Molecular Link Between the Active Component of Marijuana and Alzheimer's Disease Pathology

[G_j]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562334/

Molecular Link Between the Active Component of Marijuana and Alzheimer's Disease Pathology

Abstract
Alzheimer's disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer's disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients as well as reduce the health care costs attributable to Alzheimer's disease. Here, we demonstrate that the active component of marijuana, ?9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid ?-peptide (A? aggregation, the key pathological marker of Alzheimer's disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of A? aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.

Keywords: Cannabinoids, Alzheimer's disease, Acetylcholinesterase

Introduction
Since the characterization of the Cannabis sativa-produced cannabinoid, ?9-tetrahydrocannabinol (THC) (Figure 1), in the 1960's,1 this natural product has been widely explored as an anti-emetic, anti-convulsive, anti-inflammatory, and analgesic.2 In these contexts, efficacy results from THC binding to the family of cannabinoid receptors found primarily on central and peripheral neurons (CB1) or immune cells (CB2).3 More recently, a link between the endocannabinoid system and Alzheimer's disease has been discovered4 which has provided a new therapeutic target for the treatment of patients suffering from Alzheimer's disease.5 New targets for this debilitating disease are critical as Alzheimer's disease afflicts over 20 million people worldwide, with the number of diagnosed cases continuing to rise at an exponential rate.6,7 These studies have demonstrated the ability of cannabinoids to provide neuroprotection against ?-amyloid peptide (A? toxicity.8-10 Yet, it is important to note that in these reports, cannabinoids serve as signaling molecules which regulate downstream events implicated in Alzheimer's disease pathology and are not directly implicated as effecting A? at a molecular level.

<snip>
Conclusion
We have demonstrated that THC competitively inhibits AChE, and furthermore, binds to the AChE PAS and diminishes A? aggregation. In contrast to previous studies aimed at utilizing cannabinoids in Alzheimer's disease therapy,8-10 our results provide a mechanism whereby the THC molecule can directly impact Alzheimer's disease pathology. We note that while THC provides an interesting Alzheimer's disease drug lead, it is a psychoactive compound with strong affinity for endogenous cannabinoid receptors. It is noteworthy that THC is a considerably more effective inhibitor of AChE-induced A? deposition than the approved drugs for Alzheimer's disease treatment, donepezil and tacrine, which reduced A? aggregation by only 22% and 7%, respectively, at twice the concentration used in our studies.7 Therefore, AChE inhibitors such as THC and its analogues may provide an improved therapeutic for Alzheimer's disease, augmenting acetylcholine levels by preventing neurotransmitter degradation and reducing A? aggregation, thereby simultaneously treating both the symptoms and progression of Alzheimer's disease.

[ChairmanAgnostic]

1. translation: To keep your brain working, stay stoned as you age.

[roody]

2. I'm doing my best!

[Blue_In_AK]

22. My motto.

[haydukelives]

38. count me in

[Rosa Luxemburg]

45. I knew that there was a purpose

[TexasTowelie]

47. Pass it around.

[woofless]

51. " 'ere."

[ronnie624]

70. Lol. n/t

[LittleGirl]

53. made me giggle

your post. must be something I can look forward to...never getting that dreaded disease.

[Egalitarian Thug]

3. K&R. There's a scientist (biochemist IIRC) in Colorado Springs that has been working on this

principle for years. Every animal on earth is built to accept/utilize cannabinoids, we all evolved that way. The medicinal potential of Marijuana is literally awesome, but of course, because it is a natural plant and cannot be patented, the pharmaceutical industry has blocked research at every opportunity.

[truedelphi]

10. If he ever needs help, I have plenty of friends who

Could chronicle their experiences.

And you' re right about how Big Pharma is opposed to making the plant legal.

[RainDog]

60. Robert Melamede n/t

[Egalitarian Thug]

62. That's the guy, thank you. n/t

[Warren Stupidity]

4. fuck! now it is never going to be legal.

No way is Big Pharma going to let herb get in the way of the boomer Alzheimer cash cow. We are doomed!

