Current Drug Targets - CNS & Neurological Disorders, 2005, 4, 507-530507
1568-007X/05 $50.00+.00© 2005 Bentham Science Publishers Ltd.
Nova-Institut, Goldenbergstraße 2, D-50354 Hürth, Germany
Abstract: Since the discovery of an endogenous cannabinoid system, research into the pharmacology and therapeutic
potential of cannabinoids has steadily increased. Two subtypes of G-protein coupled cannabinoid receptors, CB1 and CB2,
have been cloned and several putative endogenous ligands (endocannabinoids) have been detected during the past 15
years. The main endocannabinoids are arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG),
derivatives of arachidonic acid, that are produced “on demand” by cleavage of membrane lipid precursors. Besides
phytocannabinoids of the cannabis plant, modulators of the cannabinoid system comprise synthetic agonists and
antagonists at the CB receptors and inhibitors of endocannabinoid degradation. Cannabinoid receptors are distributed in
the central nervous system and many peripheral tissues, including immune system, reproductive and gastrointestinal
tracts, sympathetic ganglia, endocrine glands, arteries, lung and heart. There is evidence for some non-receptor dependent
mechanisms of cannabinoids and for endocannabinoid effects mediated by vanilloid receptors.
Properties of CB receptor agonists that are of therapeutic interest include analgesia, muscle relaxation,
immunosuppression, anti-inflammation, antiallergic effects, improvement of mood, stimulation of appetite, antiemesis,
lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. The current main focus of
clinical research is their efficacy in chronic pain and neurological disorders. CB receptor antagonists are under
investigation for medical use in obesity and nicotine addiction. Additional potential was proposed for the treatment of
alcohol and heroine dependency, schizophrenia, conditions with lowered blood pressure, Parkinson's disease and memory
impairment in Alzheimer's disease.
Keywords: Cannabis, THC, cannabinoids, cannabinoid receptors, endocannabinoids, cannabinoid receptor antagonists,
therapeutic potential, side effects.
Despite a long history of medicinal use lasting back more
than 4,000 years [1, 2], the introduction of cannabinoids into
modern medicine is only beginning. Unlike opiates and
many other plant constituents used for therapeutic purposes,
the most active ingredient ?9-tetrahydrocannabinol (?9-THC,
dronabinol) was been identified only 40 years ago (see Fig.
1). In addition, less than 20 years have passed since the
detection of an endogenous system of specific receptors and
their endogenous ligands, the "endocannabinoid system" or
In the 1930s and 1940s, the chemical structure of the first
phytocannabinoids had been successfully characterized ,
and the first synthetic derivatives of THC (parahexyl,
DMHP) were successfully tested in clinical studies for
epilepsy , depression  and dependency to alcohol and
opiates . However, it was not until 1964 that ?9-THC was
stereochemically defined and synthesized .
Both discoveries, the identification of THC, which
allowed basic and clinical studies with defined and
reproducible doses, and the detection of the endocannabinoid
system in mammals, which allowed the investigation of
mechanisms of cannabinoid actions and the exploration of
the therapeutic potential of inhibitors of endocannabinoid
*Address correspondence to the author at the Nova-Institut,
Goldenbergstraße 2, D-50354 Hürth, Germany Tel: +49-2247-968085; Fax:
+49-2247-9159223; E-mail: firstname.lastname@example.org
degradation and cannabinoid receptor antagonists, resulted in
a considerable boost in research activities. The number of
publications listed in
(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) rose from
very few to about 400 per year in 1972, then declined to 250
in 1982, remained at this level until 1989, and then steadily
rose to about 1100 per year in 2004.
the database PubMed
Fig. (1). Chemical structure of THC, the main cannabinoid in the
cannabis plant, according to the monoterpenoid system (?1-THC)
and dibenzopyran system (?9-THC).
508 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5Franjo Grotenhermen
2. CANNABINOID RECEPTORS
To date, two cannabinoid receptors have been identified,
the CB1 (cloned in 1990) , and the CB2 receptor (cloned in
1993) , exhibiting 48% amino acid sequence identity.
Besides their difference in amino acid sequence, they differ
in signaling mechanisms, tissue distribution, and sensitivity
to certain agonists and antagonists that may show marked
selectivity for one or the other receptor type .
Activation of the CB1 receptor produces effects on
circulation and psychotropic effects common to cannabis
ingestion, while activation of the CB2 receptor does not.
Hence, selective CB2 receptor agonists have become an
increasingly investigated target for therapeutic uses of
cannabinoids, among them being analgesic, anti-
inflammatory and anti-neoplastic actions [11, 12].
The endocannabinoid system is teleologically, millions of
years old and has been found in mammals, birds,
amphibians, fish, sea urchins, molluscs, leeches and even
primitive Hydra vulgaris [13, 14]. The nucleotide sequences
of genes encoding the cannabinoid receptors vary from
species to species, their identity with the human CB
sequence being proportional to the evolutionary distances
between the organisms. The CB1 gene (CNR1) of the rhesus
monkey (Macaca mulata) is 100% identical to the sequence
of the human CNR1, whereas the CB1 gene of the leech
(Hirudo medicinalis) shares only 58% of the human gene
. Comparisons between human, rat and mouse CB1
receptor sequences showed extensive homology both at the
nucleotide and protein levels . The CB1-receptor
nucleotide sequences of humans and rats are 90% and those
of humans and mice are 91% identical. CB2 receptors show
greater interspecies differences with a similarity of 82%
between the mouse and human receptor protein, the human
CB2 being 13 amino acids longer at the carboxyl terminus
 and 81% amino acid homology between the rat and
human CB2 receptor . Pronounced species selectivity at
the rat cannabinoid CB2 receptor compared to the human
CB2 receptor was observed for two synthetic cannabinoids
(AM-1710 and AM-1714), whereas JWH-015 and
endocannabinoids were more human receptor selective .
These findings of pharmacological species differences are
critical for characterizing cannabinoid receptor ligands in in
vivo rodent models for drug discovery purpose.
A first spliced amino-truncated variant (isoform) of the
CB1 receptor cDNA, CB1a, has been isolated by Rinaldi-
Carmona et al. (1996) . Recently, another group reported
the detection of another spliced variant (CB1b) and noted that
both variants have a unique pharmacological profile and that
their RNA's are expressed at low levels in several tissues
Attempts have been made to investigate a possible
association between the predisposition to certain diseases
and mutations or variants in the CB1 receptor gene.
Schizophrenia  and depression in Parkinson's disease
 may be related to a genetic polymorphism of the CNR1,
while Tourette's syndrome and delirium tremens in
alcoholism  do not seem to be associated with a mutation
of the CB1 receptor gene . Individuals with a 9-repeat
allele of an AAT-repeat polymorphism of the gene may have
a 2.3-fold higher susceptibility to schizophrenia .
Both CB1 and CB2 receptors belong to the class A
(rhodopsin like) G-protein-coupled receptors (GPCR). G-
proteins coupled to cannabinoid receptors are sensitive to
pertussis toxin, an inactivator of inhibiting Gi and Go
proteins. Among the class A GPCRs are receptors for
melatonin, thyrotropin-releasing hormone, prostanoid and
the leukotriene B4 receptor. GPCRs are the most common
receptors, containing 1000-2000 members in vertebrates
(>1% of the genome) . GPCRs are involved in the
recognition and transduction of messages as diverse as light,
Calcium ions, odorants, nucleotides and peptides, as well as
proteins, controlling the activity of enzymes, ion channels
and transport of vesicles .
CB1 receptors are mainly found on neurons in the brain,
spinal cord and peripheral nervous system, but are also
present in certain peripheral organs and tissues, among them
being immune cells, spleen, adrenal and pituitary glands,
sympathetic ganglia, heart, lung and parts of the
reproductive, urinary and gastrointestinal tracts . In the
central nervous system, the CB1 receptor is the most
abundant G-protein coupled receptor.
CB1 receptors are highly expressed in the cerebral cortex,
basal ganglia (substantia nigra pars reticulata, globus
pallidus, nucleus caudatus and putamen) cerebellum,
hippocampus, periaqueductal grey, rostral ventromedial
medulla, certain nuclei of the thalamus and amygdala, and
dorsal primary afferent spinal cord regions, which reflect the
importance of the cannabinoid system in motor control,
memory processing and pain modulation, while their
expression in the brainstem is low , which may account
for the lack of cannabis-related acute fatalities, e.g. due to
depression of respiration. Many CB1 receptors are expressed
at the terminals of central and peripheral nerves and inhibit
the release of neurotransmitters.
CB1 receptors have also been found at the central and
peripheral terminals of small diameter C-fibers and larger
diameter A?/A?-fibers of primary afferent neurons. This
helps to explain the efficacy of CB1 receptor agonists in
neuropathic pain, since this kind of pain is thought to be
elicited in part by abnormal spontaneous discharges of A?
and A? fibers .
CB2 receptors occur principally in immune cells, among
them being leukocytes, spleen and tonsils . Immune cells
also express CB1 receptors, but there is markedly more
mRNA for CB2 than CB1 receptors in the immune system.
Levels of CB1 and CB2 mRNA in human leukocytes have
been shown to vary with cell type (B cells > natural killer
cells > monocytes > polymorphonuclear neutrophils, T4 and
T8 cells) . One of the functions of CB receptors in the
immune system is modulation of cytokine release. Activation
of CB2 receptors has also been reported to produce
antinociception, by stimulating peripheral release of
endogenous opioids .
Cannabinoids Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 509
2.3. Mechanisms of Action
Agonistic stimulation of both types of cannabinoid
receptors activates a number of signal transduction pathways
[25, 27]. Both are coupled through inhibiting G-proteins (Gi/o
proteins), negatively to adenylate cyclase and positively to
mitogen-activated protein kinase. Inhibition of adenylate
cyclase results in the inhibition of the conversion of ATP to
cyclic AMP (cAMP). CB1, but not CB2 receptors are also
coupled to several ion channels through Gi/o proteins,
negatively to N-type and P/Q-type calcium channels and D-
type potassium channels, positively to A-type and inwardly
rectifying potassium channels. CB1 receptors may also
mobilize arachidonic acid, close 5-HT3 receptors ion
channels, modulate nitric oxide production and mobilize
arachidonic acid and intracellular calcium stores . CB1
receptor activation can also initiate ceramide production
through a non-G protein mediated mechanism, and under
certain conditions, CB1 receptors may also activate adenylate
cyclase and/or reduce outward potassium K current through
stimulating G proteins (Gs proteins) .
In vitro experiments have demonstrated that CB1
receptors can mediate inhibition of the neuronal release of a
multitude of neurotransmitters and neuromodulators,
including acetylcholine, dopamine, ?-aminobutyric acid
(GABA), histamine, serotonin (5-hydroxytryptamine),
glutamate, cholecystokinin, D-aspartate, glycine and
noradrenaline (norepinephrine) in several brain regions and
outside the brain (see Table 1 ). Inhibition of
neurotransmitters by CB1 receptor activation in the central
nervous system is caused by presynaptic inhibition of
neurotransmitter release from axon terminals . In the
CNS, this inhibition is caused by both endocannabinoids and
exogenous cannabinoids. Presynaptic inhibition of
neurotransmitters by exogenous cannabinoids that bind to
the peripheral CB1 receptor has also been described in the
sympathetic nervous system, but endocannabinoid-mediated
presynaptic inhibition was not observed in all assays
investigating their action in the sympathetic nervous system
In some experiments, CB1 receptor agonists have been
reported not to inhibit but to enhance the release of certain
neurotransmitters. However, it is possible that these effects
also result from a CB receptor-mediated inhibitory effect on
neurotransmitter release, resulting in a stimulatory effect on
neurotransmitter release at some point downstream of the
side of the initial inhibitory effect .
