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Old 10-12-2019, 01:07 PM   #1
R.B.
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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."

https://www.fda.gov/consumers/consum..._source=Eloqua


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.


OMEGA 6s


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120766/

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]."



OMEGA 3s

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685292/

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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Old 10-13-2019, 02:47 AM   #2
R.B.
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

This is a useful summary from Harvard Health

These products may well have significant uses but there is still a lot we do not know.

Might concentrated Omega 3 endocannabinoids do the same things - for me it is likely they would in terms of pain etc - hopefully one day somebody will do the necessary research.



https://www.health.harvard.edu/blog/...-2018082414476

Cannabidiol (CBD) — what we know and what we don’t
Posted August 24, 2018, 6:30 am , Updated August 27, 2019, 5:21 pm
Peter Grinspoon, MD
Peter Grinspoon, MD
Contributor


Is cannabidiol safe?

"Side effects of CBD include nausea, fatigue and irritability. CBD can increase the level in your blood of the blood thinner coumadin, and it can raise levels of certain other medications in your blood by the exact same mechanism that grapefruit juice does. A significant safety concern with CBD is that it is primarily marketed and sold as a supplement, not a medication. Currently, the FDA does not regulate the safety and purity of dietary supplements. So you cannot know for sure that the product you buy has active ingredients at the dose listed on the label. In addition, the product may contain other (unknown) elements. We also don’t know the most effective therapeutic dose of CBD for any particular medical condition."


"The bottom line on cannabidiol

Some CBD manufacturers have come under government scrutiny for wild, indefensible claims, such that CBD is a cure-all for cancer, which it is not. We need more research but CBD may be prove to be an option for managing anxiety, insomnia, and chronic pain. Without sufficient high-quality evidence in human studies we can’t pinpoint effective doses, and because CBD is currently is mostly available as an unregulated supplement, it’s difficult to know exactly what you are getting. If you decide to try CBD, talk with your doctor — if for no other reason than to make sure it won’t affect other medications you are taking."
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Old 10-13-2019, 03:01 AM   #3
R.B.
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

Omega 6 endocannabinoids and the brain - this paper gives an idea of the importance of Omega 6 endocannabinoids and brain function.

No mention of Omega 3s though - situation normal - you cannot patent natural Omega 3 fats - and they are an established market - which probably explains the lack of mainstream focus into research into the area.



Endocannabinoid signalling and the deteriorating brain

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471876/

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Old 10-13-2019, 03:17 AM   #4
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

This gives a hint of the importance of cannabinoid receptors - as above, many of the reported beneficial effects of hemp derived cannabinoids could be a reflection of low levels of Omega 3 and excess Omega 6s in peoples' diets.

Yes complicated and of course this very much is a generality - but vendors are not saying sort out your Omega 3 - 6 profile / wider diet first/as well, and see if that works, they are instead offering hemp products, in part because the basic mechanisms are not widely appreciated..

Yes, and as above, hemp products have a heap of uses, including for making hemp fiber products, but hemp oil products do not address all the issues that arise from Omega 3 - 6 imbalances - they only 'block' the CB receptors - normally filled by Omega 3s and 6s derivatives; and that is only one of many important roles of Omega 3s and 6s - there are massive families of bio-active products of both Omega 3 and 6, and lack of Omega 3 and excess of Omega 6s have a host of biological effects - further hemp oil may contain a wider range of other factors of uncertain effect as highlighted by the Harvard commentary above.

CBD indeed likely has useful as yet very imperfectly understood pharmacological roles, but as with other palliative products, should we not be sorting out more long-term, underlying, causes of the rising incidence of non-communicable oxidative and inflammatory related conditions?


Docosahexaenoyl ethanolamide (DHEA) is an Omega 3 endocannabinoid


https://www.caymanchem.com/product/10007534

"Docosahexaenoic Acid (DHA) is an essential fatty acid and the most abundant ω-3 fatty acid in neural tissues, especially in the retina and brain. Docosahexaenoyl ethanolamide (DHEA) is the ethanolamine amide of DHA that has been detected in both brain and retina at concentrations similar to those for arachidonoyl ethanolamide (AEA).1,2 A 9.5 fold increase of DHEA was observed in brain lipid extracts from piglets fed a diet supplemented with docosahexaenoic acid (DHA) compared to a control diet without DHA.3 DHEA binds to the rat brain CB1 receptor with a Ki of 324 nM, which is approximately 10-fold higher than the Ki for AEA.4 DHEA inhibits shaker-related voltage-gated potassium channels in brain slightly better than AEA, with an IC50 of 1.5 µM.5"

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Old 10-13-2019, 03:48 PM   #5
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

I have not read extensively into these topics but just post these by way of examples, of the contention intervention in the Omega 3 and 6 cannabinoid and related pathways might have significant effects - more reading by me and research by scientists in the field required.

