The scientific understanding of the endogenous
cannabinoid system consisting of specific cannabinoid receptors
and their endogenous ligands (endocannabinoids) has considerably
increased since 1995. It largely supports and helps explain
many of the therapeutic benefits of cannabis and cannabinoids
In recent years, the results of numerous basic
research studies have been published. Their findings on the
mode of action of cannabinoids provide scientific explanations
for the testimony of patients submitted to the first marijuana
rescheduling proceedings, which adds considerable weight to
their testimony and renders it and other so-called anecdotal
evidence relevant to the existing proceedings.
In 1989, the Administrator of DEA rejected the
recommendation of an Administrative Law Judge that marijuana
be placed in schedule II ( 54 FR 53,767 - 53,785). In those
proceedings, petitioners presented numerous affidavits and
testimony regarding individuals' therapeutic use of marijuana.
According to DEA, this information has no value.
"The evidence presented by the pro-marijuana
parties regarding use of marijuana to treat various other
ailments such as pain, decreased appetite, alcohol and drug
addiction, epilepsy, atopic neuroderatitis, sclerodermia and
asthma was limited to testimony of individuals who had used
marijuana for those conditions and the testimony of the psychiatrists
or general practice physicians mentioned earlier. There is
not a shred of credible evidence to support any of their claims."(
54 Fed. Reg. 53,772 (1989))
Petitioners presented testimony of patients
with multiple sclerosis whose use of marijuana allowed them
to get up out of their wheelchairs and walk, when without
the drug, they could not. According to DEA, these patients
are suffering from drug-induced delusions.
"Why do scientists consider stories from
patients and their doctors to be unreliable? First, sick people
are not objective scientific observers, especially when it
comes to their own health. We have all heard of the placebo
effect. . . Second, most of the stories come from people who
took marijuana at the same time they took prescription drugs
for their symptoms . . . Third, any mind-altering drug that
produces euphoria can make a sick person think he feels better.
. . Fourth, long-time abusers of marijuana are not immune
to illness. Many eventually get cancer, glaucoma, MS and other
diseases. People who become dependent on mind-altering drugs
tend to rationalize their behavior. They invent excuses, which
they can come to believe, to justify their drug dependence."
(57 Fed. Reg. 10,499 (1992))
The discovery of the cannabinoid receptor system
and subsequent basic research on the therapeutic effects of
cannabanoids provides substantial credible evidence to corroborate
these and countless other patient reports. All of this research
provides a sophisticated and widely recognized understanding
on the part of the scientific and medical communities of the
veracity and reliability of the existing record of patient
accounts. In fact, many research studies on the medical uses
of marijuana cite such evidence as part of their scientific
In recent years, it has been established that
most cannabinoid effects are mediated through actions at specific
receptor sites. Cannabinoid receptors and their endogenous
ligands together constitute the "endogenous cannabinoid
system," or the "endocannabinoid system," teleologically
millions of years old (De Petrocellis et al. 1999). Thus,
it has played a physiological role in man and many other species
for a long time.
Some non-receptor mediated effects of phytocannabinoids
and synthetic derivatives have also been described, e.g. some
effects on the immune system (Bueb et al. 2001) and neuroprotective
effects in ischemia and hypoxia (Hampson et al 2002). The
anti-emetic effects of THC are in part non-receptor mediated,
which is the rationale for the clinical use of THC as an anti-emetic
in children receiving cancer chemotherapy (Abramamov et al.
1995). Due to the lower CB1 receptor density in the brain
of children compared to adults, they tolerated relatively
high doses of Delta-8-THC in a clinical study without significant
side effects (Abramamov et al. 1995).
To date, two cannabinoid receptors have been
identified, CB1 receptors (cloned in 1990), and CB2 receptors
(cloned in 1993). CB1 receptors are found mainly on neurons
in the brain, spinal cord and peripheral nervous system, but
are also present in certain peripheral organs and tissues,
among them endocrine glands, leukocytes, spleen, heart and
parts of the reproductive, urinary and gastrointestinal tracts.