Interaction of THC effects with other neurotransmitters is
supported by the fact that antagonists of these
neurotransmitters blocked specific THC effects. The memory
disruptive effects of THC were completely reversed by the
GABA antagonist bicuculline, while other THC effects were
unaffected . Opioid receptor antagonists blocked several
behavioral effects of CB1 agonists [32, 33]. A number of
pharmacological effects can be explained (at least in part) on
the basis of interactions with other neurotransmitters. For
example, tachycardia and hyposalivation with dry mouth
[34, 35] are mediated by effects of THC on release and turn-
over of acetylcholine . In a rat model, cannabinoid
agonists inhibited activation of 5-HT3 receptors, explaining
antiemetic properties of cannabinoids to be based on
interactions with serotonin . Therapeutic effects in
movement and spastic disorders could be ascribed in part to
interactions with GABAergic, glutamergic and dopaminergic
transmitters systems . The effects on GABA, glutamate
and glycine release in the periaqueductal grey, rostral
ventromedial medulla and substantia nigra may contribute to
the modulation of pain perception.
Cannabinoids may cause contradictory effects with
suppression or induction/intensification of somatic and
psychic effects, including convulsion, emesis, pain, tremor
and anxiety, depending on subject and condition. Cannabis
and THC are used against nausea and vomiting caused by
anti-neoplastic drugs but may rarely cause vomiting. They
are used as analgesics but sometimes may increase pain ;
they may cause anxiety but may also be anxiolytic , etc.
These observations are probably based on the control of
these effects by several neuronal circuits influenced by
cannabinoids. Recently, it has been demonstrated that
signaling of the CB1 receptor is profoundly altered by a
Table 1. Neurotransmitter Functions Under Cannabinoid Control
Neurotransmitter Associated disorder
Excitatory amino acids
Glutamate Epilepsy, nerve-cell death in ischemia and hypoxia (stroke, head trauma, nerve gas toxicity)
Inhibitory amino acids
GABA Spinal cord motor disorders, epilepsy, anxiety
Glycine Startle syndromes
Noradrenaline Autonomic homoeostasis, hormones, depression
SerotoninDepression, anxiety, migraine, vomiting
Dopamine Parkinson’s disease, schizophrenia, vomiting, pituitary hormones, drug addiction
Neuromuscular disorders, autonomic homoeostasis (heart rate, blood pressure), dementia, parkinsonism, epilepsy,
Neuropeptides Pain, movement, neural development, anxiety
510 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5Franjo Grotenhermen
regulated association of CB1 and dopamine-2 receptors .
The highest level of CB1/D2 receptor complexes was
detected when both receptors were stimulated with sub-
saturating concentrations of agonists. Concurrent receptor
stimulation promoted a shift of CB1 signaling from a
pertussis toxin sensitive inhibition to a partly pertussis toxin
insensitive stimulation of adenylate cyclase and
phosphorylation by extracellular signal-regulated kinases 1
and 2 (ERK1/2) . A cross-talk between the CB1 receptor
and other receptors in the brain has also been reported for the
corticotropin releasing hormone receptor type 1 (CRHR1) in
olfactory regions, in several cortical and limbic structures,
and in some hypothalamic and thalamic nuclei  and for
the ?-opioid receptor in the dorsal horn of the spinal cord
Interactions of cannabinoids with other neurotransmitter
systems may cause unexpected effects. While studies in
animals have demonstrated that opioid receptor antagonists
precipitated a cannabinoid-like withdrawal syndrome in
cannabinoid-dependent rats , opioid receptor antagonists
did not block the subjective effects of THC in humans in one
study  or even increased the subjective effects THC in
another study .
Not all compounds that activate cannabinoid receptors
are cannabinoids. e.g. alkylamides of the Echinacea plant
upregulated TNF-alpha mRNA, which was mediated by CB2
2.4. Additional Cannabinoid Receptors
Not all cannabinoid effects are mediated by CB
receptors. The endocannabinoid 2-arachidonoyl glycerol
suppressed interferon-gamma expression in splenocytes and
there was no difference in magnitude of effect between cells
derived from CB1(-/-)/CB2(-/-) knockout mice and from
controls . The ability of cannabidiol to impair the
migration of tumor cells was independent of CB1 and CB2
receptor activation . The mechanisms of these effects are
unknown. There is increasing evidence for the existence of
additional cannabinoid receptor subtypes in the brain and
periphery [49-51]. These receptors are more likely to be
functionally related to the known cannabinoid receptors than
have a similar structure, as there is no evidence for additional
cannabinoid receptors in the human genome.
The identification of cannabinoid receptors was followed
by the detection of endogenous ligands for these receptors,
endogenous cannabinoids or endocannabinoids [52-54]. All
endocannabinoids are derivatives of arachidonic acid, thus
differing in chemical structure from phytocannabinoids of
the cannabis plant. To date, five endocannabinoids have been
identified. These are N-arachidonoyl ethanolamide (AEA,
anandamide) , 2-arachidonoyl glycerol (2-AG) [54, 55],
2-arachidonoyl glyceryl ether (noladin ether) , O-
arachidonoyl ethanolamine (virodhamine) , and N-
arachidonoyl-dopamine (NADA) . The most important
of these eicosanoid molecules are anandamide and 2-
arachidonoyl glycerol (see Figs. 2 and 3). Noladin ether was
initially synthesized as a stable analog of 2-AG. Whether it
is present in mammalian brain is controversial, since it was
claimed to be an endocannabinoid by Hanus et al. (2001)
, but could not be detected by another group in
mammalian brains of several species, suggesting that it does
not play a role in the central endocannabinoid system .
Fig. (2). Arachidonoyl ethanolamide (AEA, anandamide).
3.1. Binding to Cannabinoid and Vanilloid Receptors
When protected from enzymatic hydrolysis, anandamide
has a similar affinity to the CB1 receptor as ?9-THC .
Affinity to the CB1 receptor is greater than CB2 affinity.
Anandamide behaves as a full agonist at the CB1 receptor
 and as a partial agonist at the CB2 receptor. This means
that anandamide elicits a lower maximal response than that
of higher efficacy cannabinoid receptor agonists at the CB2
receptor, possessing the mixed agonist-antagonist properties
typical of partial agonists. In one experiment, anandamide
was found to attenuate CB2 receptor mediated responses to
2-AG, which was 3-fold more potent than anandamide .
Fig. (3). 2-Arachidonoyl glycerol (2-AG).
Noladin ether and 2-AG are both cannabinoid receptor
agonists, noladin ether having a much higher affinity for the
CB1 receptor than for the CB2 receptor . Virodhamine is
a partial agonist with in vivo antagonist activity at the CB1
receptor and full agonist activity at the CB2 receptor .
NADA is an agonist at the CB1 receptor .
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 receptors (VR1)
[58, 62, 63]. The VR1 is associated with hyperalgesia and
may play a part in nociception. Since VR1 is also widely
distributed in the skin, it was recently proposed that this
receptor does also play a central role in maturation and
function of epithelial cells .
The historical designation of anandamide as an
“endocannabinoid” seems to be only one part of the
physiological reality, and cannabinoid receptors seem to
amount only to some of the “anandamide receptors”. The
potency and efficacy of anandamide at the vanilloid
receptors is rather low. However, metabolites of anandamide
may serve as endogenous ligands for these receptors .
NADA is a potent vasorelaxant, an effect mediated through
VR1 and CB receptors .
3.2. Production and Metabolism
The first two discovered endocannabinoids, anandamide
and 2-AG, are best studied. They are synthesized in neuronal
cells, including cortical and striatal neurons, but not
astrocytes, and their synthesis is increased in response to
depolarization-induced release is characteristic of classical
neurotransmitters. However, in contrast to classical
Cannabinoids Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 511
neurotransmitters that are being synthesized and stored in
intraneural vesicles, endocannabinoids are produced “on
demand” by cleavage of membrane lipid precursors and
released immediately from cells into the synapse in a
stimulus-dependent manner . The precursor of
anandamide is N-arachidonoyl-phosphatidylethanolamine,
which is hydrolyzed to the endocannabinoid by a
phospholipase D-catalyzed process . After release,
endocannabinoids are rapidly deactivated by uptake into
cells and metabolized. Metabolism of anandamide and 2-AG
occurs by enzymatic hydrolysis by fatty acid amide
hydrolase (FAAH) and monoacylglycerol lipase [53, 68].
FAAH degrades anandamide to arachidonic acid and
ethanolamide. In mice, lack of FAAH resulted in
supersensitivity to anandamide and enhanced endogenous
cannabinoid signaling . Anandamide may also be
converted to other metabolites by lipoxygenase or
cyclooxygenase . Other metabolic processes include
acylation of noladin ether , oxidation of 2-AG and
methylation of the aromatic moiety of NADA.
In all cases, cellular uptake must proceed metabolism
since metabolism occurs only in the cells. Endocannabinoid
uptake by cells seems to happen by “enhanced diffusion”
through the cell membrane [57, 58, 71], even though an
active carrier system has not been detected so far. Simple
passive diffusion following a concentration gradient into the
cells where they are quickly metabolized by FAAH, is
regarded as unlikely, since several substances have been
developed that are thought to inhibit anandamide cellular
uptake without inhibiting FAAH, among them being Arvanil
 and VDM11 , and noladin ether and NADA are
rapidly taken up into cells even though they are rather stable
or refractory to enzymatic hydrolysis [58, 70]. However, the
discussion on the existence of a transport system is not
finished, and one group demonstrated that Arvanil and other
substances regarded as anandamide transport inhibitors
(olvanil, AM404) were actually inhibitors of FAAH .
Intracellular uptake of endocannabinoids is a temperature
dependent and rapid process with a half time of a few
minutes, compared to hours in the case of exogenous plant
As with the gene of the CB1 receptor, there is interest in a
possible contribution of variations of the gene encoding
FAAH to the etiology of diseases. The sparse data on a
possible link between drug abuse and dependence and a
mutation of the FAAH gene and subsequent functional
abnormalities in the endocannabinoid system are conflicting
[75, 76]. A naturally occurring missense gene polymorphism
(FAAH 385 A/A genotype) was reported to be associated
with overweight and obesity .
3.3. Tonic Activity of the Cannabinoid System
When administered alone, cannabinoid receptor
antagonists may behave as inverse agonists in several
bioassay systems. In addition to blocking the effects of
exogenous cannabinoidsm, they may also produce effects
that are opposite in direction from those produced by
cannabinoid receptor agonists, e.g. resulting in hyperalgesia
, suggesting that the endogenous cannabinoid system is
tonically active. 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 endocannabinoid system has been
demonstrated in several conditions. Endocannabinoids have
been shown to be tonically active in the dorsal horn neurons
of the spinal cord, thus attenuating acute nociceptive
transmission at the level of the spinal cord .