[BainsBane]

6. They'll put it in pills

and sell it for big bucks.

[G_j]

34. you can count on that. nt

[Dustlawyer]

41. They already have a pill but they don't work, that's why you don't hear much about it.

[Egalitarian Thug]

63. And it doesn't work very well, but does cost a lot. Corporatocracy. n/t

[Recursion]

15. It was never going to be legal as a grown weed

It will probably be legal at some point as an inhaler produced by RJR or Brown & Williamson with God-knows-what-else added to it.

[Comrade Grumpy]

27. It is legal as a grown weed in Colorado right now, and...

look for more states to come on board, if not this year in legislatures, then in 2014 and 2016 through the initiative process.

It may never be a medicine as a grown weed, but that's a different story.

[JackInGreen]

55. Seattle

Screamin' in here. Legal as the day is long, our local constabulary thankful to not bust stoners, and the world a friendlier place (and trust me, my uptight neighbors need it). Come on up sometime and enjoy the fog

[mitchtv]

5. Marijuana

forget about Alzheimers!

[immoderate]

32. !

--imm

[BuddhaGirl]

7. awesome news!!

The spice turmeric also inhibits amyloid beta.

to natural substances that work!

[LiberalEsto]

13. Great!

I can't stand marijuana.

[cthulu2016]

8. Lose your short term memory now so you don't lose it later!

[tridim]

12. You forgot your sarcasm tag.

Otherwise that's pure reefer madness.

[KittyWampus]

37. As someone who smoked pot on a prodigious level many years ago it most certainly is not.

Last edited Sat Mar 9, 2013, 02:10 PM - Edit history (1)

It's sad how far into denial some pot smokers are. The Science isn't behind you.

How marijuana makes you forget

The drug impairs users’ working memory — the ability to retain and use information over short periods of time. Neuroscientists Giovanni Marsicano of the University of Bordeaux, France, and Xia Zhang of the University of Ottawa Institute of Mental Health Research now show that this common side effect occurs because of a previously unknown signalling mechanism between neurons and non-neuronal cells called astrocytes. Their work is published today in Cell1.

The star-shaped astrocytes have long been considered nothing more than support cells that protect neurons. “Our study provides compelling evidence that astrocytes control neurons and memory,” says Zhang. “The supporting actor has become the leading actor.”

The psychoactive ingredient of marijuana is tetrahydrocannabinol (THC). Using microelectrodes implanted into the brains of anaesthetized rats, the researchers found that the compound weakens the connections, or synapses, between neurons in the hippocampus, a structure that is crucial for memory formation.

They repeated these experiments in two types of mice that had been genetically modified to alter their production of CB1 receptors, the molecules that interact with THC in the brain. One mouse strain lacked CB1 receptors in hippocampal neurons that synthesize the neurotransmitter glutamate; the other lacked them in those that synthesize the neurotransmitter GABA.

http://www.nature.com/news/how-marijuana-makes-you-forget-1.10152#/ref-link-1

[liberal_at_heart]

52. I know several medical marijuana patients who would strongly disagree with you

It does not matter how much reefer madness people put out there. It does not matter what prohibitive laws they pass. It does not matter how many people they put in jail. Patients will never stop using their medicine. They know it works for them because they see and feel a decrease in their symptoms when they use it, and they will never give it up.

[KittyWampus]

64. WTF does that have to do with the FACT MJ effects short term memory. Cause that's all I addressed.

the poster I responded to wrongly asserts that saying mj effects our short term memory is reefer madness bullshit.

It's not bullshit.

It's medical fact.

And as someone who smoked quite a lot back in the day… I can't imagine why anyone would deny it.

[tpsbmam]

71. You're putting anecdotal evidence on the same footing with A LOT of statistical

evidence that cannabis doesn't cause neuropsychological/cognitive changes even after long-term use. On an anecdotal level, it's entirely possible that one or more other causes underlie memory problems. It's also possible that heavy long-term cannabis use might affect certain brain conditions negatively -- there aren't any that I know of, but I only stay abreast of the research very casually these days. (Gotta run....there have been some good posts on this thread backing up my statements.)

