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15/10/2007 00:00:00

Cannabis Use, Effect And Potential Therapy For Alzheimer's, MS and

Cannabis (marijuana) is the most widely produced plant-based illicit
drug worldwide and the illegal drug most frequently used in Europe. Its
use increased in almost all EU countries during the 1990s, in particular
among young people, including school students. Cannabis use is highest
among 15- to 24-year-olds, with lifetime prevalence ranging for most
countries from 20--40% (EMCDDA 2006).

Recently there has been a new surge in the level of concern about
potential social and health outcomes of cannabis use, although the
available evidence still does not provide a clear-cut understanding of
the issues. Intensive cannabis use is correlated with non-drug-specific
mental problems, but the question of co-morbidity is intertwined with
the questions of cause and effect (EMCDDA 2006). Prevention is of
importance in adolescents, which is underlined by evidence that
early-onset cannabis-users (pre- to mid-adolescence) have a
significantly higher risk of developing drug problems, including
dependence (Von Sydow et al., 2002; Chen et al., 2005).

The illegal status and wide-spread use of cannabis made basic and
clinical cannabis research difficult in the past decades; on the other
hand, it has stimulated efforts to identify the psychoactive
constituents of cannabis. As a consequence, the endocannabinoid system
was discovered, which was shown to be involved in most physiological
systems -- the nervous, the cardiovascular, the reproductive, the immune
system, to mention a few.

One of the main roles of endocannabinoids is neuroprotection, but over
the last decade they have been found to affect a long list of processes,
from anxiety, depression, cancer development, vasodilatation to bone
formation and even pregnancy (Panikashvili et al., 2001; Pachter et al.,

Cannabinoids and endocannabinoids are supposed to represent a medicinal
treasure trove which waits to be discovered.

Raphael Mechoulam will tell the discovery story of the endocannabinoid
system. His research has not only helped us to advance our understanding
of cannabis use and its effects, but has also made key contributions
with regard to understanding "neuroprotection," and has opened the door
for the development of new drugs.

Endocannabinoid system

In the 1960s the constituent of the cannabis plant was discovered --
named tetrahydrocannabinol, or THC -- which causes the 'high' produced
by it (Gaoni & Mechoulam, 1964). Thousands of publications have since
appeared on THC. Today it is even used as a therapeutic drug against
nausea and for enhancing appetite, and, surprisingly, has not become an
illicit drug -- apparently cannabis users prefer the plant-based
marijuana and hashish.

Two decades later it was found that THC binds to specific receptors in
the brain and the periphery and this interaction initiates a cascade of
biological processes leading to the well known marijuana effects. It was
assumed that a cannabinoid receptor is not formed for the sake of a
plant constituent (that by a strange quirk of nature binds to it), but
for endogenous brain constituents and that these putative 'signaling'
constituents together with the cannabinoid receptors are part of a new
biochemical system in the human body, which may affect various
physiological actions.

In trying to identify these unknown putative signaling molecules, our
research group in the 1990s was successful in isolating 2 such
endogenous 'cannabinoid' components -- one from the brain, named
anandamide (from the word ´ananda, meaning ´supreme joy´ in Sanscrit),
and another one from the intestines named 2-arachidonoyl glycerol (2-AG)
(Devane et al., 1992; Mechoulam et al., 1995).


The major endocannabinoid (2-AG) has been identified both in the central
nervous system and in the periphery. Stressful stimuli -- traumatic
brain injury (TBI) for example -- enhance brain 2-AG levels in mice.
2-AG, both of endogenous and exogenous origin, has been shown to be
neuroprotective in closed head injury, ischemia and excitotoxicity in
mice. These effects may derive from the ability of cannabinoids to act
through a variety of biochemical mechanisms. 2-AG also helps repair the
blood brain barrier after TBI.

The endocannabinoids act via specific cannabinoid receptors, of which
the CB1 receptors are most abundant in the central nervous system. Mice
whose CB1 receptors are knocked out display slower functional recovery
after TBI and do not respond to treatment with 2-AG. Over the last few
years several groups have noted that CB2 receptors are also formed in
the brain, particularly as a reaction to numerous neurological diseases,
and are apparently activated by the endocannabinoids as a protective

Through evolution the mammalian body has developed various systems to
guard against damage that may be caused by external attacks. Thus, it
has an immune system, whose main role is to protect against protein
attacks (microbes, parasites for example) and to reduce the damage
caused by them. Analogous biological protective systems have also been
developed against non-protein attacks, although they are much less well
known than the immune system. Over the last few years the research group
of Esther Shohami in collaboration with our group showed that the
endocannabinoid system, through various biological routes, lowers the
damage caused by brain trauma. Thus, it helps to attenuate the brain
edema and the neurological injuries caused by it (Panikashvili et al.,
2001; Panikashvili et al., 2006).