Endocannabinoid levels were increased in a pain circuit of
the brain (periaqueductal gray) 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 found in a rat model
of chronic neuropathic pain  and in a mice 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 . Elevated endocannabinoid
levels have been detected in cerebrospinal fluid of
schizophrenic patients . In other models, tonic or
enhanced activity could not been demonstrated, e.g. in a rat
model of inflammatory hyperalgesia .
4. MODULATORS OF THE ENDOCANNABINOID
Exogenous modulators of the endocannabinoid system
comprise cannabinoid receptor agonists (cannabinoids), CB
receptor antagonists and inhibitors of degradation and re-
uptake of endocannabinoids that promote accumulation of
endocannabinoids in situ. Antagonists have allowed a
detailed investigation of mechanisms of cannabinoid actions
and proved that not all cannabinoid effects were mediated by
cannabinoid receptors, but that other mechanisms of action
were involved. Both antagonists and agonist cannabinoids
are under clinical investigation for a broad number of
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 ("classical" vs. "non-classical") with
4.1. Phytocannabinoids and their Metabolites
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.
512 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5Franjo Grotenhermen
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)
, with the chemical structure of perrottetinenic acid in
liverwort being similar to that of ?9-THC in cannabis.
Fig. (4). Cannabidiol.
More than 60 cannabinoids have been detected in
cannabis, mainly belonging to one of 10 subclasses or types
, of which the cannabigerol type (CBG), the
cannabichromene type (CBC), the cannabidiol type (CBD),
the ?9-THC type, and the cannabinol type (CBN) are the
most relevant in quantity. Cannabinoid distribution varies
between different cannabis strains and usually only three or
four cannabinoids are found in one plant in relevant
concentrations. ?9-THC is largely responsible for the
pharmacological effects of cannabis including its
psychotropic properties, but other compounds of the
cannabis plant are involved in these effects .
Concentrations of ?9-THC are below 0.2% in fiber-type
cannabis varieties (hemp) used for the production of fiber
and seeds, and may vary between 2 and 30% in the flowering
tops and upper leaves in the female drug-type cannabis plant
used for recreational and medicinal purposes.
Fig. (5). 11-OH-THC (11-hydroxy-THC).
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 [93, 94]. 11-nor-9-carboxy-THC (THC-
COOH) is the most important non-psychotropic metabolite
Fig. (6). THC-COOH (11-nor-9-carboxy-THC).
4.2. Synthetic Cannabinoids
According to their degree of kinship with the
phytocannabinoids, synthetic cannabinoids may be described
as classical or non-classical derivatives. Among the classical
synthetic cannabinoids that retain the phytocannabinoid ring
structures and their oxygen atoms are nabilone, nantradol,
HU-210, and HU-211. Nabilone is available on prescription
in several countries with a similar pharmacological profile as
THC . HU-210, an analog of ?8-THC with a
dimethylheptyl side chain, is between 80 and 800 times more
potent than THC [96, 97], while its enantiomer (mirror
image) HU-211, is completely devoid of psychoactivity .
The latter, also called dexanabinol, is an NMDA antagonist
with neuroprotective properties in hypoxia and ischemia
. CT3 or ajulemic acid, a derivative of the ?8-THC
metabolite THC-COOH, is under clinical investigation for
inflammation and pain .
Fig. (7). Nabilone.
Levonantradol (Pfizer), a non-classical cannabinoid with
a more radical deviation of the typical structure, was under
clinical investigation for the treatment of pain  and the
side effects of chemotherapy  and radiotherapy .
Other non-classical cannabinoids are the aminoalkylindol
WIN-55,212-2, which has a 6.75-fold affinity towards the
CB2 receptor  and the bicyclic cannabinoid analog CP-
55,940, a widely-used agonist for the testing of cannabinoid
receptor affinity with potency 4-25 times greater than THC
depending on assay .
Fig. (8). Dexanabinol (HU211).
4.3. Endocannabinoid Analogs
Several anandamide congeners have been synthesized,
among them is (R)-(+)-?-methanandamide that possesses
both a four-fold higher affinity for the CB1 receptor and a
greater catabolic resistance than anandamide. Further
anandamide analogs are arachidonoyl-2'-chloroethylamide
(ACEA) and arachidonoyl cyclopropylamide (ACPA).
4.4. Inhibitors of Endocannabinoid Degradation
Fatty acid-based compounds have been synthesized that
mimic the structure of anandamide, but act as inhibitors of
membrane transport or of the catabolic enzyme FAAH .
The first of these compounds was N-(4-hydroxyphenyl)
arachidonoylamide, usually designated as AM404. AM404
increases the plasma levels of anandamide in rats and causes
a time-dependent decrease of motor activity, which is
reversed by a cannabinoid CB1 receptor antagonist . It
is unclear whether AM404 is a selective inhibitor of
Cannabinoids Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 513
anandamide transport or an inhibitor of FAAH . It also
activates vanilloid receptors and binds to CB1 receptors, but
it does not seem to be a CB1 receptor agonist or antagonist
. Another inhibitor of membrane transport or FAAH is
VDM-11, which also binds to CB1 receptors.
Fig. (9). CT3 (ajulemic acid, IP751).
A frequently used inhibitor of FAAH is
phenylmethylsulfonyl fluoride (PMSF). The irreversible
FAAH inhibitors palmitylsulphonoyl fluoride (AM374) and
stearylsulphonoyl fluoride (AM381) are approximately 20
times more potent than PMSF in preventing the hydrolysis of
anandamide in brain homogenates . They both are only
weak CB1 receptor ligands . Even more potent FAAH
inhibitors have recently been developed .
4.5. Cannabinoid Receptor Antagonists
The first reported antagonist of a cannabinoid receptor
binding site was announced by Rinaldi-Carmona et al.
(1998) as the potent and orally-active CB1-selective
compound, SR141716A, that is also called rimonabant
(Acomplia®) in clinical studies . Rimonabant is a
diarylpyrazole and the majority of CB1 receptor antagonists
can be regarded as a structural modification of this molecule
. A CB2 selective antagonist synthesized by the same
group at Sanofi-Synthelabo is SR144528. Both also bind to
the other receptor type in higher concentrations. Further CB
receptor antagonists with CB1 selectivity are the
diarylpyrazoles AM251 and AM281, and the substituted
benzofuran LY320135. A CB2 selective antagonist is the
aminoalkylindole 6-iodopravadoline (AM630). Several
pharmaceutical companies besides Sanofi-Synthelabo have
patented CB receptor antagonists, among them being Pfizer,
Bayer, Merck, Solvay Pharmaceuticals, Hoffmann-La Roche
and AstraZeneca .
4.6. Affinity to the Cannabinoid Receptor
Both antagonists and CB receptor agonists show different
affinity to CB1 and CB2 receptors. Synthetic cannabinoids
have been developed that act as highly selective agonists at
one of these receptor types [111, 27]. Several synthetic
cannabinoid receptor agonists with significant selectivity for
CB2 receptors have a classical structure (L-759633, JWH-
133, HU-308). The hydroxy group of THC has been replaced
by a methoxy group or removed in these molecules. A
potentially important class of CB1 receptor selective agonists
are anandamide analogs, including (R )-(+)-? -
methanandamide, ACEA and ACPA.
?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.
The affinity to CB receptors and the pharmacological
activity of ?9-THC is stereoselective, with the natural (-)-
trans isomer (dronabinol) being 6-100 times more potent
than the (+)-trans isomer depending on the assay . Not
all phytocannabinoids are agonists to the cannabinoid
receptor. The mechanism of action and the pharmacology of
CBD considerably differ from that of THC. As with THC
and other phytocannabinoids, the natural CBD is a (-)-
enantiomer. However, in contrast to (-)-?9-THC, (-)-
cannabidiol does not have a significant affinity to
cannabinoid receptors, while its synthetic (+)-enantiomer
Fig. (10). Cannabinoid receptor antagonists, SR 141716A (A), a
selective CB1 receptor antagonist,and SR 144528 (B), a selective
CB2 receptor antagonist.
The best-studied modulator of the endocannabinoid
system is the phytocannabinoid and CB receptor agonist ?9-
THC. While THC is still favored in clinical studies; basic
research is often conducted with more potent CB receptor
agonists, such as WIN55,212-2, HU-210 and CP-55,940.
5.1. ? ?9-THC and Other CB Receptor Agonists
The majority of THC effects are mediated through
agonistic actions at cannabinoid receptors. Some non-CB
mediated effects of THC and synthetic derivatives have also
been described, e.g. some effects on the immune system
, some neuroprotective effects , and anti-emetic
effects. The anti-emetic effects of THC are reported to be in
part mediated by CB1 receptors  and in part by non-CB
mechanisms; the rationale for the clinical use of THC as an
anti-emetic in children receiving cancer chemotherapy .
Due to the lower CB1 receptor density in the brain of
children compared with adults, they tolerated relatively high
514 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 Franjo Grotenhermen
doses of ?8-THC in a clinical study, without significant CB1
receptor mediated adverse effects . In a study with cells
stably transfected with the human 5-HT3A receptor, several
(endo)cannabinoids (THC, WIN55,212-2, anandamide, etc.)
directly inhibited currents induced by 5-hydroxytryptamine
. Since 5-HT3 antagonists are potent anti-emetic drugs,
this may be one mechanisms by which cannabinoids act as
It is possible that several effects previously thought to be
non-receptor mediated are mediated by cannabinoid receptor
subtypes that have not yet been identified.
The activation of the cannabinoid system via
phytocannabinoids such as THC, and synthetic and
endogenous cannabinoids causes numerous actions that have
been extensively reviewed [113, 120-128]. Some effects of
cannabinoid receptor agonists show a biphasic behavior in
dependency of dose, e.g. low doses of anandamide
stimulated phagocytosis and stimulated behavioral activities
in mice, while high doses decreased activities and caused
inhibitory effects on immune functions .
Psyche, Cognition and Behavior
In many species, the behavioral actions of low doses of
THC are characterized by a unique mixture of depressant and
stimulant effects in the CNS . In humans, THC or
cannabis consumption, respectively, is usually described as a
pleasant and relaxing experience. Use in a social context
may result in laughter and talkativeness. Occasionally, there
are unpleasant feelings such as anxiety that may escalate to
panic. A sense of enhanced well-being may alternate with
dysphoric phases. THC improves taste responsiveness and
enhances the sensory appeal of foods . It may induce
sleep [130, 131].
Acute THC intoxication impairs learning and memory
[132-134], and adversely affects psychomotor and cognitive
performance , reducing the ability to drive a car and to
operate machinery. Reduced reaction time also affects the
iris constriction response of the eye. A brief light flash
shows decreased amplitude of constriction and a decelerated
velocity of constriction and dilation . Tolerance may
develop to the impairment of psychomotor and cognitive
performance with long-term use. In a study that compared
information processing in heavy cannabis users with non-
users there was no difference when users were under the
influence of the drug, while there were significantly slowed
information-processing speeds in the subacute phase in the
cannabis users, which may be attributed to withdrawal .