Mice are not humans, lab work is not real life, and these things need to be well established, but these historic observations would suggest care, until proven otherwise, would be prudent.

There are certainly plausible generalized pathways for endocrine disruption; intervention in the omega 6 pathways can impact hormone production in utero, including through PGE2 pathways, which could impact gender outlook and physical reproductive organ development, dependent on timing and power of effect on testosterone levels.

This suggests care should be taken, and wider viewpoints considered, when making recommendations as to the usage of THC/CBD products, particularly in females who are pregnant or hoping to get pregnant, and or breast feeding.





Effects of Cannabinoids and Female Exposure on the Pituitary-Testicular Axis in Mice: Possible Involvement of Prostaglandins

https://academic.oup.com/biolreprod/.../2/315/2766959

"Chronic exposure to THC, CBN, or cannabidiol (CBD), beginning at 30 days of age through adulthood, influenced the endocrine responses to a sexually receptive female. Thus, weights of testes and seminal vesicles were reduced in males from all cannabinoid-treated groups on the day after exposure to a female, compared with treated males housed in all-male groups."


"Both psychoactive and nonpsychoactive constitutents of marihuana are capable of altering the function of the pituitary-gonadal axis and of influencing the endocrine responsivity to female-related exteroceptive cues in male mice."



Maternal or Paternal Exposure to Cannabinoids Affects Central Neurotransmitter Levels and Reproductive Function in Male Offspring

https://link.springer.com/chapter/10...59259-710-9_43

"The F1 male offspring of male mice treated with CBN, CBD, or THC presented evidence of reduced fertility and testicular chromosomal abnormalities. In addition, two of the F1 male offspring of the THC-treated mice sired litters containing pups with severe congenital malformations.

These findings indicate that maternal or paternal exposure to cannabinoids can influence developmental and reproductive functions in offspring. Thus, cannabinoids appear to be both mutagenic and teratogenic in mice."

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Old 10-14-2019, 06:45 AM   #6
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

More questions than answers!

A bit complicated but confirms the point raised that Omega 3s and 6s and their downstream oxidized products including prostaglandins are crucial to the reproductive pathways, and cannabinoids impact these pathways.

Prostaglandin pathways also factor in cancers "Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer." https://www.hindawi.com/journals/ijcb/2012/723419/ Again it is complicated, but the Omega 3:6 thread tries to highlight the functional relevance of Omega 3 and 6 to cancer. http://her2support.org/vbulletin/showthread.php?t=24410



"Cannabinoids stimulate prostaglandin production by human gestational tissues through a tissue- and CB1-receptor-specific mechanism"

https://www.physiology.org/doi/full/...r_pub%3dpubmed

"This study demonstrates a potential role for endocannabinoids in the modulation of prostaglandin production in late human pregnancy, with potentially important implications for the timing and progression of term and preterm labor and membrane rupture."

"several studies (5, 21) have indicated that the incidence of cannabis use during pregnancy is ∼5–15%. These studies were mainly conducted in intercity hospitals, and in some cases their findings may be confounded by the use of other illicit substances as well as smoking. Cannabis use during pregnancy has been associated with many adverse outcomes such as low fetal birth weight, preterm delivery, and miscarriage (25).

The active ingredient in cannabis exerts its actions through brain-type (CB1) and spleen-type (CB2) cannabinoid receptors. Two key naturally occurring endogenous cannabinoid ligands, 2-arachidonyl-glycerol (2-AG) and anandamide (AEA), have been identified (25), and recent years have seen the identification of a number of enzymes involved in their synthesis and degradation (1). AEA is degraded by the enzyme fatty acid amide hydrolase (FAAH), which metabolizes it into arachidonic acid and ethanolamide. CB1, CB2, and FAAH have all been identified and their expression characterized in gestational tissues (8, 17).