Clinical importance

Furthermore it is assumed that the endocannabinoid system may be
involved in the pathogenesis of hepatic encephalopathy, a
neuropsychiatric syndrome induced by fulminant hepatic failure. Indeed
in an animal model the brain levels of 2-AG were found to be elevated.
Administration of 2-AG improved a neurological score, activity and
cognitive function (Avraham et al., 2006). Activation of the CB2
receptor by a selective agonist also improved the neurological score.
The authors concluded that the endocannabinoid system may play an
important role in the pathogenesis of hepatic encephalopathy.

Modulation of this system either by exogenous agonists specific for the
CB2 receptors or possibly also by antagonists to the CB1 receptors may
have therapeutic potential. The endocannabinoid system generally is
involved in the protective reaction of the mammalian body to a long list
of neurological diseases such as multiple sclerosis, Alzheimer's and
Parkinson's disease. Thus, there is hope for novel therapeutic

Numerous additional endocannabinoids -- especially various fatty acid
ethanolamides and glycerol esters -- are known today and regarded as
members of a large ´endocannabinoid family´. Endogenous cannabinoids,
the cannabinoid receptors and various enzymes that are involved in their
syntheses and degradations comprise the endocannabinoid system.

The endocannabinoid system acts as a guardian against various attacks on
the mammalian body.


The above described research concerning the endocannabinoid-system is of
importance in both basic science and in therapeutics:

* The discovery of the cannabis plant active constituent has helped
advance our understanding of cannabis use and its effects.
* The discovery of the endocannabinoids has been of central
importance in establishing the existence of a new biochemical system and
its physiological roles -- in particular in neuroprotection.
* These discoveries have opened the door for the development of
novel types of drugs, such as THC for the treatment of nausea and for
enhancing appetite in cachectic patients.
* The endocannabinoid system is involved in the protective reaction
of the mammalian body to a long list of neurological diseases such as
multiple sclerosis, Alzheimer's and Parkinson's disease which raises
hope for novel therapeutic opportunities for these diseases.


Avraham Y, Israeli E, Gabbay E, et al. Endocannabinoids affect
neurological and cognitive function in thioacetamide-induced hepatic
encephalopathy in mice. Neurobiology of Disease 2006;21:237-245

Chen CY, O´Brien MS, Anthony JC. Who becomes cannabis dependent soon
after onset of use" Epidemiological evidence from the United States:
2000-2001. Drug and alcohol dependence 2005;79:11-22

Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain
constituent that binds to the cannabinoid receptor. Science

[EMCDDA 2006] European Monitoring Centre for Drugs and Drug Addiction.
The state of the drugs problem in Europe. Annual Report 2006

Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an
active constituent of hashish. J Amer Chem Soc 1964;86:1646-1647

Journal Interview 85: Conversation with Raphael Mechoulam. Addiction

Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an
endogenous 2-monoglyceride, present in canine gut, that binds to
cannabinoid receptors. Biochem Pharmacol 1995;50:83-90

Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain injury.
Trends Mol Med 2002;8:58-61

Pachter P, Batkai S, Kunos G. The endocannabinoid system as an emerging
target of pharmacotherapy. Pharmacol Rev 2006;58:389-462

Panikashvili D, Simeonidou C, Ben-Shabat S, et al. An endogenous
cannabinoid (2-AG) is neuroprotective after brain injury. Nature

Panikashvili D, Shein NA, Mechoulam R, et al. The endocannabinoid 2-AG
protects the blood brain barrier after closed head injury and inhibits
mRNA expression of proinflammatory cytokines. Neurobiol Disease

Von Sydow K, Lieb R, Pfister H, et al. What predicts incident use of
cannabis and progression to abuse and dependence" A 4-year prospective
examination of risk factors in a community sample of adolescents and
young adults. Drug and alcohol dependence 2002;68:49-64

Note: This story has been adapted from material provided by European
College of Neuropsychopharmacology.

Author: Science Daily via UKCIA

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