):1-4.
2. Di Marzo V, De Petrocellis L. Plant, synthetic,
and endogenous cannabinoids in medicine. Annu
Rev Med 2006;57:553-74.
3. ElSohly M. Chemical constituents of cannabis.
In: Grotenhermen F, Russo E, editors. Cannabis
and cannabinoids. Pharmacology, toxicology, and
therapeutic potential. Binghamton/New York:
Haworth Press, 2002. p. 27-36.
4. Grotenhermen F. Cannabinoids. Curr Drug Targets
CNS Neurol Disord 2005;4(5):507-530.
5. Grotenhermen F. Clinical pharmacodynamics of
cannabinoids. In: Russo E, Grotenhermen F, editors.
The Handbook of Cannabis Therapeutics:
From Bench to Bedside. Binghamton/New York:
Haworth Press, 2006. p. 117-170.
6. Hazekamp A. An evaluation of the quality of
medicinal grade cannabis in the Netherlands.
Cannabinoids 2006;1(1):1-9.
7. Howlett AC, Barth F, Bonner TI, Cabral G,
Casellas P, Devane WA, Felder CC, Herkenham
M, Mackie K, Martin BR, Mechoulam R,
Pertwee RG. International Union of Pharmacology.
XXVII. Classification of cannabinoid receptors.
Pharmacol Rev 2002;54(2):161-202.
8. IACM-Bulletin. Bulletin of the International
Association for Cannabis as Medicine. Available
from: 420 MAGAZINE.
org/english/bulletin/iacm.php.
9. Pertwee R. Receptors and pharmacodynamics:
natural and synthetic cannabionoids and endocannabinoids.
In: Guy GW, Whittle B, Robson P,
editors. The Medicinal Uses of Cannabis and
Cannabinoids. London, Chicago: Pharmaceutical
Press; 2004. p. 103-139.
10. Price MR, Baillie GL, Thomas A, Stevenson LA,
Easson M, Goodwin R, McLean A, McIntosh L,
Goodwin G, Walker G, Westwood P, Marrs J,
Thomson F, Cowley P, Christopoulos A, Pertwee
RG, Ross RA. Allosteric modulation of the cannabinoid
CB1 receptor. Mol Pharmacol
2005;68(5):1484-95.
Source: Cannabinoids And The Endocannabinoid System