[RainDog]

61. One of the values of mj for PTSD

One of the values of mj for PTSD is the weakening of the connections between emotional response and memory.

The temporary issue of occasional difficulty with memory loss during the time when someone is high, however, is not a permanent feature of cannabis use, as other studies have also demonstrated.

Even in the case of heavy, long term use:

The researchers found only a "very small" impairment in memory and learning among long-term marijuana users. Otherwise, scores on thinking tests were similar to those who don't smoke marijuana, according to a new analysis of 15 previous studies.

In those studies, some 700 regular marijuana users were compared with 484 non-users on various aspects of brain function -- including reaction time, language and motor skills, reasoning ability, memory, and the ability to learn new information.

The marijuana users in those 15 studies -- which lasted between three months to more than 13 years -- had smoked marijuana several times a week or month or daily. Still, researchers say impairments were less than what is typically found from using alcohol or other drugs.

"I just re-published a paper of the first survey for marijuana toxicity done in 1863 by the British government in India that was the most exhaustive medical study of its time in regards to possible difficulties and toxicity of cannabis. And it reached the same conclusion as Grant," Mikuriya tells WebMD. (Tod Mikuriya, MD, former director of non-classified marijuana research for the National Institute of Mental Health Center for Narcotics and Drug Abuse Studies and author of The Marijuana Medical Handbook: A Guide to Therapeutic Use is considered one of the experts in the field of cannabis research/medicine.) "This is merely confirming what was known over 100 years ago, as well as what was learned by various government findings doing similar research -- marijuana is not toxic, but it is a highly effective medicine."

http://www.webmd.com/mental-health/news/20030701/heavy-marijuana-use-doesnt-damage-brain

It's sort of out of proportion to blame people who support legalization for the lies the govt has told about marijuana for more than 70 years, including the FALSE claim made by Ronnie Raygun that marijuana killed brain cells. After years of putting off releasing the scientific study from which this claim was made... )and WHO CHOOSES TO HIDE SCIENTIFIC RESEARCH unless they're merely spouting bullshit propaganda?) Anyway, that study actually found that suffocating animals with carbon dioxide causes cell damage. But not marijuana.

There are far, far more studies that show the benefits of marijuana - real scientific experiments without a political agenda - than there are those showing a reason to continue prohibition. And, frankly, the drugs that pharmaceutical companies make have far worse side effects - so why don't you go off on them for marketing substances that kill, destroy organ function, destroy mental capacity, create permanent damage - you know - maybe some realism is required to not have your hair on fire when someone says something positive about the use of marijuana.

[RainDog]

66. Here's the meta analysis that showed NO impairment after 25 days of abstinence.

http://www.ncbi.nlm.nih.gov/pubmed/22731735

Cannabis is the most widely used illicit drug in the U.S., and the number of illicit and licit users is rising. Lasting neurocognitive changes or deficits as a result of use are frequently noted despite a lack of clarity in the scientific literature. In an effort to resolve inconsistencies in the evidence of lasting residual effects of cannabis use, we conducted two meta-analyses. First, we updated a previous meta-analysis on broad nonacute cognitive effects of cannabis use through inclusion of newer studies. In a second meta-analysis, we focused on evidence for lasting residual effects by including only studies that tested users after at least 25 days of abstinence.

In the first meta-analysis, 33 studies met inclusion criteria. Results indicated a small negative effect for global neurocognitive performance as well for most cognitive domains assessed. Unfortunately, methodological limitations of these studies prevented the exclusion of withdrawal symptoms as an explanation for observed effects.

In the second meta-analysis, 13 of the original 33 studies met inclusion criteria. Results indicated no significant effect of cannabis use on global neurocognitive performance or any effect on the eight assessed domains. Overall, these meta-analyses demonstrate that any negative residual effects on neurocognitive performance attributable to either cannabis residue or withdrawal symptoms are limited to the first 25 days of abstinence. Furthermore, there was no evidence for enduring negative effects of cannabis use.


Seems like the science isn't behind you. It's ahead of you.

