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  • Guest's Avatar
    Guest replied
    Not cancer related, but a Pub-Med study re. tx-resistant epilepsy, and the results of a CBD tx., versus CBD tx that incorporated other cannabinoids, to include THC, and 'the entourage effect'.

    Maybe (that's a MAYBE) some answers re. the questions posted?

    https://pubmed.ncbi.nlm.nih.gov/30258398/

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  • Guest's Avatar
    Guest replied
    Originally posted by trichrider View Post
    i never had a science class other than the one you just described...


    those studies ARE difficult to comprehend, and yes they are written for scientists.
    it's like trying to retrieve honey from a beehive with a fork in the woods while naked.


    CB1=Brain and CNS
    CB2=Organs
    THC=CB1
    CBD=CB1 & CB2


    which is the true target of taking the CBD?
    edit: now that i think about it why take both if CBD acts on both receptors?
    That was my question as well, a little bit ago, in re. to the evidence that CBD brings about apoptosis, and THC-a now has been shown to have reduced the size & weight of pancreatic tumors.

    Why eat more than one of these, unless maybe its to minimize any resistance that was toyed with as a concept, by alternating the source of benefit? And why eat so much decarbed oil to treat the cancers, if THC-a and CBD do what RSO has been slated as being capable of, and the first 2 (THC-a and CBD) don't leave a person walking on their lips?

    I like getting high, and have done so for close to 48 years now. But orally ingesting a gram of decarbed oil each day is something like becoming a brain surgeon for me; I'm not likely to ever do either one.

    So, it seems to me that alternating on what ever thought-out schedule, between THC-a and CBD, and trying not to vape or smoke so much cannabis when I'm on a CBD regimen, logically makes the most sense to me.

    But there's no warranties in any of this. Pretty new turf. If it goes catawampus, I can look in the mirror and say, "You're one GULLIBLE/NAIVE IDIOT!", or maybe threaten to sue myself for malpractice.

    So, onward...

    And thanks again, trich.

    ---------------------------------------------------------------------------

    Coupla' young guys, nailing a cover of 'Knockin' on Heaven's Door'

    Josh Turner Guitar

    https://www.youtube.com/watch?v=syCU871iprU

    Homespun album from the same fellow, Josh Turner

    'Public Life'

    https://www.youtube.com/watch?v=3Fs18SpOmRM

    Kids these days! I'm envious!
    Last edited by moose eater; 02-01-2021, 00:50.

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  • trichrider
    replied
    i never had a science class other than the one you just described...


    those studies ARE difficult to comprehend, and yes they are written for scientists.
    it's like trying to retrieve honey from a beehive with a fork in the woods while naked.


    CB1=Brain and CNS
    CB2=Organs
    THC=CB1
    CBD=CB1 & CB2


    which is the true target of taking the CBD?
    edit: now that i think about it why take both if CBD acts on both receptors?

    Leave a comment:


  • Guest's Avatar
    Guest replied
    Originally posted by trichrider View Post
    Immune Responses Regulated by Cannabidiol