CB2 receptors occur principally in immune cells, among them
leukocytes, spleen and tonsils. There is some evidence for
the existence of one or more additional cannabinoid receptor
subtypes (Breivogel et al. 2001, Di Marzo et al. 2000, Pertwee
1999). Activation of the CB1 receptor produces cannabis-like
effects on psyche and circulation, while activation of the
CB2 receptor does not.
The identification of cannabinoid receptors
was followed by the detection of endogenous ligands for these
receptors, or endogenous cannabinoids or endocannabinoids,
a family of endogenous lipids. The most important of these
endocannabinoids are arachidonylethanolamide (anandamide)
and 2-arachidonylglycerol, both of which are thought to serve
as neurotransmitters or neuromodulators (De Petrocellis et
al. 2000, Pertwee 2002).
Endocannabinoids are released from cells in a stimulus-dependent
manner by cleavage of membrane lipid precursors (Giuffrida
et al 2001). After release, they are rapidly deactivated by
uptake into cells via a carrier-mediated mechanism and enzymatic
hydrolysis by fatty acid amide hydrolase (FAAH) (Giuffrida
et al 2001).
The endogenous cannabinoid system has been demonstrated
to be tonically active in several conditions. Endocannabinoid
levels have been demonstrated to be increased in a pain circuit
of the brain (periaqueductal gray) following painful stimuli
(Walker et al. 1999). 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 (Baker et al. 2001). An increase of
cannabinoid receptors following nerve damage was demonstrated
in a rat model of chronic neuropathic pain (Siegling et al.
2001) and in a mice model of intestinal inflammation (Izzo
et al. 2001). 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 (Di Marzo et al. 2001) and with regard to vomiting
in emetic circuits of the brain (Darmani 2001).
Tonic activity of endocannabinoids following
damage (pain, spasticity) and increase of cannabinoid receptor
density provide a strong rationale basis for several therapeutic
effects of cannabis preparations and single cannabinoid receptor
Many animal studies help to understand observations
made in humans, support these observations, or even open the
way for new indications. Some of them published in 2001 and
2002 will be shortly summarized here.
Researchers at the Center for Sleep and Ventilatory
Disorders at the University of Illinois in Chicago investigated
the effects of THC and the endocannabinoid oleamide on sleep,
respiratory pattern and sleep apnoea in rats. Carley et al.
found that THC and oleamide each stabilized respiration during
all sleep stages and decreased apnea (Carley et al. 2002).
Authors derive from their findings an important role for endocannabinoids
in maintaining autonomic stability during sleep. They further
demonstrate potent suppression of sleep apnea by both THC
and endocannabinoids, and that this effect may be relevant
to the medicinal treatment of sleep-related breathing disorders
Researchers at the University of Nottingham
Medical School (UK) are studying the effects of endocannabinoids
on circulation (PA News of 29 December 1998). Anandamide (N-arachidonylethanolamide)
has been shown to be a vasorelaxant, particularly in the resistance
vasculature (arteries), which can reduce blood pressure. The
effects seem to be in part cannabinoid receptor dependent
(Randall et al. 1997) and in part cannabinoid receptor independent
(Plane et al. 1997). The study is being funded with a £120,000
grant from the British Heart Foundation.
The Endocannabinoid system may be involved in
the cardioprotection triggered by lipopolysaccharide (LPS)
(Lagneux & Lamontagne 2001). The cardioprotective effects
of LPS treatment, in terms of infarction and functional recovery
after ischemia in rat hearts, were abolished by a CB(2) receptor
antagonist. A CB(1) receptor antagonist had no effect. "Our
results suggest an involvement of endocannabinoids, acting
through the CB(2) receptors, in the cardioprotection triggered
by LPS against myocardial ischemia," researchers write
in the European Journal of Pharmacology.
In an animal model of Huntington's disease,
the administration of an endocannabinoid uptake inhibitor
(AM404) reduced motor hyperactivity (Lastres-Becker et al.
2002). The application of an uptake inhibitor results in higher
endocannabinoid level acting at CB1 recpetors.