Disruptions in the balance of AEA levels and FAAH activity have been implicated in poor implantation in the mouse (15). Low FAAH activity and high levels of AEA are apparent in the blood of women who suffer from spontaneous miscarriages (14). Furthermore, increased circulating AEA levels lead to poor implantation in patients undergoing in vitro fertilization as well as embryonic transfer procedures (13).

It is well established that prostaglandins play a critical part in multiple aspects of pregnancy, including delivery at term and preterm (1st and 2nd trimester), and that the fetal membranes play a major role in intrauterine prostaglandin production. Since endocannabinoids are both a source of AA that can then be a substrate for the production of prostaglandins and are also CB ligands with potential effects on placental tissues, the aim of the present study was to determine the effects of endocannabinoids on the production of prostaglandins by extraplacental membranes: amnion, chorion, and decidua
."

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Old 10-14-2019, 08:55 AM   #7
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

As above blocking / altering Omega 6 endogneous cannabinoid activity, and intervening in the Omega 3 : 6 cannabinoid messaging metabolic control see-saw in pregnancy is going to have physiological effect.

What is the effect of cannabinoids in CBD - we simply do not know - but we do know plant based cannabinoids may well impact brain development and later physiology - and THC in cannabis likely does - further the body is so complex - it is unlikely that interventions with non-endogenous plant based cannabinoids outcomes in pregnancy will be overall generally beneficial.

Given we do not have the answers, surely caution should be the way to go, and mothers should be made fully aware of the issues surrounding CBD, more particularly cannabinoids in pregnancy, breast feeding and ealry rearing, and which arguably they are not at the moment.





Prenatal Exposure to Cannabis Affects the Developing Brain
Children born to moms who smoked or ingested marijuana during pregnancy suffer higher rates of depression, hyperactivity, and inattention.


https://www.the-scientist.com/featur...ng-brain-65230

"When marijuana is ingested or smoked during pregnancy, exogenous cannabinoids enter the blood and cross easily through the pla*cental barrier."

"To date, the three largest longitudinal studies of the children of women who smoked marijuana once a week or more during their pregnancies have identified remarkably consistent outcomes during early development and through young adulthood. In infants, these include increased impulsivity, hyperactivity, and delinquent behaviors, as well as memory dysfunction and decreased IQ scores. During adolescence and early adulthood, fetal cannabis exposure has been linked to persistent reduction in memory and concentration, higher rates of drug use, and an increased incidence of hyperactivity, signs of depression, and psychotic and schizophrenic-like symptoms. These mental health issues are further evidenced by increased reports from both parents and schoolteachers of problematic behavior and delinquency in cannabis-exposed kids."

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Old 10-14-2019, 09:11 AM   #8
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

Yes this is primarily looking at THC, but the impact is due to intervention in the cannabinoid pathways - were studies looked at impact of THC in cannabis; to what extent were they reflecting the co-impact of other cannabinoids. In the words of others:

"it is imperative that significant efforts be immediately dedicated to evaluating the potential consequences of exposure for the fetus. 2017/2018 "


Cannabis Use during Pregnancy: Pharmacokinetics and Effects on Child Development

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211194/

"Given the possibility of increased use in pregnant women and the fact that cannabis is being widely investigated as a novel treatment for a variety of diseases, including epilepsy, multiple sclerosis and cancer, it is imperative that significant efforts be immediately dedicated to evaluating the potential consequences of exposure for the fetus."

"The eCB signaling system plays an overarching regulatory role during the initial stages of embryo development, implantation and ensuing prenatal development and differentiation. It undergoes a drastic switch in function from the prenatal determination of cell fate to the homeostatic regulation of metabolic pathways and transmission in the mature CNS. The functional role of CB1R and CB2R during this early stage of embryogenesis is not well understood but is likely linked to their ability to control cell proliferation and differentiation (Galve-Roperh et al., 2013)."

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Old 10-14-2019, 10:12 AM   #9
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

Are CBD products bio-active in PGE2 and other pathways - yes https://www.google.com/search?client...b-d&q=CBD+PGE2

Might that have pharmacological potential in particular circumstances - yes

Are Omega 6 and 3 and downstream product pathways including COX and LOX products central in tissue creation and repair including in pregnancy - yes

Do we know what effect CBD cannabinoids are having in pregnancy and early development - no



Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action

http://www.scielo.br/scielo.php?scri...62008000300015

"In the last 45 years it has been possible to demonstrate that CBD has a wide range of pharmacological effects, many of which being of great therapeutic interest, but still waiting to be confirmed by clinical trials. It is important to highlight that many effects of CBD draw a bell-shaped dose-response curve, suggesting that the dose is a pivotal factor in CBD research. The wide range of CBD effects can be explained by the multiple mechanisms through which CBD acts, although further research is needed to clarify the precise mechanisms that underlie some of the potentially beneficial effects of CBD."