    https://www.liebertpub.com/doi/10.1089/can.2018.0073

    Conclusions, Challenges, and Knowledge Gaps

    Considering all the studies conducted on immune responses and inflammation, the data overwhelmingly demonstrate that CBD is immune suppressive and anti-inflammatory (Fig. 1). Critical targets of suppression include cytokines such as TNF-?, IFN-?, IL-6, IL-1?, IL-2, IL-17A, and chemokines, such as CCL-2. The overall mechanism of CBD involves direct suppression of target cells, such as effector T cells and microglial cells, through suppression of kinase cascades and various transcription factors. An example of this is CBD-induced suppression of phosphorylated p38, leading to compromised AP-1 or NF-?B activity. Direct suppression of target cells also includes induction of I?B, which could contribute to decreased NF-?B activity. The involvement of regulatory cell induction by CBD is also a major part of the mechanism by which CBD controls immune responses, and CBD has been shown to induce Tregs and MDSCs. Finally, CBD-induced apoptosis is likely an important mechanism in many target cells.
    View ImageFIG. 1. Summary of CBD's mechanisms of immune suppression. Overall, CBD's immune system suppression is mediated by direct inhibition of various cell types (microglial, innate, and T cells) and induction of apoptosis and regulatory cells (Tregs and MDSCs). CBD, Cannabidiol; MDSCs, myeloid-derived suppressor cells; Treg, regulatory T cell.
    It is often argued that the concentrations/doses at which CBD acts in vitro/in vivo are high. However, it should be noted that CBD is highly lipophilic and subject to first-pass metabolism after oral dosing.190 In fact, we have shown that in mice at 6?h after oral CBD at 75?mg/kg/day for 3 days resulted in plasma CBD levels of ?40?ng/mL and were not detectable by 24?h.191 This is ?0.12??M CBD, which is on the lower end of concentrations typically used in vitro to evaluate the effects of CBD as detailed in this review. On the other hand, recent data obtained in one human clinical trial that was used to support the indication of CBD as Epidiolex in epilepsy studies showed that plasma CBD levels were as high as 400?ng/mL following 20?mg/kg/day dosing for 22 days.192 This concentration is ?1.2??M CBD, which is a more common concentration used in vitro at which CBD effects are observed. These two studies in mice and humans191,192 suggest that the doses and concentrations of CBD used in many of the studies in this review are appropriate. There are still limitations on our knowledge about CBD dosing and plasma levels and how those relate to immune modulation. Some of these limitations might be clarified with many of the planned clinical trials with CBD in the coming years. Specifically related to immune effects of CBD, there is a planned randomized, open-label interventional study assessing CBD and THC on immune cell activation in HIV+ patients.193 Importantly, this trial will evaluate dose escalation of relatively high CBD doses compared to THC; the dose escalation for CBD will go from 45–225?mg/kg/day over a 5-week period and then maintain the highest dose for an additional 7 weeks.193
    In addition to the need for more data on CBD dosing and pharmacokinetics, this broad summary of immune and inflammatory effects of CBD revealed a number of data gaps that should be addressed. First, identification of the receptor(s) through which CBD acts in the immune system remains a critical question. An important part of this question is whether CBD-induced FAAH inhibition generates anandamide metabolites that bind to various receptors to mediate some of the immune suppressive or anti-inflammatory effects of CBD. Coupled with the observation that some of the effects of CBD can be attenuated with PPAR-? antagonists,92–98 the possibility exists that CBD-mediated anandamide production drives the subsequent production of (yet unidentified) metabolites that activate PPAR-?. Another critical determination needed for many of the receptor studies is identification of the cell type(s) on which the receptors are expressed, which are mediating the CBD effects. Second, although combined cannabinoids were not a major focus of this review, it will be critical to determine the CBD contribution to immune function compromise in cannabis and/or combined pharmaceuticals such as Sativex. Third, there are still several cell types for which little data exist, notably B cells and dendritic cells. Even in the rich CBD-T cell literature, several well-established targets have not been extensively studied in T cells. In fact, there are limited data examining CBD's effects on various T cell subsets. Fourth, increasing our understanding of CBD's effects in response to a variety of immune stimuli and degrees of immune stimulation will help in interpreting effects of CBD in humans and other outbred species that are naturally exposed to a variety of pathogens. Thus, the last identified knowledge gap is the need for increased studies on the effects of CBD in human and veterinary immune responses. These include well-controlled studies considering differences with administration routes, dose, and pharmacokinetics.


    https://www.liebertpub.com/doi/10.1089/can.2018.0073


    https://www.youtube.com/watch?v=2l6J...ture=emb_title
    Tom MacDonald - "Fake Woke"
    Seems they're stating that there's as much or more unknown, but stating in the opener that CBD is able to suppress (over-active) immune systems and works to help with inflammation. (I'd add, not withstanding some sort of allergy, which would be/is fairly ironic).

