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The Endocannabinoid System

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40 years ago when I started working with Cannabis there were just the classic Cannabinoids, all from Cannabis, then came the endo-cannabinoids, not phyto-Cannabinoids but still reacting with the two CB receptors, along came synthetic Cannabinoids which I felt were not Cannabinoids, but they did bind to the 2 receptors to different degrees, but they were in the Cannabinoid or extended Cannabinoid family.

As well as various analogs of anandamide, they are synthetic, endo-cannabinoids, some reseachers call them Cannabinoids.

Now terpenes, and alkylamides found in echinecea purpurea, and honokiol and magnolol are considered Cannabinoids? As well as Thujone? Are they real Cannabinoids, or just Cannabinomimetics?

I think people are way to inclusive to include some of these compounds as Cannabinoids. They are not Classical, Phyto-Cannabinoids, they are something else, the endo-Cannabinoids I understand a bit, the synthetic ones are surely a different class.

My two cents.

Hempsci

Edited by hempsci

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I think I understand your frustration.  I highly doubt they anticipated the ECS to be as significant as it is.  Let's say you're honokiol or magnolol.  Over 2000 years documented history of use.  Anti-inflammatory, anti-cancer, anxiolytic, sedation, but not a clue as to how or why.  They're legal, so folks have had access.  They've been more than able to demonstrate the end results of some of their pharmacological characteristics, but largely unable to describe the pharmacology itself.  They've only known about the ECS for about 20 years.  Research has since literally been expanding exponentially.  When they come to the conclusion that the primary physiological processes targeted is the endocannabinoid system, I'm not sure what else they're supposed to call it. 

 

Same with beta-caryophyllene. It's a full CB2 agonist. That's the primary receptor targeted in the human body.  It's the only full natural CB2 agonist that I'm aware of. 

 

Cannabis is the bees knees and all, but it's not as important as the ECS, imo.    

 

I guess one thing I'd point out is that with thujone, and other compounds, the primary physiological processes targeted isn't the ECS. I'm pretty sure it's the 5-HT system.  These systems are closely interrelated, and modulate one another, but I think in order for a compound to be classified as a phytocannabinoid is that the ECS needs to be the primary target.  Maybe even take that one step further and say that it has to modulate CB1/CB2 signaling (at least until they determine if they should reclassify GPR55/GPR119).  

 

State a terpene that you're interested in.  I'll show you what I mean about looking at how they might interact.  I can't gaurantee we'll learn anything, but we might.  

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This is from another thread:


 

I was searching info about GI issues, and came across an article on curcumin. It was interesting so I did a search for it, noticed it has anti-inflammatory, analgesic, and neuroprotectant characteristics. I thought that sounded like a cannabinoid, so I searched for that. Not a direct agonist, but it's been shown to increase endocannabinoid levels in a 'brain region specific manner'.

 

 

Quote


Abstract

Increasing interest has recently been attracted towards the identification of natural compounds including those with antidepressant properties. Curcumin has shown promising antidepressant effect, however, its molecular target(s) have not been well defined. Based on the interaction between the neurotrophins and endocannabinoid system as well as their contribution to the emotional reactivity and antidepressant action, here we show that 4-week treatment with curcumin, similar to the classical antidepressant amitriptyline, results in the sustained elevation of brain nerve growth factor (NGF) and endocannabinoids in dose-dependent and brain region-specific fashion. Pretreatment with cannabinoid CB1 receptor neutral antagonist AM4113, but not the CB2 antagonist SR144528, prevents the enhancement of brain NGF contents. AM4113 exerts no effect by itself. Our findings by presenting the CB1 receptor-mediated endocannabinoid signaling and NGF as novel targets for curcumin, suggest that more attention should be focused on the therapeutic potential of herbal medicines including curcumin.

 

The CB1 Receptor-Mediated Endocannabinoid Signaling and NGF: The Novel Targets of Curcumin

 

 

Expect to see much more of this in the years to come. Teams currently seem to be scrambling to identify new cannabinoids so they can develop new compounds based on their structures.  

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Expect to see much more of this in the years to come. Teams currently seem to be scrambling to identify new cannabinoids so they can develop new compounds based on their structures.

So they can muscle in on cannabis, the cash cow of this decade. Substitute something in for something that already works good so you can patent it, corner the market, and make a fortune. Then they can finally kill this pot nonsense dogma for good. And we thought they were just going to tell us why cannabis works. Silly now weren't we? There's no money in that.

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Why don't they take all the synthetic garbage and find something natural we can substitute in for that? What? We did that? OH YEAH, I remember, that's why we chose cannabis.