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Old 10-14-2019, 01:47 PM   #10
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

Endocannabinoid Signaling in Female Reproduction


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382454/

"Since then, numerous studies have been published on cannabinoid signaling in female reproductive events, including preimplantation embryo development, oviductal embryo transport, embryo implantation, placentation, and parturition."

"almost all pregnancy events are regulated by endocannabinoid signaling, and in most cases, optimal outcomes can only be achieved under normal physiological endocannabinoid levels. Either silenced or enhanced endocannabinoid signaling derails these processes. This is a trait of endocannabinoid signaling that provides a route for medical manipulation in each pregnancy event. However, the in-depth mechanism by which endocannabinoid signaling exerts its role is still not clear. In addition, it would be interesting to study the mechanism behind how lower and higher cannabinoid signaling generates similar phenotypes. Further studies on endocannabinoid signaling with respect to female reproduction will generate new molecular mechanisms governing pregnancy events."

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Old 10-16-2019, 04:42 AM   #11
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

A friend Amrita helpfully commented and provided this comment and reference;

"Since endocannabinoids are synthesized naturally from omega 3 and omega 6 fatty acids, the body has control over maintaining the adequate levels required, i.e., it optimises the amount needed for proper functioning and development, by regulating the conversion process. However, artificially synthesised, and plant-based-non-Omega-3/6-derived-cannabinoids, could have an adverse effect on fetal development and growth, possibly because of; their difference in molecular structures (in comparison to those of naturally derived omega 3/6 based cannabinoids), so their different mechanisms of action, or dependent on dosage uncertainties including from unregulated and uncertain quantities of intake, particularly given the wide range of possible sources.

Further, consumption of external non-Omega 3/6 cannabinoids could interfere with biological processes, in ways those produced from Omega 3 and 6 in our diet does not because; provided our body has adequate and balanced Omega 3 and 6 precursors, our system controls the appropriate amounts of endocannabinoids produced; externally supplied non-Omega 3/6 plant based cannabinoids however could deregulate those processes."


Abstract


"A new study in animal tissue reveals the cascade of chemical reactions that convert omega-3 fatty acids into cannabinoids that have anti-inflammatory benefits -- but without the psychotropic high." https://www.sciencedaily.com/release...%20cannabinoid.



"Cannabinoid exposure during pregnancy and its impact on immune function."

"Cannabinoids are the most commonly abused illicit drugs worldwide. While cannabis can be beneficial for certain heath conditions, abuse of potent synthetic cannabinoids has been on the rise. Exposure to cannabinoids is also prevalent in women of child-bearing age and pregnant women. These compounds can cross the placental barrier and directly affect the fetus. They mediate their effects primarily through G-protein coupled cannabinoid receptors, CB1 and CB2. In addition to significant neurological effects, cannabinoids can trigger robust immunomodulation by altering cytokine levels, causing apoptosis of lymphoid cells and inducing suppressor cells of the immune system. Profound effects of cannabinoids on the immune system as discussed in this review, suggest that maternal exposure during pregnancy could lead to dysregulation of innate and adaptive immune system of developing fetus and offspring potentially leading to weakening of immune defenses against infections and cancer later in life. Emerging evidence also indicates the underlying role of epigenetic mechanisms causing long-lasting impact following cannabinoid exposure in utero.

Last edited by R.B.; 10-25-2019 at 03:15 AM..
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Old 10-21-2019, 02:53 PM   #12
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

HER2 Support helped make a difference?


U.S. FDA - Abstract - (recent announcement)

https://www.fda.gov/consumers/consum..._source=Eloqua

"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."


"FDA wants you to know there may be serious risks to using cannabis products, including those containing CBD, if you are pregnant or breastfeeding."

which was linked here
https://www.healthline.com/health-ne...-breastfeeding

Last edited by R.B.; 10-24-2019 at 08:59 AM..
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Old 10-24-2019, 08:56 AM   #13
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

Long chain Omega 3 is important to retinal function, thus one would expect that Omega 3 endocannabinoids play important roles in visual processing.