    I'm going to need more time with this one. The problem we amateurs have with scientific research is that all too often, it's written for science folks. While I clearly recall skipping science classes, sitting on the school lawn, eating LSD, and watching bumble bees land on dandelions. Lotsa' catching up to do now.

    Leave a comment:


  • trichrider
    replied
    Immune Responses Regulated by Cannabidiol


    https://www.liebertpub.com/doi/10.1089/can.2018.0073

    Conclusions, Challenges, and Knowledge Gaps

    Considering all the studies conducted on immune responses and inflammation, the data overwhelmingly demonstrate that CBD is immune suppressive and anti-inflammatory (Fig. 1). Critical targets of suppression include cytokines such as TNF-?, IFN-?, IL-6, IL-1?, IL-2, IL-17A, and chemokines, such as CCL-2. The overall mechanism of CBD involves direct suppression of target cells, such as effector T cells and microglial cells, through suppression of kinase cascades and various transcription factors. An example of this is CBD-induced suppression of phosphorylated p38, leading to compromised AP-1 or NF-?B activity. Direct suppression of target cells also includes induction of I?B, which could contribute to decreased NF-?B activity. The involvement of regulatory cell induction by CBD is also a major part of the mechanism by which CBD controls immune responses, and CBD has been shown to induce Tregs and MDSCs. Finally, CBD-induced apoptosis is likely an important mechanism in many target cells.
    FIG. 1. Summary of CBD's mechanisms of immune suppression. Overall, CBD's immune system suppression is mediated by direct inhibition of various cell types (microglial, innate, and T cells) and induction of apoptosis and regulatory cells (Tregs and MDSCs). CBD, Cannabidiol; MDSCs, myeloid-derived suppressor cells; Treg, regulatory T cell.
    It is often argued that the concentrations/doses at which CBD acts in vitro/in vivo are high. However, it should be noted that CBD is highly lipophilic and subject to first-pass metabolism after oral dosing.190 In fact, we have shown that in mice at 6?h after oral CBD at 75?mg/kg/day for 3 days resulted in plasma CBD levels of ?40?ng/mL and were not detectable by 24?h.191 This is ?0.12??M CBD, which is on the lower end of concentrations typically used in vitro to evaluate the effects of CBD as detailed in this review. On the other hand, recent data obtained in one human clinical trial that was used to support the indication of CBD as Epidiolex in epilepsy studies showed that plasma CBD levels were as high as 400?ng/mL following 20?mg/kg/day dosing for 22 days.192 This concentration is ?1.2??M CBD, which is a more common concentration used in vitro at which CBD effects are observed. These two studies in mice and humans191,192 suggest that the doses and concentrations of CBD used in many of the studies in this review are appropriate. There are still limitations on our knowledge about CBD dosing and plasma levels and how those relate to immune modulation. Some of these limitations might be clarified with many of the planned clinical trials with CBD in the coming years. Specifically related to immune effects of CBD, there is a planned randomized, open-label interventional study assessing CBD and THC on immune cell activation in HIV+ patients.193 Importantly, this trial will evaluate dose escalation of relatively high CBD doses compared to THC; the dose escalation for CBD will go from 45–225?mg/kg/day over a 5-week period and then maintain the highest dose for an additional 7 weeks.193
    In addition to the need for more data on CBD dosing and pharmacokinetics, this broad summary of immune and inflammatory effects of CBD revealed a number of data gaps that should be addressed. First, identification of the receptor(s) through which CBD acts in the immune system remains a critical question. An important part of this question is whether CBD-induced FAAH inhibition generates anandamide metabolites that bind to various receptors to mediate some of the immune suppressive or anti-inflammatory effects of CBD. Coupled with the observation that some of the effects of CBD can be attenuated with PPAR-? antagonists,92–98 the possibility exists that CBD-mediated anandamide production drives the subsequent production of (yet unidentified) metabolites that activate PPAR-?. Another critical determination needed for many of the receptor studies is identification of the cell type(s) on which the receptors are expressed, which are mediating the CBD effects. Second, although combined cannabinoids were not a major focus of this review, it will be critical to determine the CBD contribution to immune function compromise in cannabis and/or combined pharmaceuticals such as Sativex. Third, there are still several cell types for which little data exist, notably B cells and dendritic cells. Even in the rich CBD-T cell literature, several well-established targets have not been extensively studied in T cells. In fact, there are limited data examining CBD's effects on various T cell subsets. Fourth, increasing our understanding of CBD's effects in response to a variety of immune stimuli and degrees of immune stimulation will help in interpreting effects of CBD in humans and other outbred species that are naturally exposed to a variety of pathogens. Thus, the last identified knowledge gap is the need for increased studies on the effects of CBD in human and veterinary immune responses. These include well-controlled studies considering differences with administration routes, dose, and pharmacokinetics.


