Cannabinoids 2006;1(1):10-14 10 © International Association for Cannabis as Medicine

Cannabinoids 2006;1(1):10-14 10  © International Association for Cannabis as Medicine

Mini-review 
Cannabinoids and the Endocannabinoid System  
Franjo Grotenhermen 
nova-Institut, Goldenbergstraße 2, D-50354 Hürth, Germany 
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. '
9
-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 
'
9
-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. Grotenhermen 
Cannabinoids Œ Vol 1, No 1 Œ September 17, 2006  11  
O
OH
O
OH
9
8
3
4
5
6
6'
5'
4'
3'
2'
1'
1
3
2
7
3' 5
10b
10
1'
11
9
8
7
13
12
6a
6 5
4
2
1
Monoterpenoid numbering  Dibenzopyran numbering
10
1" 3" 5"
10a
Figure 1. Chemical structure of 
THC (dronabinol), the main 
cannabinoid in the cannabis 
plant, according to the monoterpenoid system ('
1
-THC) and 
dibenzopyran system ('
9
-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  '
9
-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%.  '
9
-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-'
9
-tetrahydrocannabinol (11-OH-THC) is the 
most important psychotropic metabolite of  '
9
-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 '
9
-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 
H 
O
OH
Figure 2. Cannabidiol Mini-review 
12  Cannabinoids Œ Vol 1, No 1 Œ September 17, 2006 
N
O
H OH
Figure 3. Arachidonoylethanolamide (AEA, anandamide) 
O
O
OH
CH2
OH
Figure 4. 2-Arachidonoylglycerol (2-AG) 
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 demanda 
(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. '
9
-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  com- Grotenhermen 
Cannabinoids Œ Vol 1, No 1 Œ September 17, 2006  13
O
O
OH
Figure 5. Nabilone 
O 
OH
COOH 
Figure 6. CT3 (ajulemic acid, IP751) 
OH
O
O
HOOC O
Figure 7. Cannabinor 
N
N
Cl
Cl
Cl
H-N
N
O
Figure 8. Rimonabant (SR 141716A), Aclompia® 
pounds 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  '
9
-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 Mini-review 
14  Cannabinoids Œ Vol 1, No 1 Œ September 17, 2006 
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. 
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