THC and the endocannabinoid anandamide reduced
the time until rats started to eat (Williams & Kirkham
2002). Apart from its rapid onset, cannabinoid-induced eating
retained the normal, species-typical characteristics. Data
suggest that cannabinoids promote eating by increasing the
incentive value of food. Research also suggests that endocannabinoids
are part of the brain's complex system for controlling when
and how much to eat (Di Marzo et al. 2001). It has been known
for some time that leptin is the key hormone for the regulation
of the circuit in the hypothalamus responsible for appetite
control. Leptin reduces food intake by upregulating appetite-reducing
factors and downregulating appetite-stimulating factors. The
finding that endocannabinoids (anandamide and 2-arachidonyl
glycerol) are involved in this process helps explain why people
get hungry after using cannabis or THC and why it helps patients
with loss of appetite and weight. In the study published in
the journal Nature, researchers found that mice lacking CB1
cannabinoid receptors ate less than normal mice did. Also,
when ordinary mice were given the cannabinoid receptor antagonist
SR141716A that blocks endocannabinoids from acting at these
receptors, they ate less than normal as well. Furthermore,
reduced levels of leptin were associated with elevated levels
of endocannabinoids in the hypothalamus, and application of
leptin reduced endocannabinoid levels. These findings indicate
that endocannabinoids in the hypothalamus may activate CB1
receptors to maintain food intake, and that they can act independently
of the level of certain other appetite-triggering substances.
Cannabinoids decrease secretion in the small
intestine. Thus, "they may have therapeutic potential
for diarrhoea unresponsive to available therapies," researchers
of the Oklahoma Foundation for Digestive Research in Oklahoma
City/U.S.A suggest in an article in the European Journal of
Pharmacology (Tyler et al. 2000). Findings show that cannabinoids
inhibit neurally mediated secretion via cannabinoid CB1-receptors
and may be useful for treating some forms of diarrhoea.
An international research group has discovered
why marijuana causes coughing in some situations but may inhibit
bronchospasm and cough in others. This finding could lead
to better treatments of respiratory diseases. In a report
in the journal Nature, scientists from the Institute of Experimental
Medicine in Budapest (Hungary), the University of Naples (Italy)
and the University of Washington (U.S.A) showed how the endocannabinoid
anandamide influences the airways in the lungs. In animal
studies with guinea pigs and rats, anandamide exerted a dual
effect on bronchial responsiveness. If the muscles in the
lungs were constricted by an irritant (capsaicin), the endocannabinoid
relaxed the smooth muscles and strongly inhibited coughing.
But if the airways were relaxed (by removing the constricting
effect of the vagus nerve) anandamide caused a coughing spasm.
"We think that by targeting cannabinoid receptors in
the upper airways we can control coughs in a number of conditions,"
Dr. Daniele Piomelli, one of the researchers of the team and
pharmacologist at the University of California, said in an
interview (Reuters, November 1, 2000). "That's important
because most treatments currently available basically act
on the brain cough centre, a small region of the brain that
is the target for codeine and similar drugs." The group
hopes to begin tests in humans soon.
Researchers of the Virginia Commonwealth University
in Richmond examined the effect of short-term exposure to
THC, morphine, or both drugs in combination on receptor density
in a mouse model (Cichewicz et al. 1999). They demonstrated
that all three types of opioid receptors were significantly
decreased in morphine-tolerant mice, while this reduction
was not seen in combination-treated animals. The scientists
concluded that a combination of THC and morphine retains high
pain mitigating properties without causing changes in receptors
that may contribute to tolerance.
Research has shown that endocannabinoids play
an important role in emetic circuits of the brain (Darmani
2001). Canadian researchers of Wilfrid Lauier University,
Waterloo, Ontario, demonstrated in an animal model of anticipatory
nausea and vomiting that THC is able to prevent this form
of nausea (Parker et al. 2001). Their study based on the emetic
reactions of the musk shrew is published in Neuroreport. Retching
caused by an injection of lithium chloride was completely
suppressed by pre-treatment with a moderate dose of THC. This
provides the first experimental evidence in support of reports
that THC suppresses anticipatory vomiting. Opiates often cause
nausea and vomiting. Cannabinoids were able to reduce opioid-induced
vomiting in an animal study with ferrets (Simoneau et al.