    https://www.liebertpub.com/doi/10.1089/can.2018.0073


    https://www.youtube.com/watch?v=2l6J...ture=emb_title
    Tom MacDonald - "Fake Woke"

    Leave a comment:


  • Guest's Avatar
    Guest replied
    Originally posted by buzzmobile View Post
    I owned that album at one time. I listened to it many times. I always liked Southbound Train.

    Tomorrow a calendar page turns and the future becomes today.
    Thanks buzz, your positive outlook is always welcome!!

    Nerves are more solid this morning, though there's admittedly some anxiety re. pending correspondence, and getting closer to a decision. Like getting ready to go off the floating high-dive platform for the 1st time as a kid, at summer camp.

    -------------------------------------------

    For those who are contemplating the 'whole-plant, nutrient-rich diet' now advocated by a fair number of oncological Docs, we have completed some amount of review of plant-based meat sausages. Few of them compare to really good old-world European sausages, which have always been a part of our diet here.

    However, among those we've tried, we're intent, if possible, on never buying another Tofurkey product again.

    The Field Roast brand of Apple and Sage plant based sausages, and their Garlic & Fennel sausages, come a whole lot closer to resembling a sausage. Still a little ways to go, but heads and shoulders above the other. They're apparently textured with egg plant, and no where near as dry or sawdust-like in filling.

    Also of good content and flavor are the Beyond Meat brand brats.

    One key among these for providing a better consistency and flavor is the use of healthy fats. Sausages are supposed to have fat, not be dry, and what kind of fat matters.

    ------------------------------------

    Weight loss and proper diet not only benefit getting the body functions up and running again, re. gastro-intestinal, pancreas, and such, but the research also states weight loss and physical activity, before the surgery or tx for prostate cancer, and after, assist in rehabilitation where erectile dysfunction is concerned.

    I can say, after monitoring my data fairly closely, that this recent 46 lbs. (currently) of relatively rapid weight loss, required about 3-4 times as much time as it did 11 years ago, to bring some of the same normalcy in function back on line (pancreas and processing of glucose, specifically). It was also more harsh on my heart, and etc., and required a lower BMI or weight to achieve the 'kick-starting' than it did back then, as well.

    In other words, a person can probably save themselves a LOT of grief, and potential damage to their body, by keeping their labs as close to where they need to be as possible, and NOT doing this amazing, "jerk everything back into place in short order" stuff.

    But at this point, however much longer it took, and how ever much more stress was placed on my heart, etc., my pancreas seems to be functioning more closely to properly now.... about 4 months into this effort.

    There's a lot I could write about the liver converting fat to carbs in times of no incoming carbs, or very few, and credible literature at a Canadian site re. diabetes and the liver manufacturing carbs from fat in times of stress, but I'll spare the space for the moment. Already a lengthy post.

    -----------------------------------------

    For my wife's birthday present, I got her a book titled, 'The Boreal Herbal' (subtitled: 'Wild Food and Medicine Plants of the North').