[cherokeeprogressive]

72. I had to go back and remind myself what the thread was about. n/t

[Uncle Joe]

9. Kicked and recommended.

Thanks for the thread, G_j.

[tridim]

11. Side effects may include arrest, fines, loss of freedom and possible jail time.

Legalize it NOW. Geez Lou-freaking-ise.

Alzheimer's runs in my family and I will use natural medications as a preventative measure if I want to. Fuck you DEA, it's none of your business.

[barbtries]

14. the title scared me

i was afraid it was going to say that alzheimer's is on the upswing because everyone's getting high!

[stlsaxman]

16. Same here- I had to skip to the conclusion for clarity.

[mitchtv]

33. Don't worry, those "studies" come out regularly

like clockwork

[Dryvinwhileblind]

17. A gram a day to keep the...

...bloody insurance scam driven corporate managed care system away.

[aint_no_life_nowhere]

18. Smoking cigarettes also inhibits Alzheimer’s

Researchers have long noted that smokers have a lower rate of AD (although smoking is definitely not a good thing overall).

http://www.sciencedirect.com/science/article/pii/S0006899398001383

http://www.prohealth.com/library/showarticle.cfm?libid=2596

Michael Mullan, the scientist who first discovered the role of beta amyloid plaques in AD has discovered a compound in the tobacco leaf called anatabine that accounts for the diminution of inflammation in the Alzheimer brain. The compound if available to the public OTC.

[The Wizard]

57. Cigarettes also shorten life

and many users never get old enough to get Alzheimer's.

[aint_no_life_nowhere]

58. Absolutely - that's why my post stated "although smoking is definitely not a good thing overall"

[caseymoz]

19. I would think this would be easy to test.

Survey the general population, find out if there's an inverse correlation between marijuana use and development of dementia in old age.

If there is, they're onto something. Problem is, I'm not certain the stoner generation has reached old age yet. It may take a while.

Second problem, it's not certain the ameloids cause Alzheimers. They may be just a by-product of the disease progression, though if that's the case, they definitely aggravate it.

Remember, computer modelling tells you only what should happen, not what actually happens.

[Blue_In_AK]

26. It depends on your definition of "old age,"

and I would wager that even "old" stoners (such as myself at 66) don't feel old. I sure as hell don't. My husband, who is a year younger than me, doesn't smoke, and he's always complaining about feeling old.

[caseymoz]

29. Glad to feel like that, but . . .

. . . that's why scientists choose objective standards, like how many years have you been alive, as criteria for their test and control groups. If you feel great at 66 you belong in the study, because statistically a certain number of people that age are going to feel the same way.

[SemperEadem]

20. light up, everybody!!!

fire 'em up!

[Loudestlib]

21. inflammation

It sounds like it just helps with inflammation. It's good news but I thought a lot of people already knew this about MJ. I think Alzheimers results from bio-film and the inflammation that it causes .

[alfredo]

23. The smoking lamp is lit.

[Cal Carpenter]

24. This is interesting, thanks for posting

[Indepatriot]

25. After years of painstaking independent research I can report only one worrisome side effect...

Occasional weight gain due to excessive late night snacking. These effects, like so many other problems, are easily countered with a regime of regular aerobic exercise. In my case, bicycling a few times a week in the mountains near my home does the job.

[green for victory]

28. This is why the Feds took out a patent on the use of cannabinoids

#6630507

Cannabinoids have been found to have antioxidant properties, unrelated to NMDA receptor antagonism. This new found property makes cannabinoids useful in the treatment and prophylaxis of wide variety of oxidation associated diseases, such as ischemic, age-related, inflammatory and autoimmune diseases. The cannabinoids are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and HIV dementia

See. if everyone knew the feds had patents*(thanks to an alert DU'er there are many-haven't had time to read up) on the use of the main ingredient in Cannabis how many convictions would juries return for someone growing a plant?

but most people just can't seem to put it together.

Federal Medical Marijuana Prisoners and Cases
http://www.canorml.org/costs/federal_medical_marijuana_prisoners_and_cases

The war on the most useful plant on the planet could be over tomorrow- if the people could just do a little research.