The most conspicuous psychological effects of THC in
humans have been divided into four groups: affective
(euphoria and easy laughter), sensory (increased perception
of external stimuli and of the person’s own body), somatic
(feeling of the body floating or sinking in the bed), and
cognitive (distortion of time perception, memory lapses,
difficulty in concentration) .
These effects only appear if an individually variable
threshold of dose is exceeded. During a study on the efficacy
of dronabinol (THC) in 24 patients with Tourette's syndrome
who received up to 10 mg THC daily for 6 weeks no
detrimental effects were seen on neuropsychological
performance (learning, recall of word lists, visual memory,
divided attention) .
Stress, Anxiety and Fear
The endocannabinoid system may serve as a novel
approach to the treatment of anxiety-related disorders.
Endocannabinoid signaling negatively modulates the
function of the hypothalamic-pituitary-adrenal axis in a
context-dependent manner . Upon exposure of mice to
acute stress, hypothalamic 2-arachidonoyl glycerol content
was reduced compared with the control value; however, after
5 days of stress, which resulted in an attenuated
corticosterone response, the hypothalamic 2-AG content was
increased compared with the control value. The CB1 receptor
agonist CP55940 reduced blood corticosterone levels in
stressed mice, while a CB1 receptor antagonist increased
corticosterone concentrations . A similar effect was
achieved by the administration of the putative
endocannabinoid transport inhibitor AM404, or the FAAH
inhibitor URB597. Another group observed reduced
hippocampal 2-AG levels following chronic stress .
Chronic stress impaired reversal learning and induced
perseveratory behavior in the Morris water maze, an
impairment that was reversed by exogenous cannabinoid
administration, suggesting deficient endocannabinoid
signaling. Data on the effects of cannabinoids on stress are
conflicting. In humans, cannabis may cause anxiety and
panic, reactions that may be potentiated by stress. Animal
research demonstrated that there may be a synergistic
interaction between stress and CB1 receptor agonists (THC,
CP55940) in the effects on amygdalar activity .
CB1-deficient mice showed strongly impaired short-term
and long-term extinction of aversive memories , and
blockade of the CB1 receptor in rats led to a dose-dependent
decrease in extinction of conditioned fear . These
effects may explain the anxiety reducing effects in
posttraumatic stress disorder and similar conditions.
However, in contrast to AM404, which enhanced the
extinction of conditioned fear, the administration of the CB1
agonist WIN 55,212-2 did not appear to affect extinction
One important physiological role of endocannabinoids
seems to be neuroprotection . Ischemia and hypoxia in
the CNS induce abnormal glutamate hyperactivity and other
processes that cause neuronal damage. These processes also
play a role in chronic neurodegenerative diseases such as
Parkinson’s and Alzheimer’s disease and multiple sclerosis.
Neuroprotective mediators are also released in ischemia and
hypoxia, including anandamide and 2-AG. When these two
endocannabinoids were administered after traumatic brain
injury in animals, they reduced brain damage .
Neuroprotective cannabinoid mechanisms observed in
animal studies include reduction of glutamate toxicity by
inhibition of excessive glutamate production, inhibition of
calcium influx into cells, anti-oxidant properties which
reduce damage caused by oxygen radicals and modulation of
vascular tone [99, 116, 146]. Cannabinoids reduce brain
inflammation. The CB agonist WIN55,212-2 reduced the
production of several key inflammatory mediators by
activated human astrocytes, including NO (nitric oxide),
Cannabinoids Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 515
TNF-alpha (tumor necrosis factor alpha), and several
chemokines . CB1 receptors seem to play a major role
in neuroprotection by endocannabinoids, since CB1(-/-) mice
showed little spontaneous recovery after closed head injury
compared to controls . Receptor-stimulated inhibition
of protein kinase A was reported to be required for the
neuroprotective effects of CB1 receptor activation .
THC was neuroprotective in rats given the toxic agent
ouabain. THC treated animals showed reduced volume of
edema by 22% in the acute phase and 36% less nerve
damage after 7 days . CB1 and CB2 receptor agonists
reduce amyloid-beta toxicity in vitro and in vivo [151, 152].
Enhanced amyloid-beta peptide deposition along with glia
cell activation in senile plaques plays a major role in the
pathology of Alzheimer's disease (AD). CB1 positive
neurons are greatly reduced in areas of microglial activation,
and CB1 receptor protein expression is markedly decreased
in AD brains . Amyloid-beta induced activation of
microglial cells, cognitive impairment and loss of neuronal
markers was prevented by cannabinoids in rats .
THC can induce tachycardia  and increase cardiac
output with increased cardiac labor and oxygen demand
. It can also produce peripheral vasodilation, orthostatic
hypotension [125, 154] and reduced platelet aggregation
. Data on cerebral blood flow effects are contradictory.
Regional increases and decreases of blood flow with no
mean change of flow were reported by one group ,
while a recent report suggests that systolic velocity and the
pulsatility index, a measure of cerebrovascular resistance,
were significantly increased in cannabis users . These
effects persisted in heavy users for more than one month of
monitored abstinence and were regarded as a partial
explanation for cognitive deficits in heavy cannabis users.
In young healthy subjects, the heart is under control of
the vagus that mediates bradycardia. Tachycardia by THC
may easily be explained by vagal inhibition (inhibited
release of acetylcholine) through presynaptic CB1 receptors
, which can be attenuated by beta-blockers  and
blocked by the selective CB1 antagonist SR141716A .
Regular use can lead to bradycardia . The
endocannabinoid system plays an important role in the
control of blood pressure. Hypotension is mediated by
central inhibition of the sympathetic nervous system,
apparently by activation of CB1 receptors, since this effect
can also be prevented by a CB1 antagonist .
Endocannabinoids are produced by the vascular
endothelium, circulating macrophages and platelets .
Vascular resistance in the coronaries and the brain is lowered
primarily by direct activation of vascular cannabinoid CB1
Appetite, Eating and Digestion
The endogenous cannabinoid system plays a critical role
in milk ingestion of new-born mice . Blockade of the
CB1 receptor results in death of new-borns .
Anandamide induces over-eating in rats through a CB1
receptor mediated mechanism . Endocannabinoids in
the hypothalamus are part of the brain's complex system for
controlling appetite including a significant component that is
regulated by leptin . Leptin is a major signal through
which the hypothalamus senses nutritional state and
modulates food intake and energy balance. Leptin reduces
food intake by upregulating appetite-reducing neuropeptides,
such as alpha-melanocyte-stimulating hormone, and
downregulating appetite-stimulating factors, primarily
neuropeptide Y. In animal research, reduced levels of leptin
were associated with elevated levels of endocannabinoids in
the hypothalamus, and application of leptin reduced
endocannabinoid levels . Cannabinoid-induced eating is
ascribed to an increase of the incentive value of food .
Cannabinoid agonists inhibit gastrointestinal motility and
gastric emptying in rats . In a study with humans, THC
caused a significant delay in gastric emptying . In
addition, CB agonists inhibited pentagastrin-induced gastric
acid secretion in the rat , mediated by suppression of
vagal drive to the stomach through activation of peripheral
CB1 receptors [169, 170].
Animal and cell experiments have demonstrated that
THC exerts complex effects on cellular and humoral
immunity [171, 172]. It is not clear; to what extent these
effects are of clinical relevance in humans with respect to
beneficial (inflammation [173, 174], allergies ,
autoimmune processes ) and undesirable effects
(decreased resistance towards pathogens and carcinogens)
. THC was shown to modulate the immune response of
T lymphocytes . It suppressed the proliferation of T
cells and changed the balance of T helper 1 (Th1) and T
helper 2 (Th2) cytokines. It decreased the pro-inflammatory
Th1 reaction (e.g. the production of interferon-gamma) and
increased the Th2 reaction. This may explain why THC is
effective against inflammation with a strong Th1 reaction,
e.g. in multiple sclerosis, Crohn's disease and arthritis. The
regulation of the activation and balance of human Th1/Th2
cells seems to be mediated by a CB2 receptor-dependent
Additional Organ Systems and Effects
Antiviral actions. Incubation with THC reduced the
infectious potency of herpes simplex viruses .
Micromolar concentrations of THC inhibit Kaposi's Sarcoma
Associated Herpes virus and Epstein-Barr virus reactivation
in virus infected B cells .
THC also strongly inhibited lytic replication of several
oncogenic viruses in vitro .
Bones and cartilage. Preliminary observations presented
by Mechoulam et al. in 2003 at the First European
Workshop on Cannabinoid Research in Madrid, Spain, show
that endocannabinoids seem to stimulate bone formation.
During differentiation, osteoblast precursor cells have
progressively increased levels of CB2 but not of CB1 as
measured by reverse transcription polymerase chain reaction.
In addition, normal mice treated systematically with 2-AG
showed a dose dependent increase in trabecular bone
formation. The peptide leptin is not only known to
negatively regulate endocannabinoid activity in appetite
516 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5Franjo Grotenhermen
control, but also to influence osteoblastic activity. Results of
experimental research by another group suggest that some
cannabinoids may prevent cartilage resorption, in part, by
inhibiting proteoglycan degradation and also by inhibiting
cytokine production of chondrocytes induced by the free
radical nitric oxide (NO) .
Eye. The evidence of cannabinoid receptors at different
sites (anterior eye, retina, corneal epithelium) suggests that
cannabinoids influence different physiological functions in
the human eye . Vasodilation in the eye is observed as
conjunctival reddening after THC exposure . THC and
some other cannabinoids decrease intraocular pressure [180,
181]. CB1 receptors in the eye are involved in this effect,
while CB2 receptor agonists do not reduce intraocular
Genetic and cell metabolism. THC can inhibit DNA,
RNA, and protein synthesis, and can influence the cell cycle.
However, very high doses are required to produce this effect
in vitro . Cannabinoid agonists inhibited human breast
cancer cell proliferation in vitro [184, 185], and, directly
applied at the tumor site, showed antineoplastic activity
against malignant gliomas in rats .
Hormonal system and fertility. THC interacts with the
hypothalamic-pituitary adrenal axis influencing numerous
hormonal processes . Minor changes in human
hormone levels due to acute cannabis or THC ingestion
usually remain in the normal range . Tolerance
develops to these effects, however, and even regular
cannabis users demonstrate normal hormone levels.
Pregnancy. Anandamide levels during pregnancy show a
characteristic pattern . Mean plasma levels were 0.9 nm
in the first trimester and 0.4 nm in the second and third
trimester. During labor, anandamide plasma levels rose to
2.5 nm. Postmenopausal and luteal-phase levels were similar
to those in the first trimester. It is currently unclear whether
implantation of the embryo can be disrupted by THC.
Sperm. After several weeks of daily smoking 8-10
cannabis cigarettes, a slight decrease in sperm count was
observed in humans, without impairment of their function
. In animal studies high doses of cannabinoids inhibited
the acrosome reaction .
