Raising endocannabinoid levels: Arachidonic acid or other possibilities?

[psyche]

So do any of you swimmers have experience with this supplement? Does it have strong effect on mood? Do they have a slightest similarity to Cannabis in high doses?(ofcourse you can't get high with these, but the change they may cause in mood). Anandamide has rather short half-life and it isn't as abundant as 2-AG, but should be more active(?). Would it also be useful to eat omega-3 fatty acids alongside, because nowadays people are already getting a very high ratio of omega-3 to omega-6(which include AA and linoleic acid, which is converted to AA), which is unhealthy and quite propably increases the risk of cancer.

AA metabolises with glycerol to 2-AG, so could one change his diet in order to change that ratio of AA to 2-AG? From wikipedia, these contain some amounts of glycerol.

Foods and beverages
- Serves as humectant, solvent and sweetener, may help preserve foods.
- Solvent for flavors (such as vanilla) and food coloring.
- Humectant and softening agent in candy, cakes and casings for meats and cheeses.
- Manufacture of mono- and di-glycerides for use as emulsifiers
- Used in manufacture of polyglycerol esters going into shortenings and margarine.
- Used as filler in low-fat food products (i.e., cookies).
- Used as thickening agent in liqueurs.

Edit: AA is also converted to prostaglandins(responsible for ie. inflammation and pain signalling to the brain) by cyclooxygenase(COX). This conversion is irreversibly(until new COX is created) inhibited by aspirin. My question is would it help and be worth it if one coadministered aspirin, say once a week, with daily AA?

[snapper]

What effect are SWIY trying to achieve with this? Are SWIY planning on ingesting AA or 2-AG ? 2-AG is a potent emetic, so unless puking elevates SWIYs mood, it's probably not worth it.
Aspirin is good at causing gastrointestinal ulcers and should not be combined with anything that increases prostaglandin synthesis, since that would increase the risk of GI ulcers even more. Maybe some famotidine would be better with this combo.
Also, without naming sources, is AA even commercially available ?


Nissar A. Darmani
The Potent Emetogenic Effects of the Endocannabinoid, 2-AG (2-Arachidonoylglycerol) Are Blocked by 9-Tetrahydrocannabinol and Other Cannnabinoids
The Journal of Pharmacology and Experimental Therapeutics Vol. 300, Issue 1, 34-42, January 2002

[psyche]

I doubted it's availability too, but it turned out to be easily found. SWIM isn't propably going to try this anytime soon, but thought the idea was interesting. He was pondering on whether rising the endogenous cannabinoids would have anywhere near similar effects in nature on his mood than the exogenous ones and how strongly they would be felt. As the reference he has only tried 5-HTP of supplements, which ofcourse doesn't get you high but the effects are easily noticed. He was thinking if it was possible to have similar 'cannabis supplement'.

Looked up famotidine and the search engine popped up 'pepcid', which instantly remainded SWIM of the tv commercial about pepsid duo which is sold OTC in Finland. But SWIM think's it's propably not worth the side effects of aspirin. Originally he just thought about not having to take unnecessarily much omega-6 and being more specific but the hell with that, better just take extra omega-3 to balance it out and stick to AA I guess.

Originally SWIM pondered this concept more generally; since many drugs have closely related endogenous agents, would it be possible to specifically and markedly enhance their levels in a supplement-like way by diet and/or precursors. But since this isn't general practise, he thought that it isn't possible to get anywhere near satisfactory results, and diet only would be way too unspecific.

SWIM would appreciate anyone's experience with supplementary AA.

[Valseedian]

Originally Posted by psyche

I doubted it's availability too, but it turned out to be easily found. SWIM isn't propably going to try this anytime soon, but thought the idea was interesting. He was pondering on whether rising the endogenous cannabinoids would have anywhere near similar effects in nature on his mood than the exogenous ones and how strongly they would be felt. As the reference he has only tried 5-HTP of supplements, which ofcourse doesn't get you high but the effects are easily noticed. He was thinking if it was possible to have similar 'cannabis supplement'.