[Dustlawyer]

43. I my case study of 1 I found that it helps my small fiber sensory neuropathy which is,

in my case, my immune system attacks the peripheral nerves causing them to short circuit and send false signals that my feet are on fire, being electrocuted suddenly and w/o warning, ants crawling and biting... It is one of the most painful, chronic conditions. Pot operates to put me in a dissociative state where I can compartmentalize the pain, forgetting it for awhile altogether. None of the powerful pain meds I am prescribed EVER stop me from feeling pain altogether. I would compare the side effects and pot wins hands down there too! Lastly, it's cheaper than the pills by a long shot. Just wish insurance would pay for it anyway, that would be cool to make an insurance company have to pay for my weed!

[Hestia]

30. Wow, this is from the NIH. Seems they don't always agree with FDA on too much.

You ought to go read their abstracts and studies. [Desperately hoping the pugs don't go after their funding and stays off their radar.]
I've spent a lot of time at NIA.NIH.gov lots of good resources though NIA (National Institute on Aging) is a bit childish, like they think seniors want primary colors splashed all over the place

[napoleon_in_rags]

31. It makes intuitive sense.

When you get stoned, memory decreases, but it comes back as it wears off. So it must kick in some part of the brain responsible for recovering memory.

[Auntie Bush]

35. So we can all be legally stoned in our old age.

Nursing homes will give it out along with daily medicine. Bet you'd see a rise in the number of nursing home patients.

[SCVDem]

36. Side effects may include happiness and peace.

Well Hell!

We can't have that. Of course big pharma will turn a simple fix into an expensive pill without those pesky side effects!

What could go wrong?

[Zorra]

40. Awesome! I smoked so much herb from the time that I was 18 until I was 33 that I should

easily have enough residual THC in my system to make me immune from Alzheimer's for the rest of my life.

[Fire Walk With Me]

42. The US Government owns the patent on cannabinoids as treatment for Alzheimer's and other illnesses.

The Significance of US Govt Cannabinoid Patent 6,630,507

http://stopthedrugwar.org/speakeasy/2008/jul/23/significance_us_govt_cannabinoid

2008

When I was at the Patients Out of Time Medical Cannabis conference in Asilomar this last April, I overheard a remark that startled me: "The US Government has a patent on cannabis." I couldn't locate the person who made the comment, so I went home and did some online research. Sure enough, patent number 6,630,507 states unequivocally that cannabinoids are useful in the prevention and treatment of a wide variety of diseases including auto-immune disorders, stroke, trauma, Parkinson's, Alzeheimer's and HIV dementia. The patent, awarded in 2003, is based on research done by the National Institute of Health, and is assigned to the US Dept. of Health and Human Services.

So, why is this important? Here is a legal document, in the public domain, which flies in the face of the US Government's stated position with regard to the classification of cannabis as a Schedule I substance having no "currently accepted medical use". Believe me, citing this patent stops the "medical marijuana is a myth" advocates dead in their tracks. They simply cannot argue with it. The forces that would keep cannabis illegal are vocal and well funded, but they are not impervious to persistent effort. The lynch pin in the War on Drugs is cannabis. Without the suppression and interdiction of this popular and widely used substance, there simply would not be enough "illegal drug use" going on to justify the huge amount of money and resources spent on "fighting drugs."

I believe disseminating information about this patent as widely as possible, and to as many people as possible is a crucial strategy in loosening that lynch pin, and changing public perception about cannabis. I, personally, downloaded the first page of this patent and sent a copy (with the assignee highlighted) to every one of my elected representatives. I have also included information about it in "letters to the editor" referencing any cannabis related news story I come across, I use it as an argument in every State medical cannabis and decriminalization initiative, and have mentioned it in all my comments to online posts and blogs of the same nature. I would be delighted if everyone who believes the War on Drugs is a failed and destructive policy, would do the same, until the existence of this irrefutable patent becomes widely held public knowledge, and government 's rhetoric is shown to be as hollow as a busted drum.

[G_j]

44. wow!