    Mind-blowing, what's in there. Had little idea of traditionally used medicines that are here, on our property, to include wild chamomile and red clover (the red clover being cited as good for cancer, <incl. skin cancers>, prostate health & menopause) The author is Beverley Gray, who runs The Aroma Borealis Shop in Whitehorse, Yukon Territory, Canada; my stomping grounds much of this life.

    Give it a peek. Lots of supporting in-depth research in the foot notes and bibliography. My wife was quite pleased by the contents, and we'll be applying more limited changes in diet soon.

    The book's information turned many of the nuisance weeds in the garden and on the property into benefits, rather than curses. The chick weed even, which we've been over-run with, ever since using horse manure in the veggie & potato gardens, has some surprising uses and benefits. The dandelion research, to include modern research re. dandelion roots and diabetes in mainstream science.. We're apparently inundated with well-researched medicine in the yard, gardens, and woods.. Who knew?

    ----------------------------------------------

    Probably a repeat, but a worthy one. What I might regard as Sunday morning services.

    Bruce Cockburn

    'Dialogue with the Devil'

    https://www.youtube.com/watch?v=0PfDrP6X5P8
    Last edited by moose eater; 01-31-2021, 20:37.

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  • buzzmobile
    replied
    Originally posted by moose eater View Post
    (*There some serious SOOT in that stuff, buzz...)
    I owned that album at one time. I listened to it many times. I always liked Southbound Train.

    Tomorrow a calendar page turns and the future becomes today.

    Leave a comment:


  • Guest's Avatar
    Guest replied
    Thanks again, trich.

    Yes, for me, with my eyes, and everything else, reading has been the best sleep aid I've sometimes known of.

    My wife and I were going through a STACK of studies, while watching the tv version of 'Saving Private Ryan', and the number of times I dozed off, then asking her to read some key point or another again, bordered on rudeness on my part.

    With my reaction to the various stimuli, when I have dipped a gum brush into overly full '0' capsules of MY THC extract, and eaten the extract to the point of obtaining a 'normal (for me) dose', I don't get the chest tightening. But with the extract I made from the commercial CBD flowers I purchased, I get that effect pretty much every time; again, same-same in terms of the form the extract is in upon ingestion.. oil straight to the mouth, with equal parts of coconut oil and cacao butter involved.

    The answer there might be in the testing, and that may or may not be conclusive.

    I'll be heading into town for a blood draw, and a complete and thorough work-up for less than a 1/4 of the hospital lab's fees. (Not applicable to my deductible when done at the private non-profit, but they're good folks there, and they need the biz).

    Finalizing the new draft of the my wife's and my Wills today, I hope. They can always be re-filed if folks clean their acts up, but not going to gift any part of the estate to folks that are wrapped up in convoluted nonsense that disregards priorities.. Less hesitation in my heart about this.

    Looked up White Lotus for a better understanding of her profiles, and though I got (from 4 different seeds from her) 3 plants that looked very close to each other, I got a 4th that looked closer to the Satori plants; more broad leafed, etc. Anyway, they seem to have the better profiles, though no guarantees they hold the same values in cannabinoid array as what was [posted on-line.

    Thanks for the tunes, trich. Good stuff. And thank you for your time and effort in trying to help resolve some of these mysteries.

    I am left wondering if the sulforaphane has any counter-indications to the THC/CBD, etc.? As well, if the lycopene causes any interference, or vice versa.

    We're to, some degree, wading in waters not always too well understood, and experimenting on ourselves to some degree, hoping for the best, sometimes seeing improvement, but not necessarily being able to attribute cause and effect in a truly scientific manner..

    As I mentioned to another last evening via PM, there's a least 1 member in the forums who reports they had a terminal brain cancer/tumor(s), and the thing reportedly went into remission and departed on its own. I sometimes wonder how many of us have seen improvements we've attributed to one variable, but was really changed by another.