Endocannabinoids and Inhibitors of
Several similarities have been described between
endocannabinoids, with regard to their pharmacology and
medicinal effects . Inhibitors of endocannabinoid
degradation may be promising candidates for therapeutic
modulation of the endocannabinoid system.
receptor agonists and
FAAH inhibitors produced analgesia in animal models
 and AM404 reduced the expression of c-fos, a marker
of activated neurons in an experimental model of
neuropathic pain . In the latter study, both CB1 and CB2
receptors as well as vanilloid receptors were involved in the
observed effect. Another group demonstrated that blockers
of anandamide hydrolysis were able to reduce anxiety in
animal tests . These benzodiazepine-like properties
were accompanied by augmented brain levels of anandamide
and were prevented by CB1 receptor blockade. Recently, it
has been shown that two selective inhibitors of the putative
endocannabinoid transporter and hence of endocannabinoid
inactivation, provide an effective therapy for Theiler murine
encephalomyelitis, a virus-induced demyelinating disease
and an animal model of multiple sclerosis . Treatment
of infected mice with the transport inhibitors OMDM1 and
OMDM2 enhanced anandamide levels in the spinal cord,
ameliorated motor symptoms and decreased inflammatory
responses. This effect resembles that of exogenous
cannabinoid receptor agonists .
However, there are several differences in the
pharmacology of exogenous cannabinoids and
endocannabinoids . An animal study found cross-
tolerance between THC and anandamide for antinociception,
but not for suppression of spontaneous activity, catalepsy
and hypothermia in mice tolerant to THC . These
results suggest that the pharmacology of anandamide only
partially overlaps with that of THC and other exogenous
Some non CB effects of anandamide may be mediated by
vanilloid receptors. For example, inhibition of cell
proliferation of rat C6 glioma cells by endocannabinoids was
reported to involve combined activation of both vanilloid
receptors and to lesser extent, cannabinoid receptors .
The vasodilation caused by anandamide in the splanchnic
arteries was also reported to be mediated by both CB1 and
vanilloid receptors .
While anandamide and 2-AG have similar affinities to
the CB1 and to the CB2 receptor, there seem to be differences
in their pharmacology. 2-arachidonoyl glycerol was shown
to induce the migration of natural killer cells, which was
abolished by treatment with a CB2 receptor antagonist
(SR144528) . In contrast to 2-AG, anandamide and
THC did not induce the migration. In fact, the combined
application of THC and 2-AG abolished the migration
induced by the latter . Experiments with rat
hippocampal slices provide another example for differences
in the effects of anandamide and 2-AG . While 2-AG
reduced paired-pulse depression of population spikes
mediated by CB1 receptors, anandamide increased paired-
pulse depression by acting on hippocampal vanilloid
The mode of action of cannabidiol is not fully understood
and several mechanisms have been proposed: (1) CBD acts
as antagonist at the central CB1 receptor and was able to
inhibit several CB1 mediated THC effects . In a study
by Petitet et al. (1998) , CBD considerably reduced the
receptor activation by the potent classical CB1 receptor
agonist CP55940. (2) CBD stimulates the vanilloid receptor
type 1 with a maximum effect similar in efficacy to that of
capsaicin . (3) CBD inhibits the uptake and hydrolysis
of the endocannabinoid anandamide, thus increasing its
concentration [202, 203]. (4) Finally, CBD may also increase
the plasma THC level  by inhibiting hepatic
microsomal THC metabolism through inactivation of the
cytochrome P-450 oxidative system [205, 206]. However,
there was no or minimal effect of CBD on plasma levels of
THC in man [207, 208].
Cannabinoids Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 517
In a study that analyzed the mode of action of the anti-
inflammatory and anti-hyperalgesic effects of CBD,
simultaneous administration of a VR1 receptor antagonist
fully reversed the anti-hyperalgesic effects . A CB2
receptor antagonist was partly effective and a CB1 receptor
antagonist had no effect. The anti-inflammatory efficacy of
CBD was unrelated to cyclooxygenase (COX) activity, but
CBD inhibited the endothelial isoform of nitric oxide
synthase (eNOS). In a rat model of arthritis, low doses of
CBD decreased prostaglandin E2, nitric oxide and lipid
peroxide level, mediators that are all known to be involved
in the development and maintenance of arthritis .
CBD exerts sedating , anti-epileptic , anti-
dystonic , anti-emetic , and anti-inflammatory
[214, 215] effects. It reduced intraocular pressure , was
neuroprotective , and antagonized the psychotropic and
several other effects of THC .
5.4. THC Metabolites and Derivatives
After intravenous administration in humans, 11-OH-THC
was equipotent to THC in causing psychic effects and
reduction in intraocular pressure . In some
pharmacological animal tests, 11-OH-THC was 3 to 7 times
more potent than THC .
THC-COOH possesses anti-inflammatory and analgesic
properties by mechanisms similar to non-steroidal anti-
inflammatory drugs (NSAIDs) [218-220]. Typical properties
of NSAIDs apparently not shared by THC-11-oic acid are
the major adverse effects of NSAIDs, namely,
gastrointestinal and kidney toxicity . The precise basis
for this difference is not well-understood; however, it may be
partly due to a selective inhibition by THC-11 oic acid for
COX-2 vs COX-1 (cyclooxygenase). THC-COOH
antagonizes some effects of the parent drug through an
unknown mechanism, e.g. the cataleptic effect in mice .
Ajulemic acid (CT3), a synthetic derivative of THC-COOH,
shows a similar pharmacological profile as the natural
substance. Recently, a possible mechanism of action was
proposed for this derivative . Ajulemic acid binds
directly and specifically to the peroxisome proliferator-
activated receptor gamma
pharmacologically important member of the nuclear receptor
superfamily. In addition, it was shown that ajulemic acid
inhibited interleukin-8 promoter activity in a PPARgamma-
dependent manner, suggesting a link between the anti-
inflammatory action of the cannabinoid acid and the
activation of PPARgamma. Additionally, CT3 binds to CB1
and CB2 receptors, but has a more limited brain access and is
somewhat better tolerated than THC .
SR141716A was able to block the psychological and
physiological effects of THC in humans in a dose-dependent
manner . Three mechanisms are proposed to account
for inverse cannabimimetic effects of antagonists, (1)
antagonism of endocannabinoids, (2) modulation of CB1
receptors, possibly through an allosteric mechanism shifting
them from a constitutively active state to an inactive state,
(3) CB1 receptor-independent mechanisms, for example
antagonism at A1 receptors of endogenous adenosine .
Experiments with mice lacking CB1 receptors (CB1-/- mice)
or with tissues from CB1-/- mice suggest that rimonabant
(SR141716A) produces at least some of its effects by
binding to CB1 receptors. CB1 receptor knockout mice eat
less than their wild-type littermates . SR141716A has
been found to reduce food intake in CB1+/+ mice but not in
CB1-/- mice .
Reviews of the pharmacological effects of cannabinoid
receptor antagonists are presented by Pertwee (2005) and
Lange and Kruse (2004) [110, 224]. Among the effects of
CB1 antagonists reported are increased locomotor activity in
rats and mice, improvement of memory in rats and mice,
increased nociception (inflammatory and neuropathic pain or
allodynia) in rats and mice, evocation of emesis in shrews,
spasticity and tremor in a mouse model of multiple sclerosis,
accelerated intestinal transit in rats and mice, increase of
severity of induced colitis in mice, and decrease of milk-
ingestion and growth in mouse pups. Schlicker and
Kathmann (2001) reviewed the inverse cannabimimetic
effects of SR141716A on neurotransmitter release in vitro,
among them being the evocation of acetylcholine release,
noradrenaline release, GABA release, dopamine release,
glutamate release, and D-aspartate release in several brain
tissues in rats, mice and guinea-pigs .
The effects of physiological or increased
endocannabinoid levels may be reduced by the application of
CB antagonists as proven in several animal models.
Rimonabant may produce hyperalgesia due to the blockade
of endocannabinoid effects . Increased anandamide and
2-arachidonoyl glycerol levels are observed in basolateral
amygdala complex of auditory fear-conditioned mice.
Endocannabinoids are thought to promote extinction of
aversive memories in these animals, a process that was
impaired by the application of rimonabant .
Endocannabinoid concentrations are also elevated in the
brain and spinal cord of spastic mice with chronic relapsing
experimental allergic encephalomyelitis (CREAE).
Spasticity in these animals may be exacerbated by the CB1
receptor antagonist .
6. THERAPEUTIC POTENTIAL
Cannabis preparations and single cannabinoids have been
employed in the treatment of numerous diseases [123, 126,
127, 226]. Besides phytocannabinoids, several synthetic
cannabinoid derivatives are under clinical investigation that
are devoid of psychotropic effects or have fewer side effects.
Antagonists at the CB1 receptor have followed and inhibitors
of endocannabinoid degradation will presumably follow.
6.1. Cannabinoid Receptor Agonists
Clinical studies with single cannabinoids and whole plant
preparations (smoked cannabis, encapsulated cannabis
extract, sublingual liquid preparations) have often been
inspired by anecdotal experiences of patients employing
crude cannabis products. The anti-emetic , and the
appetite enhancing effects , muscle relaxation ,
analgesia , and therapeutic use in Tourette's syndrome
 were all discovered or re-discovered in this manner.
518 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5Franjo Grotenhermen
Incidental observations have also revealed therapeutically
useful effects. This occurred in a study of Volicer et al.
(1997) in patients with Alzheimer's disease, wherein the
primary issue was an examination of the appetite-stimulating
effects of ?9-THC . Not only appetite and body weight
increased, but disturbed behavior among the patients also
decreased following the intake of the drug. The discovery of
decreased intraocular pressure with THC administration in
the beginning of the 1970s was also serendipitous ,
when several research groups screened for effects of
cannabis on the human body. The investigation of anti-
cancer effects of THC and other cannabinoids was
stimulated by a long-term animal study in rats and mice that
studied possible cancer causing actions of THC .
Several surveys have shown that cannabis is self-
administered to treat a broad range of chronic illnesses. The
largest of these investigations with 2969 returned
questionnaires conducted in the United Kingdom revealed
that cannabis was used by a considerable percentage of
patients, in chronic pain (25%), multiple sclerosis (22%),
depression (22%), arthritis (21%) and neuropathy (19%)
. Sixty-eight per cent said cannabis considerably eased
their symptoms. Another survey among 252 HIV patients, of
whom 175 (69%) were on antiretroviral therapy (ART)
found that those who suffered from nausea were about three
times more likely to adhere to ART if they used cannabis
compared to non-users .
Several states of the United States allow the medical use
of cannabis and some of them have established an
identification card system. In Oregon, about 10,000 subjects
are registered card-holders with recommendations by about
1,500 physicians (http://www.dhs.state.or.us/publichealth
/mm/data.cfm). Since September 2003, cannabis is available
in Dutch pharmacies, distributed by the Office of Medicinal
Cannabis of the Health Ministry. In Canada, patients may
apply to the Health Ministry for a legal use of cannabis on
the basis of recommendations by their physicians.
Besides THC (Marinol?, Solvay Pharmaceuticals),
several whole cannabis plant preparations are currently under
clinical investigation, including Cannador? of the Institute
for Clinical Research in Berlin, Germany, a capsulated
cannabis extract, and Sativex? of the British company GW
Pharmaceuticals, an under the tongue spray. Cannador and
Sativex are both standardized on THC and CBD content,
Sativex containing equal amounts of the two cannabinoids
and Cannador containing more THC than CBD. At the
Center for Medicinal Cannabis Research at the University of
California, the therapeutic potential of smoked cannabis and
inhaled cannabis by means of a vaporizer are investigated.