I had no idea, but it figures..,

[green for victory]

65. It's a glorius day on DU!

Someone else understands the patent!

THE Key to the end of the war. Now if only a reporter could ask about it...

This Oakland Attorney gets it:

Oakland cites surprise medical pot backer

In papers filed late Tuesday with the magistrate who is considering the fate of the Harborside Health Center, lawyers for Oakland said patent and research records reveal that "the government believes in the medical efficacy of cannabis" - contrary to the Justice Department's insistence that marijuana is a dangerous drug with no legitimate use.

Cedric Chao, a lawyer for the city, cited a 2003 patent application by the U.S. government that said cannabis compounds are "useful in the treatment and prophylaxis (prevention) of a wide variety of oxidation-associated diseases," including certain types of strokes and immune-system disorders. Chao quoted another patent application, by two government scientists in 2009, that referred to the "healing properties of Cannabis sativa," or marijuana, that have been "known throughout documented history."

"How can the government credibly deny the benefits of medical cannabis when the government itself is funding cutting-edge research proving the medical benefits of cannabis and seeking patents based on such research?" Chao wrote.

U.S. Attorney Melinda Haag filed suit in July seeking the closure of Harborside and the forfeiture of its offices at 1840 Embarcadero. She said the dispensary, which supplies marijuana to 108,000 patients, is violating federal drug laws.
http://www.sfgate.com/default/article/Oakland-cites-surprise-medical-pot-backer-4113767.php

[Fire Walk With Me]

68. ...

But then it comes down "the US government as monopoly" regarding the eventual application of cannabinoids for medical use. The road to victory is a long one but worth it!

[UnrepentantLiberal]

46. I think I feel the onset of Alzheimer's...

[WillyT]

48. HUGE K & R !!!

[L0oniX]

49. I suspect that Monsterano already has its patented round up ready pot seeds ...ready for market.

Just wait till the pot growers get hauled off to court by Monsterano for cross pollinated seeds.

[olddots]

50. in my own intensive studies of pot

I have become somewhat anti materialistic so this may be why some people want pot to remain "the evil weed".

[padruig]

54. THC as antagonist for Alzheimers mechanism

this is very interesting work

[The Wizard]

56. Many of our laws are rooted

in superstition and false belief. It's time for America to set aside ignorance and accept science.

[RainDog]

59. REMOVE CANNABIS FROM SCHEDULE I

or, rather, remove it from the drug schedule entirely and let the pharmaceutical knock offs remain.

[backscatter712]

67. b-b-but Marijuana doesn't have legitimate medical uses!

The DEA told me that, so it must be true!

[RainDog]

69. Former head of the DEA called for nullification of the WA and CO laws

honestly, you're not someone who gives a shit about the law when you think you should have the right to overturn laws voted by majorities concerning an issue about which the federal govt. has been a shameful example of EVERYTHING WRONG with government use and abuse of power.

They're like religious extremists who don't care if all the evidence indicates that evolution is reality, not a 6000 year-old earth - they want to believe something and no overwhelming evidence to the contrary will make them change their minds.

....sort of like the inquisition.

It's gotten to the point that it's ridiculous. The internet made it possible for people to read studies for themselves. But those folks still believe their own propaganda - or else they care more about their own pockets than they do democracy or the scientific method.

[Javaman]

73. I have a history of Alzheimer's in my family...

I honestly wish pot or at least THC was legalized.

I've never smoked anything in my life let alone pot and frankly, my choice, I probably still won't even with this research, however, I would be more apt to taking the THC in a pill or liquid form.

As I am officially past the middle age hurdle, I worry more and more each day about my mind slipping away and leaving my GF in a really bad situation. Yes, we have taken long term measures both financial and personally, but it still worries me.

I try to challenge my mind each and every day, I have taken up the guitar and am training myself in java. I do crossword puzzles and the jumble, etc all things that are supposed to help at least delay or supposedly blunt it's effects.

It's like living with a sword of Damocles over my head.

Added to that, both breast and colon cancer run in my family.

Yayyyy. Sorry for the pity party. Cheers!