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

ScienceDaily (Oct. 15, 2007) — 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., 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 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

http://www.jneurosci.org/cgi/content/short/25/8/1904

So marijuana, which makes you forget what planet you're on, can prevent or slow the progression of Alzheimers. Seems counterintuitive but maybe it...um...hmmm...does anyone know what were we talking about?

My mother has it too. She's 82 years old but in a lot of ways she's 4 years old again. It rips my heart out at times.

I'm not one that things that suicide is typically a good response to problems, but speaking strictly for myself, I don't know if I could live like that.

My grandmother had it. I remember thinking that I don't want to go out like that. The problem is, that by the time it manifests in you, it's already too late to end your own life with dignity, because you can't remember how to do it, or even who you are. And, if you make a pact ahead of time for someone else to do it for you, they may end up in prison. I hope if I get it, someone will keep me supplied with some nice Alice B. brownies, so I can enjoy whatever I'm experiencing ... reliving my childhood or just wandering aimlessly around the yard. Also, write down now, the foods you most enjoyed when you were younger, and tell your potential caregiver not to put you on silly diets; let you have whatever makes you smile, and of course, keep you clean! Let's hope for a cure.

My mom died from ALZ, too. In 5 years she went from an intelligent, tall, robust woman to a mindless shell of less than 100 lbs. There is no dignity, no mercy, no stopping that horrible disease. If they tell me I have ALZ, I'll shoot myself while I still know what the gun is for.

Many of the drugs used presently to treat the symptoms of Alzheimer's are far more effective when given before the outward symptoms of cognitive decline set in. This would be true of new drugs as well. The problem has always been that it is unethical and potentially dangerous to administer drugs to patients who show no signs of disease. Therefore, treatment only begins after the damage starts. That damage cannot be repaired. With new tests to detect pre-Alzheimer's changes in outwardly healthy individuals years before mental decline, there is a greater possibility of stopping the disease before it really begins. Animal tests confirm this.

Tests like this one have been in the research phase for 5-10 years now and many are beginning to show ways in which we can detect the disease early. These tests represent more than just a mere early warning for potential victims, they represent a clear signal of who needs treatment and how early it should start. As these tests become widespread the prognosis for patients will begin to shift as well.

Food for thought

There is no cure, and not even a clear understanding of whether amyloids are a cause of Alzheimer's or a symptom and something else is the cause. And drugs like Aricept provide only a temporary respite from the progress of the disease (followed by a very rapid progression when they cease to work and are stopped), there is no drug that produces a significant benefit, even at huge expense (such as with Aricept.)

In cases like there early knowledge of the probability of the disease in the absence of symptoms, actually reduce quality of life far below what would be present if the person did not know. People especially begin to worry about their financial situation and the stress on their partner of a long period in a vegetative state. A shockingly high number of people actually commit suicide immediately after diagnosis.

Physicians hold out hope to the families for a "cure" and tell families to hold on as long as possible in case one is found. (The drug approval process is much longer than the life expectancy of someone diagnosed with Alzheimer's.) In the end, the for-profit medical system uses Alzheimer's as a method of "trying" various expensive drugs and transferring much if not all the families assets to the medical system.

Unfortunately Joe, the Mini Mental Test is one of the first tests they administer (silly questions) to check for this disease. At this time there is no definitive test, like the article points out. You were probably put on medication to slow memory loss down. They will do the test again in a few months: it gives them a clue as to what's going on. Then they may decide to do some scans, MRI, PET, etc. to rule out stroke, brain problems and the like. Not an easy process nor a fast one. My mom was diagnosed 4 years ago, but we had a suspicion something was wrong earlier than that, but she is stubborn. She'll be 90 next week and we try to make her life in an assisted living center as "normal (which it's not) and easy as possible. Live life one day at a time......

No SuckerFish, having a needle inserted into the base of the spine is not very risky. About two thirds of the way down the spine (at approximately the first lumbar vertibra), the spinal cord changes from gray matter or dura (similar to brain tissue, with little or no ability to regenerate and heal from damage) to a bundle of nerves known as the cauda equina that has a good ability to regenerate. Surgery and needle intrusion into this area is quite safe.

MRI's do not do anything to indicate one has ALZ.