Looked up famotidine and the search engine popped up 'pepcid', which instantly remainded SWIM of the tv commercial about pepsid duo which is sold OTC in Finland. But SWIM think's it's propably not worth the side effects of aspirin. Originally he just thought about not having to take unnecessarily much omega-6 and being more specific but the hell with that, better just take extra omega-3 to balance it out and stick to AA I guess.

Originally SWIM pondered this concept more generally; since many drugs have closely related endogenous agents, would it be possible to specifically and markedly enhance their levels in a supplement-like way by diet and/or precursors. But since this isn't general practise, he thought that it isn't possible to get anywhere near satisfactory results, and diet only would be way too unspecific.

SWIM would appreciate anyone's experience with supplementary AA.

srry all, tl/dr after that quote, I hope I'm not repeating something:



the human body is a state-based analog system; that is to say that our future perception is based on past experiences (you can't figure out where you're going if you don't know where you are, and by knowing where you've been, it's even more easily predicted.)...

to this end, my ferret would actually suggest attempting to LOWER the total endoccannabinoid density.. think of it as a tollerance phenominon: the more you take the more you NEED to take to reach that spot again. by the same token, the less your receptors are 'used' t being activated, the easier it is to activate it. if your body is used to not having much, it won't take nearly as much to push the 'high'...

Reputation Comments on this post:

Great post, advice is spot on.

[sterling77]

Swim's thought about it before based on the fact that cannabis increases consumption of AA (if remembering correctly).

[snapper]

Well, SWIPsyche is right in that it is readily available, though quite expensive. It would be interesting to hear back about the subjective effects of this supplement. It seems that it is being promoted as an anabolic supplement and at recommended doses costs a fortune. Too rich for SWIMs blood given that SWIM is skeptical of an benefits except maybe as an antiinflammatory...

[Bildo]

SWIPsyche, what are you saying probably causes cancer?
I find it hard to imagine any cannabinoids contributing to excess cell growth as as far as I'm aware anandimide actually inhibits cell replication in the S phase.

[psyche]

I don't think endocannabinoids cause cancer, but a diet of high omega-6(which AA belongs to) to omega-3 ratio increases risk of cardiovascular problems and cancer among others. Here's from pubmed:

Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects.

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Citation

Reputation Comments on this post:

Interesting, though startling, find!

[Zaprenz]

http://en.wikipedia.org/wiki/URB597

"In pre-clinical laboratory tests researchers found URB597 increased the production of endocannabinoids by blocking their degradation, resulting in measurable antidepressant effects.
URB597 is also known as KDS-4103. KDS-4103 is being developed by Kadmus Pharmaceuticals, Inc. for clinical trials in humans. Kadmus claims, on their website (linked below) that this class of compounds may have antidepressant, anti-anxiety, and pain-killing effects." Wikipedia 2007

Looks fairly simple molecule. Do you think the researchers were having a laugh when they were cataloging the compounds. URB597 (Herb' 597)

If URB597 prevents breakdown maybe supplementation with AA would enhance its effect. Although I would imagine the effect of URB597 may be too strong in itself to notice any difference with AA supplementation or not. (Possibly a bit like supplementing MDMX with 5-htp)

Reputation Comments on this post:

interesting

[psyche]

That's interesting. I would very much like to see an antidepressant based on tickling of the cannabinoid receptors.

[Gradient]

I know this is a bit of an old thread - but I'm very interested in this potential interaction, as it sounds like a great idea. Has anyone had any experience potentiating cannabis with arachidonic acid supplements?

[Ally420]

AM404, a metabolite of tylenol, it is probably responsible for a majority of the effects of tylenol, is an anandamide reuptake inhibitor, binds to the vanilloid receptor and weakly binds to the cannabinoid receptors.

BE CAREFUL taking high quantities of tylenol as many of the other metabolites are high hepatotoixc.

[Gradient]

Originally Posted by Ally420

AM404, a metabolite of tylenol, it is probably responsible for a majority of the effects of tylenol...

Cool info. AM404 isn't arachidonic acid, though. AM404 is N-arachidonoylphenolamine, and you're right, it's a metabolite of tylenol.