Hierarchy of Therapeutic Effects
Possible indications for cannabis preparations have been
extensively reviewed [123, 126, 127, 226, 237-240]. To do
justice to the scientific evidence with regard to different
indications, a hierarchy of therapeutic effects can be devised,
with established effects, effects with clinical and preclinical
confirmation and effects based on preclinical, mechanistic
studies. However the history of research into the therapeutic
benefits of cannabis and cannabinoids has demonstrated that
the scientific evidence for a specific indication does not
necessarily reflect the actual therapeutic potential for a given
?9-THC (dronabinol, Marinol) is approved in several
countries for medicinal use in refractory nausea and
vomiting caused by antineoplastic drugs used for the
treatment of cancer (for review see: ) and for appetite
loss in anorexia and cachexia of HIV/AIDS patients [228,
241, 242]. These effects can be regarded as established
effects for THC and cannabis. Nabilone (Cesamet?) is the
second cannabinoid available on prescription, against nausea
and vomiting associated with cancer chemotherapy.
In more than 30 studies, THC and nabilone have been
shown to have a similar anti-emetic efficacy as the
phenothiazines . In the 1980s, several clinical studies
with smoked cannabis have been performed in the USA, in
which smoked cannabis was effective similar as THC (for
review see: Musty & Rossi 2001). In the Lynn Pierson
Research Program of New Mexico, 256 subjects who
underwent chemotherapy received either THC or smoked
cannabis, both drugs reduced nausea from 4.5 to 2.0 on
average on a scale between 1 (no problem) and 5 (severe)
and emesis from 4.3 to 1.7 on average . There are no
clinical studies comparing cannabinoids and 5-HT3
(serotonin) antagonists, but a study with healthy subjects
showed that ondansetron was significantly more effective
than smoked cannabis . Nausea and emesis were
induced by syrup of ipecac. Cannabis significantly reduced
ratings of nausea and slightly reduced the incidence of
vomiting compared to placebo, while ondansetron
completely eliminated the emetic effects of ipecac. In a
clinical setting, 5-HT3 antagonists are usually superior to
THC, but the cannabinoid has proven to be effective at least
in some cases of intractable nausea and vomiting .
Animal research demonstrated that THC reinforces the anti-
emetic effects of ondansetron in vomiting produced by
cisplatin , suggesting that a combination of both drugs
may be meaningful in clinical practice.
THC is effective in AIDS wasting and cancer cachexia
. THC (2 x 2.5 mg) was less effective than megestrol
acetate (800 mg daily). However, in these and some other
studies, THC or cannabis may have been underdosed. It
appears that 10 to 20 mg of THC are necessary for the
treatment of weight loss . In HIV-patients with
significant loss of muscle mass, oral THC (10, 20 and 30
mg) and smoked cannabis (1.8, 2.8 and 3.9% THC) caused a
significantly increased caloric intake compared to controls
(HIV-patients without weight loss), but the highest THC
dose was not well-tolerated.
Neuropathic pain seems to be the next indication, which
can be regarded as established for a treatment with cannabis-
based medicines. In 2005 Sativex received approval by
Health Canada for relief of neuropathic pain in multiple
sclerosis. Several case reports and small clinical studies
indicate that THC and cannabis may be effective in treating
several conditions of chronic pain [249-252, 254, 255]. A
review of 2001 concluded that cannabinoids are no more
effective than codeine in controlling chronic pain , and
a commentary noted that cannabinoids may have potential in
treating neuropathic pains, particularly those with spastic
Cannabinoids Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 519
components . A therapeutic potential in neuropathic
pain is supported by experimental data on anti-hyperalgesic
properties of cannabinoid receptor agonists . Later and
studies with a larger patient population confirmed this
assumption. Berman et al. (2004) observed a significant
decrease in pain and improved sleep by two different
cannabis extracts in 48 patients with neuropathic pain from
brachial plexus avulsion . In addition, there are several
reports of pain reduction in multiple sclerosis by THC [260,
261] and cannabis [261, 262]. One recent study observed
significant analgesic effects of THC and Sativex in chronic
pain of different origins (multiple sclerosis, spinal cord
injury, brachial plexus avulsion, stiff-man syndrome, etc.)
. In contrast to these studies, Attal et al. (2004) only
found a therapeutic effect of oral THC in one of seven
patients with chronic refractory neuropathic pain .
Cannabinoid receptor agonists and opiates were shown to
act synergistically in animal models of pain [265-267], a
rationale for the observation of additive effects of THC and
morphine in pain therapy.
Effects with Clinical and Preclinical Confirmation
Several small studies in the 1980s and 1990s investigated
the therapeutic potential of THC, cannabis and nabilone in
spasticity due to spinal cord injury [25, 255, 268] and
multiple sclerosis [255, 268- 272]. This indication is another
target of current interest for cannabis-based drugs [38, 261
273-277]. Spasticity is difficult to treat with available drugs,
as reviewed by Shakespeare et al. (2000) . Only
intrathecal application of baclofen resulted in a significant
improvement in spasticity scores according to the Ashworth
Scale and activities of daily living (ADL). Tizanidine
resulted in improved spasticity but did not improve ADL,
and side effects (sleepiness, dry mouth).
Recent larger placebo controlled trials for the
investigation of the efficacy of cannabis and THC in
spasticity were restricted to multiple sclerosis patients [261,
273, 275-277], and there is only one small study on
cannabinoids in spasticity due to spinal cord injury
conducted in the past few years . Killestein et al. (2002)
were unable to find any benefits of THC and Cannador in
multiple sclerosis patients with severe spasticity, but doses
applied (2 x 2.5 mg or 2 x 5 mg THC) were probably too low
to get the desired therapeutic effects . Other studies
generally indicate significant effects in subjective ratings,
and not in objective spasticity scores [261, 275, 276].
Preliminary results of a first long term study of THC and
Cannador in multiple sclerosis suggest that THC may have
long-term beneficial effects on the course of the disease.
Results of the short-term trial (15 weeks) with eligible 630
patients are conflicting . Eighty per cent of the original
study population participated in a 12 months follow-up
study. In the 15-week study, 657 patients with stable
multiple sclerosis and muscle spasticity received a maximum
daily dose of 10-25 mg THC as single agent or in a cannabis
extract. There was no significant effect of cannabinoids on
objective spasticity scores according to the Ashworth scale,
but patients reported subjective improvements in pain and
spasticity. In the long-term study, there was a significant
improvement of spasticity scores in the THC group.
Cannabinoids may also be effective in some other
movement disorders, including Tourette's syndrome,
dystonia and levodopa-induced dyskinesia [17, 229, 279-
283]. Results were conflicting in two small clinical trials on
cannabinoids in levodopa-induced dyskinesia in Parkinson's
disease. While a study with nabilone (n=7) significantly
improved dyskinesia , a cannabis extract was
ineffective in another investigation (n=19) .
In 1971, during a systematic investigation of its effects in
healthy cannabis users, cannabis reduced intraocular
pressure, suggesting a therapeutic potential in glaucoma. In
the following 12 years, a number of studies in healthy
individuals and glaucoma patients with cannabis and several
natural and synthetic cannabinoids were conducted [233,
286-289]. Cannabis decreased intraocular pressure by an
average 25-30%, occasionally up to 50%, the effect lasting
4-6 h. Neuroprotective benefits of cannabinoids may be of
additional value in preventing damage to the optical nerve
Experiments examining the anti-asthmatic effect of THC
or cannabis in healthy and asthmatic subjects date mainly
from the 1970s, and are all acute studies [290-292]. The
effects of a cannabis cigarette (2% THC) or oral THC (15
mg), respectively, approximately correspond to those
obtained with therapeutic doses of common bronchodilator
drugs (salbutamol, isoprenaline). Experimental research
suggests that cannabinoid receptor agonists possess further
properties that may be of value in asthma. They inhibited
capsaicin-induced bronchial smooth muscle contraction and
reduced inflammation of the respiratory tract by blocking the
release of the inflammatory cytokine tachykinin .
Several phytocannabinoids possess an anti-allergic potential.
THC and cannabinol attenuated the increase of the
interleukins IL-2, IL-4, IL-5, and IL-13 in reaction to
sensitization with ovalbumin in mice. In addition, the
elevation of serum IgE and the mucus overproduction
induced by ovalbumin was markedly attenuated by the two
A few studies investigated anxiolytic properties of
nabilone [39, 294, 295]. In one of these investigations, 25
outpatients suffering from anxiety received either placebo or
nabilone over a 28-day treatment period . Those treated
with the verum showed a dramatic improvement in anxiety.
THC was shown to reduce agitation in patients with
Alzheimer's disease. Results of a small placebo controlled
trial  were confirmed by Ross and Shua-Haim in a
phase II open label parallel-group study involving 54
patients. The latter findings were presented at the American
Society of Consultant Pharmacists' annual meeting in
November 2003. Evaluation at nine weeks of treatment with
2 x 2.5 or 2 x 5 mg THC found significant reductions of
agitation scores in both groups. There also was a trend
towards a decrease in the caregiver burden scores.
In addition to the indications, above, there are several
indications, in which benefits are generally implied in case
reports. These include allergies , inflammation ,
epilepsy , intractable hiccups , depression ,
bipolar disorders , dependency to opiates and alcohol
[296, 300,], withdrawal symptoms , and post-traumatic
520 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 Franjo Grotenhermen
stress disorder . A first clinical study on THC in post-
traumatic stress disorder of Israeli soldiers is currently under
Preclinical, Mechanistic Studies
Basic research shows promising possible future
therapeutic uses, among them being neuroprotection in
hypoxia and ischemia [99, 116]. Some immunological
mechanisms of THC hint to possible benefits in autoimmune
diseases, such as multiple sclerosis, arthritis, and Crohn's
disease . In a murine model of multiple sclerosis,
cannabinoids significantly improved the neurological deficits
in a long-lasting way. On a histological level, they reduced
microglial activation and decreased the number of CD4+
infiltrating T cells in the spinal cord . Another group
found that amelioration of clinical disease in the same
multiple sclerosis model was associated with downregulation
of myelin epitope-specific Th1 effector functions (delayed-
type hypersensitivity and IFN-gamma production) and the
inhibition of the proinflammatory cytokines, TNF-alpha,
interleukin 1-beta, and interleukin-6 . Raman et al.
(2004) reported that treatment with THC was effective in a
mouse model of amyotrophic lateral sclerosis if administered
either before or after onset of disease signs, which they
attributed to the reduction of oxidative damage and anti-
excitotoxic effects of the cannabinoid in vitro .