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I think I understand your frustration. I highly doubt they anticipated the ECS to be as significant as it is. Let's say you're honokiol or magnolol. Over 2000 years documented history of use. Anti-inflammatory, anti-cancer, anxiolytic, sedation, but not a clue as to how or why. They're legal, so folks have had access. They've been more than able to demonstrate the end results of some of their pharmacological characteristics, but largely unable to describe the pharmacology itself. They've only known about the ECS for about 20 years. Research has since literally been expanding exponentially. When they come to the conclusion that the primary physiological processes targeted is the endocannabinoid system, I'm not sure what else they're supposed to call it.

 

Same with beta-caryophyllene. It's a full CB2 agonist. That's the primary receptor targeted in the human body. It's the only full natural CB2 agonist that I'm aware of.

 

Cannabis is the bees knees and all, but it's not as important as the ECS, imo.

 

WELL THAT DEPENDS ON YOUR USE? MANY RECREATIONAL USES COULD CARE LESS ABOUT THE ECS REGARDLESS IF THEY USE THEIR RECEPTORS CONSTANTLY.

 

I guess one thing I'd point out is that with thujone, and other compounds, the primary physiological processes targeted isn't the ECS. I'm pretty sure it's the 5-HT system.

MAYBE

These systems are closely interrelated, and modulate one another, but I think in order for a compound to be classified as a phytocannabinoid is that the ECS needs to be the primary target. Maybe even take that one step further and say that it has to modulate CB1/CB2 signaling (at least until they determine if they should reclassify GPR55/GPR119).

 

SO CANNABINOIDS OR TERPENES THAT DO NOT TARGET CB1/CB2/CB3 ETC ARE NOT CANNABINOIDS? EVEN IF THEY HAVE BEEN CALLED THAT FOR YEARS AND YEARS?

 

State a terpene that you're interested in. I'll show you what I mean about looking at how they might interact. I can't gaurantee we'll learn anything, but we might.

 

Ok I will try, how about some of the ones I have tried with THC, Myrcene, Pinene, Limonene, Guaiol, Nerolidol, Linalool, Caryophyllene, Caryophyllene oxide, Phytol, then there is gamma-terpinene, y-terpinene, beta-pinene that friends have reported to make THC more up, clear, euphoric, psychedelic, cerebral. Do them all if not to much trouble.

Hempsci

Edited by hempsci

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I suppose that's true. I didn't know anything about the ECS until about a year ago. That never hindered my ability to derive benefit from the plant. It kinda seems similar to other important physiological processes, you don't have to be aware of them in order for them to function (but it's absolutely essential to health/disease).

 

The point I was trying to make was that, in regards to the natural realm, known compounds are being elucidated as primarily targeting the ECS. In that regard when a cannabinoid is labeled as such it doesn't have anything to do with cannabis (ie the ecs is more important).

 

I'm not sure where you're going with the second question. I looked at thujone again and it appears that subsequent research was unable to identify any binding at CB1. The thing to keep in mind is that CB1, GABA, and 5-HT3 are all coexpressed (in some regions of the brain) presynaptically and modulate one another. I don't believe they knew this in '99. I kinda assume you might be referring to CBD. Virtually no affinity for CB1/CB2. BUT, it does directly and indirectly effect CB1/CB2 signaling. It also targets GPR55 and I think GRP119.

 

The ECS is the totality of the cannabinoid receptors, endocannabinoids and the enzymes that synthesize/degrade them. A phytocannabinoid can modulate cannabinoid receptor signaling via any and/or all of these variables.

 

Beyond that is where it starts to get tricky. When we say CB1 activation produces psychotropic effects I don’t believe that’s the end of the story. WTF doesn’t CB1 do?

 

In order to really dig into the therapeutic value of varying chemotypes (or the psychotropic effects) we need to elucidate the signal transduction pathways, as well as the other GPCRs that it modulates, and that modulate it.

 

http://jme.endocrinology-journals.org/content/44/2/75.long

 

It’s a bit of a guessing game, but I think bioassay with these compounds might help.

 

With thujone one suggestion for the psychotropic effects is inhibition of 5-HT3. Well, it just so happens that activation of CB1 inhibits 5-HT3.

 

I think if we look closely at the pharmacological characteristics of terpenes and THC that we might identify similar transduction pathways, and GPCR modulation. I can’t understand what else would make sense given that they don’t modulate the affinity of THC at CB1. I guess if it’s not the signal transduction/GPCR modulation it’s the enzymes. It seems like it’s got to be one or the other. Given the levels we’re referring to being active (0.05%), I’m betting it’s the first.

 

I thought you might throw out myrcene first. It seems to be of particular interest. You’re likely aware that I haven’t tried it. I really need to get a new round of testing done. I think that would be a good one to start with though. It’s going to take some time and effort on my part. I’m in the middle of a few things currently so it may take a minute.

 

If I go through the effort I’m going to expect this to be somewhat reciprocal. You’ve got to give up some of the goods in regards to your bioassay. That’s the aspect I feel can give us the leg up over the research community.