2001). A CB1 receptor antagonist but not a CB2 receptor antagonist
blocked this antiemetic action, suggesting that antiemetic
effects of cannabinoids appear to be mediated by the central
nervous system. Other research with animals added to the evidence
that cannabinoid receptor agonists are effective against nausea
and vomiting (Darmani 2002, Van Sickle et al. 2001).
Several recent studies demonstrated that cannabinoids
act, under certain conditions, as anti-cancer agents. In one
study, THC and a synthetic cannabinoid induced a remarkable
regression of a usually fatal type of brain tumor when tested
on laboratory rats (Galve-Roperph et al. 2000). Malignant
gliomas, a quick-killing cancer for which there is currently
no effective treatment, were induced in 45 rats. One third
was treated with THC, another third with the cannabinoid agonist
WIN-55,212-2, while the remaining animals were left untreated.
Within 18 days, the untreated rats died. In comparison, the
two cannabinoids had a dramatic effect, destroying the tumors
in a third of the treated rats over a period of seven days,
and prolonging the life of another third by up to six weeks.
12 days after cell injection, THC or WIN-55,212-2 were continually
injected directly at the site of tumor inoculation over a
period of 7 days. THC administration was ineffective in 3
animals and increased the survival of 9 rats up to 19-35 days.
The tumor was completely eradicated in 3 of the treated animals.
Likewise, the synthetic cannabinoid was ineffective in 6 rats,
increased the survival of 4 rats up to 19-43 days and completely
eradicated the tumor in 5 animals. The team led by Dr Manuel
Guzman from the Complutense University in Madrid said: "These
results may provide the basis for a new therapeutic approach
for the treatment of malignant gliomas" (UPI of 28 February
2000). He stated that the current experiment tested THC at
very low doses and at a late stage, when untreated rats were
already starting to die. He predicts that THC should work
better if given earlier. But cancer treatments that work in
animals may be too toxic or not effective in humans. Cannabinoids
are thought to kill tumor cells by inducing programmed cell
death, or apoptosis, via an intracellular signaling mechanism.
Experiments carried out with two subclones of glioma cells
in culture demonstrated that cannabinoids signal apoptosis
by a pathway involving cannabinoid receptors, sustained accumulation
of the lipid ceramide, and Raf-1/ERK (extracellular signal-regulated
kinase activation), inducing a cascade of reactions that leads
to cell death.
THC was neuroprotective in rats given the toxic
agent ouabain (van der Stelt et al. 2001). THC treated animals
showed reduced volume of oedema by 22% in the acute phase
and 36% less nerve damage after 7 days. The effect was not
CB1 receptor mediated.
The effects of an extract of cannabis in animal
tests of depression, spasticity and analgesia were examined
(Musty & Deyo 2001). The cannabis extract did not produce
an anti-depressive effect in mice. However, the extract produced
a decrease in spastic behaviours and showed analgesic properties.
These data suggest that THC extracts will be useful for spastic
conditions and for pain.
Research in rats shows that CB receptor agonists
exert an inhibitory influence on bladder motility but an excitatory
influence on uterus motility (Berkley & Dmitrieva 2001).
This inhibitory effect was greater in rats with inflamed bladders
than in rats with uninflamed bladders, suggesting that inflammation
increases effectiveness of cannabinoids in the bladder. The
effect on the uterus was reduced in rats with inflamed bladders.
This research supports the positive effects on the hyperactive
bladder in patients with multiple sclerosis and spinal cord
injury. Other research in rats showed that hyperalgesia associated
with inflammation of the urinary bladder was attenuated by
the endocannabinoids anandamide (via CB1 receptors) and palmitylethanolamide
(putatively via CB2 receptors) in a dose-dependent fashion
(Farquhar-Smith & Rice 2001).
