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Old 10-12-2019, 01:07 PM   #1
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Join Date: Mar 2006
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Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp products

"What You Should Know About Using Cannabis, Including CBD, When Pregnant or Breastfeeding

FDA strongly advises against the use of cannabidiol (CBD), tetrahydrocannabinol (THC), and marijuana in any form during pregnancy or while breastfeeding."


Cannabis/hemp products are currently becoming 'trendy': the web article "CBD Oil: Is It Safe to Use During Pregnancy and Breastfeeding?" comments "CBD oil seems to be all the rage these days as a treatment for a whole range of ailments, including stress and pain. The growing acceptance and legality of marijuana in many states has unleashed a flood of CBD oil products on the market. You can find CBD-spiked lattes, gums, candies, lotions and beauty products almost everywhere, with fans hyping their healing powers." "But none have been approved by the Food and Drug Adminstration (FDA) or regulated in terms of dosage, formulation or method of delivery. And though CBD oil, which comes from the cannabis plant, doesn't seem to be addictive, it has not been shown to be safe for pregnant and breastfeeding women." https://www.whattoexpect.com/pregnan...ing-pregnancy/ (see also posts below)

Cannabis/hemp cannabinoid containing products may indeed prove to have valuable roles, BUT, what many do not realize, and is often not explained, is that the primary natural endogenous ligands (things that bind to the cannabinoid receptors) are down-stream oxidized derivative products of the Omega 3 and Omega 6 fatty acids. Omega 3s and 6s have a sew-saw competitive regulatory relationship. Lack of omegas 3 both short and long chain will negatively impact on function, at lots of levels including pain and mental well-being.

The natural cannibinoids are endogenously made in the body in very large part. We generally have more than enough Omega 6 linoleic acid in our diet, so will never normally be 'deficient' in endocannabinoids, but may be imbalanced due to lack of Omega 3s in the diet, or blocking of conversion pathways of plant based Omega 6 to long chain Omega 6, due to a mix of excess Omega 6 intake, and/or polymorphic less efficient conversion (desaturase) pathways.

In famine, when we lack Omega 6s in our diet, the body will use the information that there are not Omega six rich plant reproductive material based foods in the environment, to moderate our metabolism, and behavioral responses to better survive food shortage, including through the endocannbinoid pathways. Omega six arguably had very early roles in the development of life and is fundamental to human function through many pathways and mechanisms, which is why getting too much in the context of an antioxidant depleted diet is an important issue. I have written on this.https://www.researchgate.net/publica..._a_Modern_Diet

There may be some plant foods that contain an Omega 6 based cannabinoid, but a very few. Cannabinoids derived from the hemp family of plants have different structures to the those derived form Omega 3 and 6. There will be very small amounts of Omega 3 and 6 based cannabinoids in higher animal products but I am not sure how much or indeed if anybody has even looked at that.

The ones highlighted in the first abstract below are Omega 6s.

There are also Omega 3 ligands, which also compete for the receptor sites - a second link and abstract to a paper is provided below, a skim of which will give you the gist.

For every Omega 6 natural ligand there is likely an equivalent Omega 3 product, plus some extras for the longer Omega 3s, EPA and DHA.

Omega 3:6 imbalances and inefficiencies will lead to imbalances in the cannabinoid ligands, thus, altering downstream cell function.

Likely, in so far and cannabis / hemp cannabinoid ligands have medical effect; it is largely because they are competing with the Omega 6 ligands, and directly or indirectly taking up the receptor space, block use of it by Omega 6 products, so changing cell function. THC (the psychoactive cannabinoid in maruajana) has active effects, and CBD (the largely non-active in hemp) likely acts by simply directly or indirectly 'blocking' receptors. CBD oils may contain THC, permitted amounts varying significantly by countries, and details are not not always on labels. A percentage is relative - so people using significant amounts of CBDs would have greater THC exposure. 113 cannabinoids have been identified in the plant family. Much remains unknown, particularly in terms of long terms usage. https://en.wikipedia.org/wiki/Cannabidiol

Yes, all plants contain bio-active products. There are some other plants that produce the Omega 6 lipid based endogenous ligands, and there maybe some other ligands (complicated), but based on current knowledge the only really significant exogenous cannabinoids are found in the cannabis/hemp family ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163475/ ). Plant endocannabinoids have different structures to the endogenous cannabinoids.