Here's a cursory description of arachidonic acid, from Dr. Barry Sears

However, there are some fats you want to restrict in your diet. These are saturated fats, trans fats and (AA) arachidonic acid. I consider these to be really "bad" fats. Arachidonic acids are found primarily in fatty red meats, egg yolks and organ meats. This particular polyunsaturaed fat may be the most dangerous fat know when consumed in excess and is known as an Omega 6 fat.

He goes on to warn that excessive amounts are deleterious to health. This is pretty common sense though; if you don't want to get too fat, don't eat too much of it.

I've been doing a little snooping around for some articles discussing a potential interaction, and found one involving assays for interactions from long-term cannabinoid exposure and arachidonic acid pathways in schizophrenic patients. It's attached, and here are some interesting quotes that make me think there may be some compelling support for this method of potentiation:

The key finding of this study is the evidence that regular use of cannabinoids influences the function of bioactive lipids (ie prostaglandins) in healthy individuals, suggesting the potential of cannabinoids to modulate an alteration of the lipid-arachidonic acid cascade...Evidence for interactions between cannabis use and abnormalities of the lipid-arachidonic acid pathway might also provide a biochemical basis for the gene-environment hypothesis of cannabis effects on schizophrenia pathophysiology (pg 4)

In summary, our results support the assumption that D9-THC may aggravate a premorbid vulnerability of lipid metabolism in schizophrenia, interfering with maintenance of membrane structure and the release of arachidonic acid, and modulating metabolic steps downward the arachidonic acid cascade. (pg 5)

So has anyone tried this combination to any success?

[Ally420]

Originally Posted by Gradient

Cool info. AM404 isn't arachidonic acid, though.

Excuse me but what does that have to do with anything?!?!

This thread is "Raising endocannabinoid levels: AA or other possibilities?"

AM404 by definition is another possibility since it raises endocannabinoid levels.

Furthermore, in your post it is not at all clear what "combination" you are asking if anyone has tried as there does not appear to be a "combination" as such discussed in the paper in question. Can you clarify please?

Finally have you all see this?

Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets.

Berger A, Crozier G, Bisogno T, Cavaliere P, Innis S, Di Marzo V.


Nestlé Research Center, Nestec Ltd., Vers-chez-les-Blanc, CH-1000 Lausanne 26, Switzerland. alvin.berger@dis.nestle.com


Endogenous ligands of cannabinoid receptors have been discovered recently and include some N-acylethanolamines (NAEs; e.g., N-arachidonoylethanolamine) and some 2-acylglycerols (e.g., sn-2-arachidonoylglycerol). Previously, we found these compounds to be active biologically when administered per os in large quantities to mice. In the present work, piglets were fed diets with and without 20:4n-6 and 22:6n-3 fatty acid precursors of NAEs, in levels similar to those found in porcine milk, during the first 18 days of life, and corresponding brain NAEs were assessed. In piglets fed diets containing 20:4n-6 and 22:6n-3, there were increases in several biologically active NAEs in brain homogenates-20:4n-6 NAE (4-fold), 20:5n-3 NAE (5-fold), and 22:5n-3 and 22:6n-3 NAE (9- to 10-fold). These results support a mechanism we propose for dietary long-chain polyunsaturated fatty acids influences on brain biochemistry with presumed functional sequelae. This paradigm will enable targeted investigations to determine whether and why specific populations such as infants, elderly, or persons suffering from certain clinical conditions may benefit from dietary long-chain polyunsaturated fatty acids.
PMID: 11353819 [PubMed - indexed for MEDLINE]

http://www.pubmedcentral.nih.gov/art...medid=11353819

[Gradient]

Okay, no need to become combative or aggressive here. The reason I pulled this discussion up from 2007 was because the supplementation of arachidonic acid co-administered somehow with an NSAID seemed an intriguing, and less-than-thoroughly discussed, potential for potentiating cannabinoids.