Cannabinoids (WIN 55,212-2, HU-210) decreased
the acid secretion induced by pentagastrin in the rat (Adami
et al. 2002). This effect was blocked by a CB1 receptor antagonist
but not by a CB2 receptor antagonist. Thus, the inhibition
of acid secretion of the stomach by cannabinoids is mediated
by CB1 receptors. This observation confirms the experience
of patients with gastric hypersecretion that natural cannabis
preparations are effective in relieving their symptoms. This
effect has already been described in the 19th century (See
The synthetic cannabinoid nabilone was effective
in reducing inflammation in a rat model of inflammation (Conti
et al. 2002). The effects were assumed to be mediated by an
uncharacterised CB2-like cannabinoid receptor. In mice, bowel
inflammation increased the potency of cannabinoid agonists
possibly by 'up-regulating' CB1 receptors (Izzo et al. 2001).
In addition, endocannabinoids, whose turnover is increased
in intestinal inflammation, might tonically inhibit bowel
motility. (Izzo et al. 2001).
Researchers of Novartis in London (UK) examined
the effects of cannabinoid agonists on hyperalgesia in a model
of neuropathic pain in the rat (Fox et al. 2001). The results
show that cannabinoids are highly potent and efficacious antihyperalgesic
agents. This activity is likely to be mediated via action
in both the central nervous system and in the periphery. Cannabinoids
that bind to the CB1 cannabinoid receptor act on a part in
the brain (called nucleus reticularis gigantocellularis pars
alpha, GiA), which plays an important role in the mitigation
of neuropathic pain (Monhemius et al. 2001). Cannabinoids
attenuated hyperalgesia evoked by intraplantar injection of
capsaicin in rats through spinal and peripheral mechanisms
(Johanek et al. 2001). The study shows that cannabinoids possess
antihyperalgesic properties at doses that alone do not produce
THC lowers intraocular pressure in the rabbit.
This effect was substantially attenuated by local pre-treatment
with indomethacin, suggesting that THC may influence intraocular
pressure at least in part by a prostaglandin-mediated process
(Green et al. 2001). Indomethacin is a non-steroidal anti-inflammatory
drug and is already known to reduce psychological effects
and tachycardia caused by THC. Cannabinoid receptors (CB1)
have been found in the trabecular meshwork and ciliary processes
of the human eye, and the endocannabinoid anandamide was detected
in the trabecular meshwork (Stamer et al. 2001). Authors assume
that the intraocular pressure-lowering effects of cannabinoids
result from activation of CB1 receptors in the trabecular
meshwork, increasing aqueous outflow.
Further research added to these results on the
antineoplastic effects of cannabinoids. One group found that
cannabinoid receptors exist in the skin and that their activation
inhibits the growth of skin cancer cells (Casanova et al.
2001). CB1 and CB2 type receptors were found in several layers
of the skin. In cell experiments, a synthetic cannabinoid
receptor agonist induced programmed cell death in skin cancer
cells of mice. Another group found that
palmitylethanolamide (PEA) enhanced the anti-cancer effect
of the endocannabinoid anandamide in human breast cancer cells,
in part by inhibiting the expression of fatty acid amide hydrolase
(FAAH) (Di Marzo et al. 2001). The FAAH is responsible for
the degradation of anandamide. PEA also enhanced the anti-cancer
effect of the cannabinoid receptor agonist HU-210.
An international research team demonstrated
that endocannabinoid levels are increased in spasticity (Baker
et al. 2001). In a multiple sclerosis model, CREAE in mice,
spasticity was tonically controlled by the endocannabinoid
system. While the endocannabinoid levels were normal in healthy
mice and in non-spastic CREAE mice, there was a marked increase
of endocannabinoids in spastic CREAE mice. Thus, spastic disorders
might be treated by modulating the endocannabinoid system.
Other researchers found changes in cannabinoid receptor binding
in certain brain regions (striatum, cortex) of rats with experimental
allergic encephalomyelitis (EAE) (Berrendero et al. 2001).