Edited by in vivo

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If CBD which does not bind to CB1 or CB2 yet is called a Cannabinoid then Thujone is just as much a Cannabinoid?

I understand that CBD and Thujone does modulate the affinity of other Cannabinoids, like THC in the case of CBD.

I am really just playing the devils advocate, trying to understand the why's.

My research was not aimed at anything besides recreational, that was my sole focus.

I have already posted on other sites pretty much what I found, which of the 10 Cannabinoids I tried (THC, CBD, CBC, CBG, CBN, THCV, CBDV, CBGV, CBCV, CBNV) which had stoney or high effects, THC, with CBN & CBNV to a degree, with CBD and THCV and maybe CBC to a much lesser degree, modulating the THC effects by delaying onset, reducing peak experiences, and making the THC last longer.

I then mixed in a tiny bit of each, one after the other in seperate tests, of the 10 terpenes to the 25mg THC samples. Each test was preceded and followed by a 100 question oganolepctic survey filled in by each subject, each test. Only one test a day. All double blind tests from testee and tester. All materials weighed with a scale with .001 accuracy. Vaporized in a Volcano on a clean stainless pad for oil as the compounds readily melt.

I already told you the two that were the best with THC Myrcene for couch lock, Limonlene for an up high. Pinene also makes THC stronger a bit and makes the THC effects more fuzzy not clear or up. Nerolidol, tastes like bitter soapy flowers, not harsh w/THC makes the THC less clear, hard to concentrate & focus. but stoney, bit stimulating. Guaiol, little bit harsh, makes THC more physical, sedative, more mental downer then physical. Linalool, tastes like earl grey tea, tastes almost good, hard on lungs, gave me a headache and I threw up. The two Caryophyllene's did not seem to help THC. Phytol I will have to look up I don't see it right now. Then there is gamma-terpinene, y-terpinene, beta-pinene that friends have reported to make THC more up, clear, euphoric, psychedelic, cerebral.

hempsci

Edited by hempsci

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Sorry for the delay.  I’ve been rather busy.  I finally got a chance to take a brief look at myrcene.  I don’t have access to most of the literature which is hindering my ability to identify all the possible interactions.  

 

However, it looks like α2-adrenoceptors play a role between myrcene and THC.

 

I found that myrcene is an α2-adrenoceptor agonist here:

Effect of myrcene on nociception in mice

 

Two of the three α2-adrenoceptors subtypes are expressed in the olfactory system:

http://en.wikipedia.org/wiki/Alpha-2_adrenergic_receptor

 

As you know CP55,940 is a CB1 agonist. They’ve shown that CB1 agonists and α2-adrenoceptor agonists potentiate one another.

Synergistic and additive interactions of the cannabinoid agonist CP55, 940 with μ opioid receptor and α2‐adrenoceptor agonists in acute pain models in mice

 

Coincidently this might also explain why CBG seems pleasant even though it doesn’t activate CB1:

Evidence that the plant cannabinoid cannabigerol is a highly potent α2‐adrenoceptor agonist and moderately potent 5HT1A receptor antagonist

 

The ECS, the 5-HT system, and α2-adrenoceptors are closely interrelated and likely in play with this association. Additionally, voltage gated ion channels like Ca2+ also look to be in play. It looks as though Ca2+ regulates the degree of modulation between the 5-HT system and the α2-adrenoceptor. That means that TRPV1 is also in play because CB1/CB2 activation inhibits Ca2+, while TRPV1 activation increases it. THC is an agonist at both (moreso at CB1/CB2) but taking into account additional cannabinoid and terpenoid activity at TRPV1 might account for some of the finer details.

 

There’s a graphic of the signal transduction pathways in the first post.

 

Here’s the citation Ca2+:

Calcium-dependent inhibition of synaptosomal serotonin transport by the α2-adrenoceptor agonist 5-bromo-N-[4, 5-dihydro-1H-imidazol-2-yl]-6-quinoxalinamine ( …

 

These systems are so closely related that we have to consider more than just functional heteromers and dimerization between with CB1/CB2 and other GPCRs.  There’s retrograde signaling to account for. One endogenous compound can regulate the release of another and vice versa. Serotonin and cannabinoids would be one example. 

 

Other interactions that you might be interested in might include opioid receptors, dopamine receptors, and likely any other receptors associated with entheogens. If you look at Pertwee’s overview you can identify the scope of these interactions. I’d search for more recent data in regards to specifics.

 

In terms of potential therapeutic value α2-adrenoceptor activation is believed to be associated with pain treatment, gastro protection, as well as the treatment of ADHD and tics.

 

CBRs are so highly expressed in the brain that there aren’t many functions that they don’t directly impact (or that don’t impact them).  If you identify the main functional mechanism targeted by a terpene and cross reference it to the ECS you’ll likely find associations similar to the one above. I would imagine that there’s more going on with myrcene and I’m working on gaining access to more literature.  Once I gain access I’ll come back to this and try to take a closer look. 