I suppose the thread is very loosely based on general methods of potentiation, but if you took a moment to read through the original and subsequent posts, it becomes clear that the thread is really focused on arachidonic acid and cannabinoids. Your contribution was interesting, but had little to do with the original question - or my restatement of the question. Were you referring to the potential inhibition of COX enzymes, as psyche suggested in his original post using aspirin as the model? You seemed to suggest that it was cannabinoid re-uptake inhibition that was the potential dynamic here - but it's unclear whether you feel that this's a potential for a synergistic action. AM404 will inhibit COX synthesis too, but it doesn't seem that this's really what you were getting at...I'm confused, who so angry? Interesting info on the second post, nicely ties the whole fatty-acid to cannabinoid activity theory! Arachidonoylethanolamine is a long name for anandamide, while 2-arachidonoylglycerol is 2-AG - and both were mentioned in the original post. I'm referring to any combination, whatsoever, that has generated any noticeable effects. Not being picky here, just would appreciate some discussion.

Valseedian - very interesting, and relevant point! Sensitization is definitely a dynamic that I didn't even think of in this situation. That'll certainly be something to consider in the long run, but I don't know that reducing the body's total cannabinoid receptor density is a realistic short-term method of potentiation - though it'll certainly be among the most effective methods of inducing sensitivity to exposure to cannabinoids. Nice thinking! Can you imagine any potential interactions of arachidonic acid with exogenous cannabinoids?

To clarify the question: Have any regular cannabis-smokers observed any notable potentiation of cannabis experiences after supplementing with arachidonic acid? If someone has taken, or is taking arachidonic acid currently - has ingesting any kind of COX-enzyme inhibitor (acetaminophen/paracetamol, aspirin, any NSAID) had any effect on cannabis experiences?

[Valseedian]

I'd read about enzyme inhibitors and cannabinoids, but swim has had 0 luck potentiating the effects of THC from plant material... never thought about inhibitors for endocannabinoids.

I've certainly never been 'high' on tylenol... despite using what would be considered very very large doses on occasion, tho I've never gone out of the way to supplement with arachindonic acid.



swim finds that these minor supplementations are just not enough to make a real difference when you use external cannabinoids... I like the analogy of supplementing lsd/phens with 5-htp...

[Ally420]

Originally Posted by Gradient

I suppose the thread is very loosely based on general methods of potentiation, but if you took a moment to read through the original and subsequent posts, it becomes clear that the thread is really focused on arachidonic acid and cannabinoids. Your contribution was interesting, but had little to do with the original question - or my restatement of the question.

Then i suggest the thread was poorly labeled. I did read the first post and it seemed my comment was in line with it. The following posts focusing more on AA and less on general endocannabinoids seemed off track to me. Go figure. 2-AG is just one endocannabinoid. Why does anandamide, also an endocannabinoid not count?

Furthermore as you point out tylenol is an NSAID and one which interacts with COX and most of the other things aspirin does. Taking AA as the piglet study points our can help increase not only 2-AG but also anandamide as well. The combo of AA and Tylenol would probably work to an extent in answer to the original question but target both anandamide and 2-AG, not jsut 2-AG alone. This answers the original question posed and is all around relavent to the general discussion.

Why so angery? Your responce was flippant and dismissive. Can't say I tend to take kindly to that.

Does it produce noticeable effects on its own? Can't really answer that because SWIM never had an opertunity to personally experiement with it on a cannabinoid free system. SWIM does however seem to get higher after eating essential fatty acid and essential fatty acid containing protien rich foods. Next time SWIM eats such a meal they will also take a 1000mg tylonel and see.

[psyche]

Glad to see this topic has been woken up. The original intention was to discover the means to increase the levels of endogenous cannabinoids in a similar manner that it's possible to supplement l-tryptophan for serotonin or l-tyrosine for dopamine. Not necessarily AA-mediated, and not necessarily in combination with cannabis.

[Gradient]

Thanks for the clarification! Accordingly, I think this is a potentially significant thread - and might present therapeutic potentials. The reason that I'm harping on cannabis potentiation is because this is an easy, accessible method of trying to determine an interaction; we can talk circles around each other with biochemical pathways and neurochemical interactions, but without a lab, we'll never come to an answer - and thus far, the biochemical pathways don't support a positive interaction. This hasn't fully convinced me, however. I know our community hosts at least a handful of cannabis-lovers, this chimp included! Figured it wouldn't be too tough or unrealistic to solicit for possible experiences of potentiation as an indicator of a potential interaction of arachidonic acid and cannabinoids, as this AA idea is particularly intriguing.