Anti-neoplastic activity of THC came into the focus of
research after a long-term animal study, designed to
investigate THC’s potential carcinogenicity, resulted in
better survival of rats dosed with THC than controls due to
lower incidence for several types of cancer . Frequency
of testicular interstitial cell, pancreas and pituitary gland
adenomas in male rats, mammary gland fibroadenoma and
uterus stromal polyp in female rats was reduced in a dose-
related manner. Later studies showed that cannabinoids
exerted antineoplastic activity in malignant gliomas [12,
197], malignant skin tumors , colorectal cancer 
and prostate cancer . CB1 and CB2 receptor agonists
were both effective in some of the studies. Cannabinoids
seem to be able to control the cell survival/death decision
. Thus, cannabinoids may induce proliferation, growth
arrest, or apoptosis in a number of cells depending on dose
. Cannabinoids were also shown to inhibit angiogenesis
of malignant gliomas by at least two mechanisms, direct
inhibition of vascular endothelial cell migration and survival
as well as the decrease of the expression of proangiogenic
factors . On the other hand it should be noted that the
immunosuppressive and proliferative action of THC and
other cannabinoids may have unfavorable consequences on
cancer growth, especially if tumours do not express
cannabinoid receptors [309, 310]. A first human phase I-II
trial to investigate the tolerability and efficacy of
intracranially applied THC in glioblastoma multiforme is
under way in Spain.
Other fields of research with CB agonists include
disorders of circulation and blood pressure [162, 311]. In
rats, daily application of a CB1 agonist after experimental
infarction prevented signs of heart failure, endothelial
dysfunction and hypotension, however, the cannabinoid also
increased left-ventricular end-diastolic pressure, which may
be negative in the long run .
Several effects observed in animal studies provide the
basis for further research, among them are effects against
diarrhea in mice  and stabilization of respiration in
sleep-related breathing disorders (e.g. apnea) .
Cannabinoids were effective in an animal model of attention-
deficit hyperactivity disorder (ADHD), in the spontaneously
hypertensive-rat (SHR) . A very impulsive subgroup of
SHR rats presented a reduced density of CB1 cannabinoid
receptors in the prefrontal cortex of the brain. The
administration of WIN55,212-2 normalized the impulsive
behavioral profile in this subgroup, but had no effect on
6.2. Other Cannabinoids
Two other cannabinoids under clinical investigation are
HU-211, which is also called dexanabinol, and CT3 or
ajulemic acid, which is now called IP751 by Indevus
Pharmaceuticals. The cannabis extracts Cannador and
Sativex contain considerable amounts of cannabidiol (CBD).
The rationale for the combination of THC and CBD is
the observation that CBD reduced the psychic side effects of
THC, which may result in an improved tolerance of the drug.
Simultaneous oral administration of CBD (1 mg/kg) with a
high THC dose (0.5 mg/kg) in healthy volunteers attenuated
the anxiogenic and psychotomimetic symptoms induced by
THC, but not the increase in pulse-rate . Other THC
effects including anti-emesis and anti-inflammation may be
increased, since these therapeutic properties are shared by
CBD, but it cannot be excluded that some therapeutic effects
of THC may be antagonized as well.
In small human studies, CBD was shown to exert potent
anxiolytic and anti-psychotic effects . Oral CBD (300
mg) attenuated anxiety induced in healthy volunteers by
having them prepare a 4-minute speech to a similar extent as
ipsapirone (5 mg) and diazepam (10 mg) . In a single
case study, CBD in increasing doses up to 1500 mg/day was
as effective as an antipsychotic as haloperidol in a
schizophrenic patient, who had significant hormonal side
effects during treatment with a typical antipsychotic .
In an open clinical study with four patients suffering
from Huntington's disease, CBD (2 x 300 mg) reduced
choreic symptoms in three participants (Sandyk et al. 1988,
cited from ). However, these effects could not be
confirmed in a double-blind crossover study with 15 patients
. Cannabidiol caused a 20 to 50 per cent reduction in
various dystonias of five patients . Results from three
controlled clinical studies on CBD in epilepsy were mixed,
but the cannabinoid seems to have some anti-epileptic
Dexanabinol or HU-211 is an antagonist of the NMDA
subtype (NMDA = N-methyl-D-aspartic acid) of the
glutamate receptor . Glutamate is the main excitatory
neurotransmitter in the brain, and excessive activation of
glutamate receptors may mediate neuronal injury or death in
a variety of pathological conditions, including stroke,
mechanical brain trauma, hypoxia and various
neurodegenerative disorders, including Parkinson's
Cannabinoids Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 521
syndrome, amyotrophic lateral sclerosis, neuropathic pain
syndromes and perhaps Alzheimer's disease . HU-211
proved to be neuroprotective in several animal models,
including closed head injury in rats , a model of focal
cerebral ischemia in spontaneously hypertensive rats ,
and optic nerve crush injury in rats . The cannabinoid
also reduced the consequences of experimental autoimmune
encephalomyelitis (EAE), a model of multiple sclerosis
So far, HU-211 has been studied in humans for two
indications, in severe head trauma and for the prevention of
cognitive deficits following coronary artery bypass surgery.
In a phase II double blind clinical trial in patients with severe
head trauma, dexanabinol attenuated elevations of
intracranial pressure and reductions of cerebral perfusion
pressure . A consistent trend towards better overall
outcome as determined by the Glasgow outcome scale was
observed in the severe patient subgroup. However, clinical
phase III studies did not confirm efficacy (Press release of
Pharmos Corporation of 20 December 2004). A phase II
study of dexanabinol for the prevention of cognitive deficits
following heart surgery is under way .
Ajulemic Acid (CT3, IP751)
The anti-inflammatory activity of CT3 was demonstrated
in animal models of acute and chronic inflammation .
The animals did not exhibit evidence of tolerance to ajulemic
acid during 30 days of treatment; a clear divergence in the
mechanism of action between the cannabinoid acids and
other cannabinoids. CT3 also markedly reduced the
behavioral responses to painful stimuli . In unrelated
studies, CT3 appeared to have potent anti-cancer effects
. According to a press release by Indevus
Pharmaceuticals on 7 March 2005, the drug was effective in
an animal model of interstitial cystitis. It significantly
reduced the bladder overactivity associated with the disease,
without affecting the normal voiding mechanism of the
In a first clinical study with 20 subjects who suffered
from chronic pain, CT3 proved to have a significant
analgesic effect without psychic side effects .
6.3. Cannabinoid Receptor Antagonists
A possible therapeutic potential of cannabinoid receptor
antagonists was proposed for obesity , schizophrenia
, in conditions with lowered blood pressure, e.g. liver
cirrhosis  and septic shock , Parkinson's disease
, Huntington's disease , alcohol and nicotine
dependency , heroine addiction , problems in
sexual behavior and sexual performance , asthma 
and to improve memory in Alzheimer's disease . The
idea that CB receptor antagonists may be useful in liver
cirrhosis follows the observation that rats with carbon
tetrachloride-induced liver cirrhosis present with low blood
pressure, which is elevated by SR141716A . The
antagonist also reduced the elevated mesenteric blood flow
and portal pressure. Compared with non-cirrhotic controls, in
cirrhotic human livers, there was a three-fold increase in CB1
receptors on isolated vascular endothelial cells .
Recently, it was reported that the density of CB1 receptors
and the levels of anandamide and 2-AG in the dorsolateral
prefrontal cortex of alcoholic suicides was higher than in a
control group of chronic alcoholics suggesting a
hyperactivity of endocannabinoidergic signaling in alcoholic
suicides and a therapeutic potential for CB1 antagonists
Many of the studies on the therapeutic potential of
cannabinoid receptor antagonists are found in the basic
research literature, and only one paper on clinical research
has been published in peer-reviewed journals . The
compound most clinically advanced is rimonabant,
registered in 2005 for approval in the US and Europe as
Acomplia. Phase IIb clinical data showed that rimonabant in
daily doses of 5, 10 and 20 mg caused a significant weight
loss in a 16-week study (cited according to ). Two
phase III trials were initiated for the treatment of obesity in
August 2001  and by September 2002 for smoking
cessation . Results of these trials showed that the drug
significantly reduced body weight within one year of
treatment (5 or 20 mg rimonabant once daily). The lower
dose resulted in a mean weight reduction of 3.4 kg, the
higher dose in a mean reduction of 6.6 kg, while the placebo
group lost 1.8 kg on average. The higher dose also had a
significant positive effect on blood lipids. Results of the
smoking cessation study were presented at the 53rd annual
scientific meeting of the American College of Cardiology in
March 2004. According to a press release by Sanofi-
Synthelabo, 700 smokers were treated either with 5 or 20 mg
of rimonabant, and about a quarter of the subjects who
received 20 mg stopped smoking in 10 weeks, which was
about twice the quit rate in the placebo group.
7. SIDE EFFECTS
Adverse effects of medical cannabis use are within the
range of effects tolerated for other medications [126, 127].
Long-term medical use of cannabis for more than 15 years
has been reported to be well-tolerated without significant
physical or cognitive impairment .
The median lethal dose (LD50) of oral THC in rats was
800-1900 mg/kg depending on sex and strain . There
were no cases of death due to toxicity following the
maximum oral THC dose in dogs (up to 3000 mg/kg THC)
and monkeys (up to 9000 mg/kg THC) . Acute fatal
cases in humans have not been substantiated. However,
myocardial infarction may be triggered by THC due to
effects on circulation [339, 340]. This is unlikely to happen
in healthy subjects but in persons with coronary heart disease
for whom orthostatic hypotension or a moderately increased
heart rate may pose a risk. The THC derivative nabilone
reduced choreatic movements in Huntington`s disease in a
single case study . Thus, cannabinoid receptor agonists
may be contraindicated in Huntington's disease.
It is controversial whether heavy regular consumption
may have a long-term negative impact on cognition [341-
343], but this impairment seems to be minimal if it exists
[341, 344]. Early users who started their use before the age
of 17 presented with poorer cognitive performance,
522 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5Franjo Grotenhermen
especially verbal IQ compared to users who started later or
Possible reasons for this difference may be (1) innate
differences between groups in cognitive ability, antedating
first cannabis use; (2) a neurotoxic effect of cannabis on the
developing brain; or (3) poorer learning of conventional
cognitive skills by young cannabis users who have eschewed
school and university . In a longitudinal study with
young adults current heavy cannabis use was associated with
reduced overall IQ, processing speed, immediate, and
delayed memory, while former heavy users showed no
difference to non-users . In a twin study cannabis-using
twins significantly differed from their non-using co-twins in
general intelligence . However, this difference was
minimal and authors concluded that these results indicate an
absence of marked long-term residual effects of cannabis use
on cognitive abilities. In a meta-analysis of studies that
investigated residual effects of cannabis on the
neurocognitive performance of adult human subjects, chronic
use was associated with decrements in the ability to learn
and remember new information, whereas other cognitive
abilities were unaffected . There is conflicting evidence
that infants exposed to THC in utero suffer developmental
and cognitive impairment .
Cannabis can induce a schizophrenic psychosis in
vulnerable persons [124, 135], and there is increasing
evidence that there is a distinct cannabis psychosis  and
that cannabis increases the risk to develop a psychosis by
Cannabis use is associated with depression, suicidal
thoughts and attempted suicide . However, a study with
dizygotic and monozygotic twins suggests that this
association may not be causal and that genetic vulnerabilities
make substantial contributions, since the association was
higher in dizygotic than in identical twins . Heavy
cannabis use has been reported to cause an "amotivational
syndrome" . A systematical examination of the mental
health of cannabis users suggests that symptoms associated
with this syndrome are due to depression .