The EAE is another animal model of multiple sclerosis. These
changes might be related to the alleviation of some motor
signs observed after the treatment with cannabinoids in multiple
In conclusion, basic research on the functioning
of the endogenous cannabinoid system as well as research with
animal models for several conditions (multiple sclerosis,
neuropathic pain, nausea, cancer and others) provide insight
into the effects of exogenous cannabinoids and whole cannabis
plant preparations and help to explain therapeutic effects
observed in humans.
Abrahamov A, Abrahamov A, Mechoulam R.
An efficient new cannabinoid antiemetic in pediatric oncology.
Life Sci 1995; 56(23-24): 2097-102
Adami M, Frati P, Bertini S, Kulkarni-Narla A, Brown DR, de
Caro G, Coruzzi G, Soldani G. Gastric antisecretory role and
immunohistochemical localization of cannabinoid receptors
in the rat stomach. Br J Pharmacol 2002;135(7):1598-606.
Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis
A, Khanolkar A, Layward L, Fezza F, Bisogno T, Di Marzo V.
Endocannabinoids control spasticity in a multiple sclerosis
model. FASEB J 2001;15(2):300-2.
Berkley KJ, Dmitrieva N. Influence of synthetic cannabinoid
ligands on the rat bladder and uterus: clinical implications.
2001 Congress on Cannabis and the Cannabinoids, Cologne, Germany,
International Association for Cannabis as Medicine, p. 8.
Berrendero F, Sanchez A, Cabranes A, Puerta C, Ramos JA, Garcia-Merino
A, Fernandez-Ruiz J. Changes in cannabinoid CB(1) receptors
in striatal and cortical regions of rats with experimental
allergic encephalomyelitis, an animal model of multiple sclerosis.
Breivogel CS, Griffin G, Di Marzo V, Martin BR. Evidence for
a new G protein-coupled cannabinoid receptor in mouse brain.
Mol Pharmacol 2001; 60(1): 155-63
Bueb JL, Lambert DM, Tschirhart EJ. Receptor-independent effects
of natural cannabinoids in rat peritoneal mast cells in vitro.
Biochim Biophys Acta 2001; 1538(2-3): 252-9
Calignano A, Katona I, Desarnaud F, Giuffrida A, La Rana G,
Mackie K, Freund TF, Piomelli D. Bidirectional control of
airway responsiveness by endogenous cannabinoids. Nature 2000;408(6808):96-101.
Carley DW, Paviovic S, Janelidze M, Radulovacki M. Functional
role for cannabinoids in respiratory stability during sleep.
Casanova ML, Blàzquez C, Fernández-Acenero MJ,
Villanueva C, Jorcano J, Guzmán M. Cb1 and CB2 receptors
are expressed in the skin and their activation inhibits the
growth of skin cancer cells. 2001 ICRS Symposium on the Cannabinoids,
Burlington, Vermont, International Cannabinoid Research Society,
Cichewicz DL, Martin ZL, Smith FL, Welch SP. Enhancement mu
opioid antinociception by oral delta9-tetrahydrocannabinol:
dose-response analysis and receptor identification. J Pharmacol
Exp Ther 1999;289(2):859-67.
Conti S, Costa B, Colleoni M, Parolaro D, Giagnoni G. Antiinflammatory
action of endocannabinoid palmitoylethanolamide and the synthetic
cannabinoid nabilone in a model of acute inflammation in the
rat. Br J Pharmacol 2002;135(1):181-7.
Darmani NA. Delta-9-tetrahydrocannabinol and synthetic cannabinoids
prevent emesis produced by the cannabinoid CB(1) receptor
antagonist/inverse agonist SR 141716A. Neuropsychopharmacology
Darmani NA. Delta-9-tetrahydrocannabinol differentially suppresses
cisplatin-induced emesis and indices of motor function via
cannabinoid CB(1) receptors in the least shrew. Pharmacol
Biochem Behav 2001; 69(1-2): 239-49
Darmani NA. The potent emetogenic effects of the endocannabinoid,
2-AG (2-arachidonoylglycerol) are blocked by delta(9)-tetrahydrocannabinol
and other cannnabinoids. J Pharmacol Exp Ther 2002;300(1):34-42.