Importantly, based on the early research the cannabinoid pathways have particular biological significance, which is why they are of above average relevance. They factor in a wider range of biological pathways, including in less obvious areas, including possibly in hormone levels so gender outlook development of males in utero or early life (see post below), appetite and obesity ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163475/ )

Arguably, making sure the body has adequate Omega 3s (the body's natural alternative to Omega 6 endocannabinoid precursors); will mean the Omega 3 endocannabinoids, will be available when necessary. to fill those receptor sites so altering cell function, by preventing their use by Omega 6 products - and that is the way nature designed the system.

Whilst science learned about these receptors in the process of trying to understand the biological roles of cannabis products (hence their names); the main known natural ligands of the cannabinoid receptors, are derivatives of Omega 3 and 6, not cannabis/hemp plant products. Some humans may have had access to cannabis / hemp on a evolutionary basis, most populations groups did not.

Yes, cannabis/hemp derived endocannabinoids do have physiological function - but oils can contain a raft of other products we do not know much about, have as yet not fully established long term effects, and they are not the primary ligands for the cannabinoid receptors.

Omega 3s are known moderators of pain, inflammation, metabolism, hormone pathways etc etc etc - see Omega 3 : 6 thread below, and the Greek Diet Thread on the main board. Omega six oxidized-products promote pain and inflammation - for example oxidised Omega 6 product 13HODE is the primary endogenous ligand /activator of the TRVP1 pathways https://en.wikipedia.org/wiki/TRPV1 https://www.ncbi.nlm.nih.gov/pubmed/23278358. 9 and 13HODE are the two most common oxidized lipids in plasma. Omega 3 helps moderate pain. Reduction of excess Omega 6 will also moderate pain (as does vitamin D - see thread). For example, studies suggested reduction of Omega 6 intake reduced serious headaches e.g. https://www.nyheadache.com/blog/chro...6-fatty-acids/

I will refine improve clarify and add to this thread over time, but it is important that people understand, that derivatives of Omega 3 and 6s, NOT cannabis/hemp products, are the primary ligands of the cannabinoid receptors. (I think I am a little dyslexic; and like most of us have more things I would like to do than hours in the day - so if I waited until things were perfect to post them they would never get done -please excuse typos etc - thank you - this is not a paper - I am just trying to flag what I believe are important under-discussed issues)

The Omega 3 and 6 roles and functions are massively complex, and hugely influential. This is emerging science. Sadly, there is more money to be made from hemp products; thus, most of the research and marketing attention is going into them, rather than Omega 3 cannabinoid receptor ligands.

Please do not misunderstand me, hemp products very likely have valuable uses; but surely it make sense, to address the dietary basics, including ensuring appropriate balances and intakes of Omega 3 and 6 fats, before - or at least at the same time - as considering hemp product use; and until there is extensive evidence as to the long term impact, to only use cannabis/hemp products as specifically targeted add-ons for very particular circumstances, people with broken pathways etc., and where used more widely, with appropriate caution.

Pragmatically for non-pregnant adults, who find CBD ameliorates symptoms for a given serious condition, from their perspective immediate relief must be weighed against the lack of research, and current pluses and minuses as set out in the "European Monitoring Centre for Drugs and Drug Addiction", 2018 document "Medical use of cannabis and cannabinoids"
http://www.emcdda.europa.eu/system/f...186ENN_PDF.pdf, in the same way as people would consider use of over the counter pharma products.