The consequences of the use of THC or cannabis by
patients with liver cirrhosis are unclear. In experimental
studies, activation of the CB2 receptor was shown to cause
antifibrogenic effects . In liver biopsy specimens from
patients with active cirrhosis of various etiologies, CB2
receptors were expressed in non-parenchymal cells. In
contrast, CB2 receptors were not detected in normal human
liver. In cultured hepatic myofibroblasts and in activated
hepatic stellate cells activation of CB2 receptors triggered
potent antifibrogenic effects, namely, growth inhibition and
apoptosis. On the other, hand an epidemiological study
presented by Hezode et al. at the 39th Annual European
Association for the Study of the Liver Conference in April
2004 suggests that daily use of cannabis may promote the
development of liver cirrhosis in persons with chronic
hepatitis C, while moderate use did not increase the risk. The
endocannabinoid system was proposed to play an important
role in the vasodilated state in advanced cirrhosis, and
anandamide is regarded as a selective splanchnic vasodilator
. Thus, the use of cannabinoids may have unfavorable
effects in advanced liver cirrhosis.
The harmful effects of combustion products produced by
smoking cannabis have to be distinguished from effects by
cannabis or single cannabinoids . The risks of smoking
cannabis are probably similar to those from smoking other
dried plant material, including tobacco .
Tolerance develops to most of the THC effects ,
among them being the cardiovascular, psychological and
skin hypothermic effects [357, 358], analgesia ,
immunosuppression , corticosteroid release , and
disruption of the hypothalamo-hypophyseal axis ,
causing alterations in endocannabinoid formation and
contents in the brain . In a 30-day study, volunteers
received daily doses of 210 mg oral THC and developed
tolerance to cognitive and psychomotor impairment and to
the psychological high by the end of the study . After a
few days, an increased heart rate was replaced by a normal
or a slowed heart rate. Tolerance develops also to
cannabinoid-induced orthostatic hypotension .
Tolerance can mainly be attributed to pharmacodynamic
changes, presumably based on receptor downregulation
and/or receptor desensitization [363, 364]. Rate and duration
of tolerance varies with different effects. Rats receiving THC
over a period of five days exhibited a decreased specific
binding ranging from 20 to 60% in different receptor sites of
the brain compared to controls . However, in another
study, no significant alteration in receptor binding was
observed after chronic administration of THC resulting in
twenty-sevenfold behavioral tolerance . Chronic
administration of anandamide as well, resulted in behavioral
tolerance without receptor downregulation , and it was
proposed that desensitization of the CB1 receptor might
account for this observation . Tolerance has been
observed to occur together with modified biotransformation
activities with regard to mitochondrial oxygen consumption,
monooxygenase activities, and the content of liver
microsomal cytochrome P450 . However, only a small
proportion of tolerance can be attributed to changes in
After abrupt cessation of chronic dosing with THC,
especially with high doses, withdrawal has been observed in
humans [357, 369]. Subjects complained of inner unrest,
irritability, and insomnia and presented "hot flashes",
sweating, rhinorrhea, loose stools, hiccups, and anorexia.
Withdrawal symptoms in humans are usually mild and the
risk for physical and psychic dependency is low compared to
opiates, tobacco, alcohol, and benzodiazepines [370-372]. A
review of several indicators of the abuse potential of oral
dronabinol in a therapeutic context found little evidence of
such a problem .
A 90-mg dose of rimonabant was well-tolerated in
healthy subjects with a history of cannabis use . In
current clinical studies, doses of 5 to 20 mg are used.
Adverse effects with rimonabant are reported to be transient
and slightly greater than placebo, with the most common
being nausea [334, 374]. A high drop-out rate was reported
for rimonabant's phase III studies in the press (New York
Times of 5 December 2004) which may be due to taste
aversion  and anxiety-like responses .
Cannabinoids Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 523
Further possible side effects of CB1 receptor antagonists
might be appetite loss  and other inverse agonistic
actions at the CB1 receptor observed in vivo, including
hyperalgesia  and inflammation. There is a report of a
subject who developed multiple sclerosis after starting
treatment with rimonabant for obesity , an effect
consistent with reported protective effects of
endocannabinoids in animal models of multiple sclerosis
8. DRUG INTERACTIONS
The knowledge of drug interactions is restricted to THC,
nabilone and cannabis, which are in use for a considerable
time. Not much knowledge is available for other
cannabinoids and cannabinoid receptor antagonists.
Interactions of THC and cannabis with other drugs may
depend on activity on similar effector systems or metabolic
interactions . Since cannabinoids are strongly bound to
proteins, interactions with other protein bound drugs may
also occur. They might also interact with drugs that, such as
THC, are metabolized by enzymes of the cytochrome P-450
complex. However, there was only a minor influence of
cannabis smoking and oral dronabinol on pharmacokinetic
parameters of antiretroviral medication used in HIV infection
and metabolized by cytochrome P-450 enzymes, and the use
of cannabinoids was regarded as unlikely to impair
antiretroviral efficacy . Tobacco and cannabis smoking
cessation was reported to result in elevated blood levels of
antipsychotic medication (clozapine or olanzapine), due to
cessation of induction of cytochrome P4501A2 (CYP1A2) by
smoke constituents .
Other medicines may enhance or attenuate certain actions
of THC or certain actions of these medicines may be
enhanced or attenuated by THC [382, 383]. Moreover, it is
possible that certain effects are enhanced and others reduced,
as is the case with phenothiazines applied against side effects
of cancer chemotherapy. In a study by Lane et al. (1991), a
combination of prochlorperazine and dronabinol was more
effective in reducing unwanted effects of the antineoplastic
medication than the phenothiazine alone, and the incidence
of cannabinoid-induced adverse effects was decreased when
dronabinol was combined with prochlorperazine, which also
has antipsychotic properties . Cannabis, caffeine and
tobacco reduced the blood pressure reactivity protection of
ascorbic acid, probably through their dopaminergic effects
Of greatest clinical relevance is reinforcement of the
sedating effects of other psychotropic substances (alcohol,
benzodiazepines), and the interaction with substances that
act on heart and circulation (amphetamines, adrenaline,
atropine, beta-blockers, diuretics, tricyclic antidepressants,
etc.) [382, 383].
A number of additive effects may be desirable, such as
the enhancement of muscle relaxants, bronchodilators and
anti-glaucoma medication  of analgesia by opiates [265,
267], the antiemetic effect of phenothiazines  and 5-
HT3 antagonists , and the antiepileptic action of
benzodiazepines . THC may antagonize the
antipsychotic actions of neuroleptics  and may improve
their clinical responsiveness in motor disorders . A
combination with other drugs may be desirable not only to
reduce side effects of the single drugs, but also to prevent the
development of tolerance. In animals studies, tolerance to
morphine was reduced by simultaneous administration of
THC . Chronic treatment with high doses of oral
morphine produced a threefold tolerance of pain-reducing
effects. Tolerance to morphine was prevented in groups
receiving a daily co-treatment with low doses of THC .
Since the cannabinoid system is linked with hormonal
control, there may be interactions in this area. The
progesterone receptor inhibitor mifepristone, which is
approved for the termination of early pregnancy, and the
glucocorticoid synthesis inhibitor, metyrapone, were shown
to potentiate the sedating effects of high THC doses in mice
The cyclooxygenase inhibitors indomethacin,
acetylsalicylic acid, and other non-steroidal anti-
inflammatory drugs antagonize THC effects. Indomethacin
significantly reduced subjective "high" , tachycardia
, decrease of contractile performance in heart muscle
 and decrease of intraocular pressure following topical
THC (eye drops) , reflecting the involvement of
cyclooxygenase activity in several THC effects.
The cannabinoid system plays a major role in signal
transduction in neuronal cells, and anandamide seems to be a
central inhibitory compound in the central nervous system
. Modulators of the cannabinoid system with
therapeutic potential include agonists and antagonists at both
receptors subtypes and inhibitors of endocannabinoid
degradation. Mechanisms of action of endogenous and
exogenous cannabinoids are complex, not only involving
activation of and interaction at the cannabinoid receptor, but
also activation of vanilloid receptors , influence of
endocannabinoid concentration , antioxidant activity
, metabolic interaction with other compounds, and
Due to the millennia-long use of cannabis for
recreational, religious and medicinal purposes, which in
recent decades was accompanied by scientists from several
disciplines, medical CB receptor agonism is predicted to
exhibit previously described side effects or adverse events.
On the other hand, information on possible side effects of
antagonists is still sparse, albeit they usually seem to be
well-tolerated in clinical studies.
The psychotropic effects of CB1 receptor agonists and the
stigma of cannabis as a recreational and addicting drug are
still major obstacles to the legal therapeutic utilization of the
whole range of potentially beneficial effects. In recent years,
large and properly designed clinical studies have been
conducted and further trials are under way or planned to
verify anecdotic experiences and the results from smaller
uncontrolled studies, and to overcome uncertainties and
Apart from CB1 receptor agonists and cannabis
preparations that cause psychic side effects, cannabinoid
524 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 Franjo Grotenhermen
analogs that do not 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 or hydrolysis.
Inhibitors of endocannabinoid degradation may exert the
maximum effect in brain areas where endocannabinoid levels
are already increased in reaction to a disease. It is remarkable
that FAAH inhibitors may already be in clinical use .
The non-steroidal anti-inflammatory agent flurbiprofen,
inhibits the metabolism of FAAH and intrathecally
administrated flurbiprofen reduced inflammatory pain by a
mechanism that was blocked by a CB1 receptor antagonist.
The anaesthetic agent propofol and the non-steroidal anti-
inflammatory drugs indomethacin also activate cannabinoid
receptors as an important part of their actions .
The discovery of the cannabinoid system has accelerated
a broad and exciting field of research, and we are in the
middle of discovering all its facets that may be of use for the
prevention and treatment of illnesses.
= ?9-Tetrahydrocannabinol (dronabinol)
= 2-Arachidonoyl glycerol
ACPA = Arachidonoyl cyclopropylamide
AD= Alzheimer's disease
ADHD= Attention-deficit hyperactivity disorder
ADL= Activities of daily living
AEA= Arachidonoyl ethanolamide (anandamide)
ART= Antiretroviral therapy
cAMP= Cyclic adenosine monophosphate
CB receptor = Cannabinoid receptor
CBD = Cannabidiol
CNR= Cannabinoid receptor gene
CREAE = Chronic
= Corticotropin releasing hormone receptor 1
DNA= Deoxyribonucleic acid
= Experimental autoimmune encephalo-
ERK= Extracellular signal-regulated kinase
FAAH= Fatty acid amide hydrolase
GABA= ?-aminobutyric acid
= G-protein-coupled receptorsGPCR
NMDA= N-methyl-D-aspartic acid
NO= Nitric oxide
NOS = Nitric oxide synthase
NSAID = Non-steroidal anti-inflammatory drug
PMSF = Phenylmethylsulfonyl fluoride
PPARgamma = Peroxisome proliferator-activated receptor
SHR= Spontaneously hypertensive-rat
Th= T helper
TNF= Tumor necrosis factor
VR= Vanilloid receptor
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