De Petrocellis L, Melck D, Bisogno T, Di Marzo V, Endocannabinoids
and fatty acid amides in cancer, inflammation and related
disorders. Chem Phys Lipids 2000; 108(1-2): 191-209
De Petrocellis L, Melck D, Bisogno T, Milone A, Di Marzo V.
Finding of the endocannabinoid signalling system in Hydra,
a very primitive organism: possible role in the feeding response.
Neuroscience 1999; 92(1): 377-87
Di Marzo V, Breivogel CS, Tao Q, Bridgen DT, Razdan RK, Zimmer
AM, Zimmer A, Martin BR, Levels, metabolism, and pharmacological
activity of anandamide in CB(1) cannabinoid receptor knockout
mice: evidence for non-CB(1), non-CB(2) receptor-mediated
actions of anandamide in mouse brain. J Neurochem 2000; 75(6):
Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z,
Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G. Leptin-regulated
endocannabinoids are involved in maintaining food intake.
Di Marzo V, Melck D, Orlando P, Bisogno T, Zagoory O, Bifulco
M, Vogel Z, De Petrocellis L. Palmitoylethanolamide inhibits
the expression of fatty acid amide hydrolase and enhances
the anti-proliferative effect of anandamide in human breast
cancer cells. Biochem J 2001;358(Pt 1):249-55.
Farquhar-Smith WP, Rice AS. Administration of endocannabinoids
prevents a referred hyperalgesia associated with inflammation
of the urinary bladder. Anesthesiology 2001;94(3):507-13.
Fox A, Kesingland A, Gentry C, McNair K, Patel S, Urban L,
James I. The role of central and peripheral Cannabinoid1 receptors
in the antihyperalgesic activity of cannabinoids in a model
of neuropathic pain. Pain 2001;92(1-2):91-100.
Galve-Roperph I, Sanchez C, Cortesz ML, Gomez del Pulgar T,
Izquierdo M, Guzman M: Antitumoral action of cannabinoids:
involvement of sustained ceramide accumulation and ERK activation.
Nature Medicine 2000;6:313-319.
Giuffrida A, Beltramo M, Piomelli D. Mechanisms of endocannabinoid
inactivation: biochemistry and pharmacology. J Pharmacol Exp
Ther 2001; 298(1): 7-14
Green K, Kearse EC, McIntyre OL. Interaction between delta-9-tetrahydrocannabinol
and indomethacin. Ophthalmic Res 2001;33(4):217-20
Hampson A. Cannabinoids as neuroprotectants against ischemia.
In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids.
Pharmacology, toxicology, and therapeutic potential. Binghamton
(NY): Haworth Press, 2002: 101-10
Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto L, Iuvone T,
Esposito G, Mascolo N, Di Marzo V, Capasso F. Cannabinoid
CB1-receptor mediated regulation of gastrointestinal motility
in mice in a model of intestinal inflammation. Br J Pharmacol
Izzo AA, Mascolo N, Capasso F. The gastrointestinal pharmacology
of cannabinoids. Curr Opin Pharmacol 2001;1(6):597-603.
Johanek LM, Heitmiller DR, Turner M, Nader N, Hodges J, Simone
DA. Cannabinoids attenuate capsaicin-evoked hyperalgesia through
spinal and peripheral mechanisms. Pain 2001;93(3):303-15.
Lagneux C, Lamontagne D. Involvement of cannabinoids in the
cardioprotection induced by lipopolysaccharide. Br J Pharmacol
Lastres-Becker I, Hansen HH, Berrendero F, De Miguel R, Perez-Rosado
A, Manzanares J, Ramos JA, Fernandez-Ruiz J. Alleviation of
motor hyperactivity and neurochemical deficits by endocannabinoid
uptake inhibition in a rat model of Huntington's disease.