Edited by in vivo

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If CBD which does not bind to CB1 or CB2 yet is called a Cannabinoid then Thujone is just as much a Cannabinoid?

I understand that CBD and Thujone does modulate the affinity of other Cannabinoids, like THC in the case of CBD.

I am really just playing the devils advocate, trying to understand the why's.

 

We have to cinsider more than the receptors. A compound that targets the enzymes associated with the synthesis and degradation of endogenous cannabinoids also need to be taken into account. CBD is a FAAH inhibitor (which increases endocannabinoids) and a AEA reuptake inhibitor. CBD doesn't have much binding affinity for CB1/CB2 but it's a agonist blocker. More murking but equally relevant is that it has a binding affinity for receptors being considered as potential CB3 candidations like GPR55 and GPR119. 

 

My research was not aimed at anything besides recreational, that was my sole focus.

I have already posted on other sites pretty much what I found, which of the 10 Cannabinoids had stoney or high effects, THC, CBN to a degree, with CBD and THCV and maybe CBC to a much lesser degree, modulating the THC effects by delaying onset, reducing peak experiences, and making the THC last longer.

 

What's funny is that it's all the same systems and functions that modulate recreation and therapeutic value.  In many ways they're one in the same.  Shoot me a link to where I can read up. I'm very interested in learning about your trials.  

 

I already told you the two that were the best with THC Myrcene for couch lock, Limonlene for an up high. Pinene also makes THC stronger a bit and makes the THC effects more fuzzy not clear or up. Nerolidol, tastes like bitter soapy flowers, not harsh w/THC makes the THC less clear, hard to concentrate & focus. but stoney, bit stimulating. Guaiol, little bit harsh, makes THC more physical, sedative, more mental downer then physical. Linalool, tastes like earl grey tea, tastes almost good, hard on lungs, gave me a headache and I threw up. The two Caryophyllene's did not seem to help THC. Phytol I will have to look up I don't see it right now.

 

Having the experience with these compounds seems like an enourmous advantage.  It seems like it might help ensuring that you're on the right track in terms of research.  You want to write a new book?    

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We have to cinsider more than the receptors. A compound that targets the enzymes associated with the synthesis and degradation of endogenous cannabinoids also need to be taken into account. CBD is a FAAH inhibitor (which increases endocannabinoids) and a AEA reuptake inhibitor. CBD doesn't have much binding affinity for CB1/CB2 but it's a agonist blocker. More murking but equally relevant is that it has a binding affinity for receptors being considered as potential CB3 candidations like GPR55 and GPR119.

 

 

 

What's funny is that it's all the same systems and functions that modulate recreation and therapeutic value. In many ways they're one in the same. Shoot me a link to where I can read up. I'm very interested in learning about your trials.

 

There is not one link, I have posted bits and pieces of the work all over. I do not even have the links. You can ask me questions but to be honest my post above #63 is good a distillation of the results, "reread I added some info". I will try and add any other info but I have to find it first. I never compiled all the info, I did it for my own knowledge only, and once I understood the facts about the terpenes I tried, and how they modified THC, that was my goal for that work. It was done over a decade ago, I was interested in developing single terpene varieties, for the top 25 terpenes, but did not finish the work. I doubt I will.....

hempsci

 

 

Having the experience with these compounds seems like an enourmous advantage. It seems like it might help ensuring that you're on the right track in terms of research. You want to write a new book?

 

Not interested at all, writing is to much work. If I wanted to work I would be working with plants not paper.

hempsci

Edited by hempsci

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 couch lock = muscle fatigue and tiredness about 15-45 minutes after inhalation?

Initial expectorant quality? I wonder if with many of them there might be an initial peak followed by a plateau that is longer lasting (and differing in effect). 

Up high = stupefied without the sedation?

I’m assuming alpha. Some sources contain high amounts of both, so it’s difficult to say.  I bet it might have a taste that lingers.  On point with clear. Any headaches on that one?     

I’m not sure what grey pearl tastes like but I bet it’s really “floral”.  That’s one that seems to have the potential to morph 5-15 min in.  You have to be careful not to use too much infusing a room with that.  Can be a bit much.    

The oxide and beta are in some sources.  Those seem like they might be very dissimilar to the others.     

I think I’ll have to spend some more time with this again.   

 

You bump it to 26mg, or did you go higher?  Any steam distillation? Going that route and switching up cannabinoid profiles might be interesting.  Maybe.

 

That's the good thing about plants from my end, but I hear ya in terms of relativity.  I'd like to see a F1 rounded THC:CGB:CBD line.  That's kids play compared to PCR analysis.  I'm obviously interested though.        

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