    That's where the better studies, hopefully with proper structure, longer term, and large samples, come into play; helping to clarify what did what.

    ---------------------------------------------------

    I was in a medium security facility in Pennsylvania at age 13 & 14, with a friend up north from there scheming to break me out, and drive me up to Canada in his Camaro. My now-deceased sister brought me a letter outlining the plans, inside this album; never searched, never found.

    Still have the Lp on vinyl, and, I believe, the letter, too; THAT Lp, the very same one.

    Edit: 'Medium security' should have read 'minimum security.' My bad. Auto-correct and fat-finger syndrome? Who knows?

    Graham Nash & David Crosby

    'Southbound Train'

    https://www.youtube.com/watch?v=xje8zfZy6eA

    -----------------------------

    Same Lp

    'Page 43'

    https://www.youtube.com/watch?v=wQNVN6IRzhY

    -----------------------------

    Same...

    'Where Will I Be'

    https://www.youtube.com/watch?v=4GAGyAiBAro

    (*There some serious SOOT in that stuff, buzz...)
    Last edited by moose eater; 01-31-2021, 05:46.

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  • trichrider
    replied
    i believe you did understand.
    i could not find anything regarding time/length of binding, but if we consider the length of time we are affected/can determine an influence of cannabis in use...several hours or shorter/longer duration it may be applicable to the notion of saturation.
    Weezards 'resistance' may be regarded as 'tolerance' as we define it in broscience, and in that regard it may be saturation. i don't know, but it makes more sense to me.
    keeping an open mind on this.


    i need sustenance, my eyes are blurring, and my neck and shoulders ache from sitting and reading. bowing out for now....

    https://www.youtube.com/watch?v=hyzgyVXZ4FY
    [youtubeif]hyzgyVXZ4FY[/youtubeif]

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  • Guest's Avatar
    Guest replied
    Originally posted by trichrider View Post
    ...ah, the saturation thingy.
    how long do cannabinoids remain attached to receptors on cells..