Monhemius R, Azami J, Green DL, Roberts MH. CB1 receptor mediated
analgesia from the Nucleus Reticularis Gigantocellularis pars
alpha is activated in an animal model of neuropathic pain.
Brain Res 2001;908(1):67-74.
Musty R, Deyo R. Effects of a cannabis extract in animal tests
of depression, spasticity and antinoception: a preliminary
report. 2001 Congress on Cannabis and the Cannabinoids, Cologne,
Germany, International Association for Cannabis as Medicine,
Parker LA, Kemp SW. Tetrahydrocannabinol (THC) interferes
with conditioned retching in Suncus murinus: an animal model
of anticipatory nausea and vomiting (ANV). Neuroreport 2001;12(4):749-751.
Parker LA, Mechoulam R, Schlievert C. Cannabidiol, a non-psychoactive
component of cannabis and its synthetic dimethylheptyl homolog
suppress nausea in an experimental model with rats. Neuroreport
2002 Apr 16;13(5):567-70.
Pertwee RG. Evidence for the presence of CB1 cannabinoid receptors
on peripheral neurones and for the existence of neuronal non-CB1
cannabinoid receptors. Life Sci 1999; 65: 597-605
Pertwee RG. Sites and Mechanisms of Action. In: Grotenhermen
F, Russo E, editors. Cannabis and cannabinoids. Pharmacology,
toxicology, and therapeutic potential. Binghamton (NY): Haworth
Press, 2002: 73-88
Plane F, Holland M, Waldron GJ, Garland CJ, Boyle JP. Evidence
that anandamide and EDHF act via different mechanisms in rat
isolated mesenteric arteries. Br J Pharmacol 1997;121(8):1509-11.
Randall MD, Kendall DA. Involvement of a cannabinoid in endothelium-derived
hyperpolarizing factor-mediated coronary vasorelaxation. Eur
J Pharmacol 1997;335(2-3):205-9.
See, G. 1890. Anwendung der Cannabis indica in der Behandlung
der Neurosen und gastrischen Dyspepsieen. Dtsch Med Wschr
60(31-34):679-682, 727-730, 748-754, 771-774.
Siegling A, Hofmann HA, Denzer D, Mauler F, De Vry J. Cannabinoid
CB(1) receptor upregulation in a rat model of chronic neuropathic
pain. Eur J Pharmacol 2001; 415(1): R5-R7
Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah TW, Porreca
F, Makriyannis A, Malan TP Jr. The cannabinoid agonist WIN55,212-2
suppresses opioid-induced emesis in ferrets. Anesthesiology
Stamer WD, Golightly SF, Hosohata Y, Ryan EP, Porter AC, Varga
E, Noecker RJ, Felder CC, Yamamura HI. Cannabinoid CB(1) receptor
expression, activation and detection of endogenous ligand
in trabecular meshwork and ciliary process tissues. Eur J
Tyler K, Hillard CJ, Greenwood-Van Meerveld B. Inhibition
of small intestinal secretion by cannabinoids is CB1 receptor-mediated
in rats. Eur J Pharmacol 2000;409(2):207-11.
van der Stelt M, Veldhuis WB, van Haaften GW, Fezza F, Bisogno
T, Bar PR, Veldink GA, Vliegenthart JF, Di Marzo V, Nicolay
K. Exogenous anandamide protects rat brain against acute neuronal
injury in vivo. J Neurosci 2001;21(22):8765-71.
Van Sickle MD, Oland LD, Ho W, Hillard CJ, Mackie K, Davison
JS, Sharkey KA. Cannabinoids inhibit emesis through CB1 receptors
in the brainstem of the ferret. Gastroenterology 2001;121(4):767-74.
Walker JM, Huang SM, Strangman NM, Tsou K, Sanudo-Pena MC.
Pain modulation by release of the endogenous cannabinoid anandamide.
Proc Natl Acad Sci U S A 1999; 96(21): 12198-203.
Williams CM, Kirkham TC. Observational analysis of feeding
induced by Delta(9)-THC and anandamide. Physiol Behav 2002;76(2):241-50.