Imbalances in Omega 6 endocannabinoids are associated with a number of ocular neurodegenerative conditions - see abstract below.

Plant based cannabinoids will impact these pathways

Research into CBD in vision is limited.




Retina and Omega-3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206354/

"In vertebrates, although DHA represents a small percentage of the fatty acids in most tissues (1–5%), it accounts for approximately 50–60% of the total fatty acid content within rod outer segments of photoreceptors (ROSs)"

Endocannabinoid receptors are found in and active in visual systems.

Much is still unknown.


"The sole output of the retina to the brain is a signal that results from the integration of excitatory and inhibitory synaptic inputs at the level of retinal ganglion cells (RGCs). Endogenous cannabinoids (eCBs) are found throughout the central nervous system where they modulate synaptic excitability. Cannabinoid receptors and their ligands have been localized to most retinal neurons in mammals, yet their impact on retinal processing is not well known." https://www.frontiersin.org/articles...019.00037/full


Retinal Cannabinoids 2017

https://pdfs.semanticscholar.org/e27...0034be2fff.pdf


"eCBs are the one of the most recently described neuromodulators to be studied in neural and non-neural tissues. Their extensive expression in the nervous system and peripheral organ systems highlights the range of their actions, and their potential in therapeutic applications. Strong evidence now suggests a wide distribution of eCBs, receptors and enzymatic machinery in key structures of the visual system, including a strong presence in the retina. Although a clear picture can ascertain of the specific effects cannabinoids can have in the retina itself, or the visual system as a whole, various mechanisms in specific cellular structures of the retina have now been reported. The cannabinoid system also appears to have several roles in neuronal survival and apoptosis in the retina, and could be linked with many other ocular disorders.However, their specific mechanisms in retinal development, neuroplasticity, and neuroprotection need to be more thoroughly investigated."

"The content of eCBs varies in certain disease states, suggesting the importance of eCBs in maintaining ocular homeostasis. For example, 2-AG levels are lower in the ciliary body of patients with glaucoma. However, in diabetic retinopathy, there are higher levels of 2-AG only in the iris, and increased levels of AEA in the retina, ciliary body, and cornea. Eyes of patients with age-related macular degeneration (AMD) also show increases of AEA in the retina, choroid, ciliary body, and cornea. Topically applied AEA reduces IOP by activation of CB1R and activation of the prostaglandin E 2 receptor after conversion of AEA to prostamides.Administration of either AEA or THC to human nonpigmented epithelium (NPE) cells induces COX-2 expression, indicating a relationship among prostaglandins, COX-2, and eCBs in lowering IOP. In addition, EP2 receptors have been localized in the NPE of mouse, porcine, and human ciliary body."

Last edited by R.B.; 10-24-2019 at 08:58 AM..
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Old 10-25-2019, 02:56 AM   #14
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

Impacts on brain development and hormonal pathways.

Again focuses on Omega 6 endocannabinoids, underlining the need for much more research on the Omega 3 cannabinoids.

Further how do plant cannabinoids impact the Omega 3 cannabioids pathways.

Again more questions than answers, but clearly again makes the point, there needs to be a mature balanced approach on all sides, better information as to both risks and benefits, susceptible groups, wider related dietary issues etc





The Role of the Endocannabinoid System and Genetic Variation in Adolescent Brain Development

"Emerging evidence suggests that during adolescence, changes in eCB signaling contribute to the maturation of local and corticolimbic circuit populations of neurons, such as mediating the balance between excitatory and inhibitory neurotransmission within the prefrontal cortex. This function of the eCB system facilitates efficient communication within and between brain regions and serves a central role in establishing complex and adaptive cognitive and behavioral processing. Although these peri-adolescent changes in eCB signaling promote brain development and plasticity, they also render this period a particularly sensitive one for environmental perturbations to these normative fluctuations in eCB signaling, such as stress, potentially leading to altered developmental trajectories of neural circuits governing emotional behaviors."


