Cannabis Use, Effect And Potential Therapy For Alzheimer's, MS and Parkinson's
Science Daily — 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). 
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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., 2006). 
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). 
Neuroprotection 
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 mechanism.
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 opportunities.
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.
Conclusion 
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.
References
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 
1992;258:1946-1949
[EMCDDA 2006] European Monitoring Centre for Drugs and Drug Addiction. The 
state of the drugs problem in Europe. Annual Report 2006 
(http://www.emcdda.europa.eu)
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 
2007;102:887-893
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 2001;413:527-531
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 2006;22:257-264
Von Sydow K, Lieb R, Pfister H, et al. What predicts incident use of cannabis 
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Note: This story has been adapted from material provided by European College 
of Neuropsychopharmacology.

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