"There is less evidence about the risks of long-term medical use of cannabinoids, but in general those reported are similar to those reported for short-term use. Over time, more people report adverse events, but these are generally mild to moderate."

In summary - FDA advised strongly against CBD use in pregnancy (See below) - Not a miracle cure-all - Definitely has pharmacological impact - Will intervene in Omega 3 and 6 pathways - May moderate pain and inflammation - side effects may exist - plant cannabinoid structures are different to Omega 3:6 cannibinoids so effects will be different - huge amounts are currently unknown - these are fundamental pathways - if consideration is being given to CBD use attention should also be given to getting long term improvements in inflammatory and pain pathways through dietary improvements - ensuring Omega 3:6 intake balance - adequate vitamin D, and wider nutrients, in consultation with medical professionals.



Endocannabinoid Binding to the Cannabinoid Receptors: What Is Known and What Remains Unknown

"The endogenous cannabinoid ligands are unsaturated fatty-acid ethanolamides, glycerols or glycerol ethers. The first endogenous cannabinoid, N-arachidonoylethanolamine (AEA, also called anandamide, 5, Chart 2), was isolated from porcine brain by Mechoulam and co-workers [35]. Two other polyunsaturated fatty acid ethanolamides, N-homo-y-linolenoylethanolamine (6, Chart 2) and N-docosatetr-aenoylethanolamine (7, Chart 2) have been isolated from porcine brain and shown to bind to the cannabinoid CB1 receptor with high affinity [36]. sn-2-arachidonoylglycerol (2-AG; 8, Chart 2) was isolated from intestinal tissue and shown to be a second endogenous CB ligand [37]. 2-AG has been found present in the brain at concentrations 170 times greater than AEA [38], 2-AG acts as a full agonist and produces the characteristic effects associated with cannabinoid agonists. In addition, 2-eicosa-5',8',H',14'-tetraenylglycerol (2-AG ether, noladin ether, 9, Chart 2), a metabolically stable ether-linked analogue of 2-arachidonoylglycerol (2-AG) has been identified as another endogenous cannabinoid ligand [39], although the presence of this compound in mammalian tissues has been questioned [40]."


Emerging Class of Omega-3 Fatty Acid Endocannabinoids & Their Derivatives


The bodies natural endocannabinoids (eCBs) "are endogenously synthesized from the omega-6 and omega-3 polyunsaturated fatty acids (PUFAs)."

"With the increasing focus towards the consumption of omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), there has been a growing interest in the discovery of omega-3 fatty acid derived eCB (endocannabinoids) or eCB-like molecules with novel bioactivity (27). Herein, we review the discovery and physiological role of omega-3 eCBs that are derived from DHA and EPA (Figure 1A)."

"Herein, we review the discovery of omega-3 fatty acid derived eCBs that are generated from long chain omega-3 PUFAs - docosahexaenoyl ethanolamide (DHA-EA or synaptamide), docosahexanoyl-glycerol (DHG), eicosapentaenoyl ethanolamide (EPA-EA), eicosapentanoylglycerol (EPG). Furthermore, we outline the lesser known omega-3 eCB-like molecules that arise from the conjugation of the omega-3 fatty acids with neurotransmitters serotonin and dopamine - DHA-serotonin (DHA-5HT), EPA-serotonin (EPA-5HT), DHA-dopamine (DHA-DA) and EPA-dopamine (EPA-DA). Additionally, we describe the role of these omega-3 eCBs and their derivatives in different disease states such as pain, inflammation and cancer. Moreover, we detail the formation and potential physiological roles of the oxidative metabolites that arise from the metabolism of omega-3 eCBs by eicosanoid synthesizing enzymes - cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 epoxygenase (CYP450). In summary, we outline the novel findings regarding a growing class of signaling molecules, omega-3 eCBs, that can control the physiological and pathophysiological processes in the body."

Last edited by R.B.; 11-02-2019 at 12:16 PM..
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