"Given the timing of puberty and changes in the eCB system, it is possible that pubertal changes in hormone secretion relate to fluctuations in eCB signaling during adolescence. Sex differences have been observed in the timing of fluctuations in eCB system expression, with CB1 receptor expression levels peaking earlier in females than males (Rodríguez de Fonseca et al, 1993). In both sexes, peak expression occurs just before the onset of puberty, which is ~PND 35 in female rodents and ~PND 40 in male rodents. Likewise, levels of AEA in hypothalamus have also been shown to peak immediately prior to puberty in female rodents (Wenger et al, 2002). Subsequently, eCB activity fluctuates throughout the estrous and menstrual cycles as well (González et al, 2000; Bradshaw et al, 2006; El-Talatini et al, 2010). A close interaction between the endocannabinoid system and gonadal hormones (Murphy et al, 1991; Rodríguez de Fonseca et al, 1994) might contribute to the major developmental changes occurring in the eCB system during pubertal maturation. The eCB system has been shown to modulate the release and activity of gonadal hormones (androgens, estrogen, and progesterone) and gonadotrophins (follicle-stimulating hormone and luteinizing hormone) in humans and rodents alike (Kolodny et al, 1974; Dalterio et al, 1977; Dalterio et al, 1983; Kumar and Chen, 1983; Rodríguez de Fonseca et al, 1994; Wenger et al, 2001; Tsutahara et al, 2011)."
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Old 10-30-2019, 09:14 AM   #15
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

Cannabinoids have a role in mitochondrial regulation, again confirming the biological importance of these pathways. Much again is unknown.

Again focus on the abstract below is on Omega 6 related endocannabinoids.

These pathways are complex and it is likely plant based endocannabinoids will have a range of impacts on these pathways which may or may not prove to have benificial pharmacological use including in cancers.

Clearly energy pathways are central to brain development, which again brings us back to the question should there be greater public education as to CBD usage, particularly for pregnant females, infants, and adolescents?

Clearly usage in adults is a very different issue, involving, as do many aspects of life, a mix of regulation and person choice.




Cannabinoid-induced changes in respiration of brain mitochondria

https://www.medicinalgenomics.com/wp...tochondria.pdf

"Early studies suggest that cannabinoids affect mitochondrial
function via lipophilic action (Bartova and Birmingham, 1976;
Martin, 1986). Recently, endocannabinoid receptor signaling has
been demonstrated to modulate numerous concomitant patho-
logical processes, including neuroinflammation, excitotoxicity,
mitochondrial dysfunction, and oxidative stress. Endocannabinoids, such as anandamide and 2-arachidonoylglycerol, were found to alter mitochondria-dependent signal transduction and thus participate in the regulation of
energy homeostasis and apoptosis. The upregulation of endocannabinoids may precede mitochondrial dysfunction in neurodegenerative disorders . Some effects of endocannabinoids are independent of their target cannabinoid receptors and are associated with a drug-induced increase in mitochondrial membrane fluidity dissipation of membrane potential, release of accumulated calcium, and opening of mitochondrial permeability transition
pores."


"exogenous and endogenous cannabinoids can activate mitochondrial CB1 receptors and down-regulate mitochondrial respiration. It is hypothesized that mitochondrial CB1 receptors depress mitochondrial respiration and enhance physiological responses mediated by endocannabinoids. We hypothesize that the inhibitory effect of cannabinoids on mitochondrial respiratory rate is caused by the changes in dynamic properties of the lipid part of inner mitochondrial membrane, activation of mitochondrial CB1 receptors, and assembly of respirasomes."
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Old 10-30-2019, 09:50 AM   #16
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Re: Cannabinoid receptors – main ligands are Omega 3 and 6 derivatives, not hemp prod

A review on cannabioids and breast cancer.

Again a focus on Omega 6 cannabinoids.

Again the caveat that the endogenous activators are downstream Omega 3s and 6s, and trying to balance these pathways long term is central.

Plant cannabinoids provide a stick to poke in these pathways that will have more immediate effect - but the reality is we have not yet worked out what they are doing what the long term implications are etc - loosing fat stores of Omega 6 will take a while - but balancing Omega 3s will also impact these pathways, as likely will exercise and part day fasting - see Springer chapter referred to in first post (One of six inter-related chapters in a Springer Publication by me)(with very many thanks to Springer and the Editors) . https://www.researchgate.net/publica..._a_Modern_Diet


If on your radar please discuss use of CBD, diet and exercise with your physician before taking action.






"Future Aspects for Cannabinoids in Breast Cancer Therapy"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479799/

"Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients. Additionally, they may decelerate tumor progression in breast cancer patients. Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models. The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way. THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both. In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway. They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis. Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor. In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression."

Last edited by R.B.; 11-02-2019 at 12:31 PM..
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