    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660261/


    Discussion

    The results reported confirm that nanomolar CBD concentrations are not able to displace the binding of WIN 55,212-2 to the orthosteric center of the CB2R in radioligand binding assays. The binding data using the non-radioactive homogeneous method performed in living cells showed, however, that the binding of the fluorescent orthosteric ligand to HEK-293T cells expressing CB2R was slightly but consistently modified by nanomolar concentrations of CBD. The most plausible interpretation of these data is an allosteric effect disclosed in HTRF-mediated binding assays and a very small difference in the binding mode of radiolabeled WIN 55,212-2 or fluorescence-labeled CM-157 to CB2R. Unfortunately, WIN 55,212-2 could not be used in non-radioactive assays as it non-specifically interacted (for unknown reasons) with the HTRF probes. We found the same non-specific interaction with the fluorescent labeled CBD (data not shown). Structural differences related to the binding of different agonists that may be revealed by HTRF have been discussed elsewhere (Martínez-Pinilla et al., 2016). In that paper, the extensively studied ligand AM630 displayed a biphasic curve on competing with CM-157 binding to CB2R. The results here presented could fit with CBD binding to the high-affinity sites disclosed using AM630 but not to the low-affinity ones. Alternatively, AM630 reduction of high-affinity binding, which occurred at subnanomolar concentrations of AM630, could be due to the same mechanism than that of CBD. In fact, the two compounds displayed on HTRF-based binding assays two components, one at low concentrations, and another at higher concentrations.
    A further piece of information from results using the selective orthosteric CB2R antagonist, SR144528, was the irreversible-like behavior when performing HTRF-based binding to living cells. In binding or functional assays using isolated membranes or tissue extracts from CB2R-expressing cells, the antagonist acts in a reversible fashion (Rinaldi-Carmona et al., 1998; Griffin et al., 1999). CBD seemingly allosteric action was detectable by functional experiments (cAMP and pERK1/2 assays) in which we show that the effect of a selective CB2R agonist was modulated by CBD at physiologically relevant (nanomolar) concentrations. The participation of a third component, acting as mediator of CBD effects on CB2R signaling cannot be ruled out.
    In the absence of consensus data showing a direct interaction between CBD and cannabinoid receptors, only indirect evidence suggests that CBD could be a modulator of endocannabinoid signaling. Accordingly, CBD was suspected to act as allosteric modulator of cannabinoid receptors (Rimoldi and Bow, 2016). In agreement with this possibility, Laprairie et al. (2015) were the first to suggest that CBD acts as allosteric modulator of CB1R; although no binding studies were performed, the allosteric site in the receptor was mapped to two cysteine residues in the N-terminal end. Therefore, CBD reduces both potency and efficacy of endogenous and exogenous cannabinoids on ERK1/2-PLC?3-dependent signaling in an heterologous expression system, and in cells endogenously expressing the receptor. Authors also reported that CBD affects the kinetics of ?-arrestin recruitment and CB1R internalization.
    Allosteric modulators of natural origin do usually provide negative modulation in both enzymology and pharmacology. Allosteric action was negative in both the results reported by Laprairie et al. (2015) on CB1R-mediated signaling and ours on CB2R-mediated signaling; the allosteric effect in both cases seems to be, at least in part, mediated by a CBD-induced decrease in affinity of the orthosteric agonist (Table ?Table11). One interesting possibility would be that cannabinoids may produce effect of allosteric nature on a variety of GPCRs. In support of this option, Lane et al. (2010) showed that the endocannabinoid 2-AG acts as an allosteric modulator of the human adenosine A3 receptor. Adenosine A3 receptors are coupled to a heterotrimeric Gi protein and the action of 2-AG resulted in a decrease in the potency of agonists and in the basal signaling of this adenosine receptor subtype. Their negative effects on the receptor-mediated cAMP response are similar to those reported here for CBD acting on CB2R. CBD is also described as an allosteric modulator of ?- and ?-opioid receptors (Vaysse et al., 1987; Kathmann et al., 2006). Both ?9-THC and CBD accelerate the dissociation of opioids from the receptors although the function of CBD on opioid receptors was not studied (Kathmann et al., 2006).
    Ligand-gated receptors are also affected by CBD. Indeed, CBD inhibits currents mediated by serotonin 5-HT3A receptors expressed in Xenopus laevis oocytes (Yang et al., 2010). Higher CBD concentrations, in the micromolar range, are able to allosterically modulate ligand-gated glycine receptors impacting on the role of glycine in postsynaptic transmission in the adult spinal cord (Ahrens et al., 2009; Foadi et al., 2010). The interacting motif is mapped to Ser276 of the alpha1 subunit of the receptor (Foadi et al., 2010), thus seemingly different from the binding motif reported for CB1R (Laprairie et al., 2015). Homologous residues to those in the CB1R sequence are not present in the CB2R one and, therefore, the putative binding site may not be located in the N-terminal domain of the CB2R; in fact, the putative N-terminal domain is much shorter for CB2 than for CB1 receptors (33 versus 116 amino acids2). Elucidation of the structure for the CB1R rises hope for a similar achievement for CB2R and, subsequently, for detecting allosteric sites that would help in designing novel drug discovery approaches targeting cannabinoid receptors. The N-terminal domain of the A3 receptor is also too short to be involved in the mode of action of 2-AG. Human ? and ? opioid receptors have longer N-terminal domains, 68 and 47, respectively, but there is no obvious homology between them. The two cysteine residues present in the N-terminal end of CB1R and that putatively conform a CBD binding site are not present in the N-terminal domain of ?-opioid receptors. In summary, further experimental effort is needed to identify common motives for endocannabinoid action on ligand-gated and GPCRs, or to identify molecules interacting with these receptors and acting as mediators of the allosteric-like effect disclosed by CBD. Finding CBD binding motives in cannabinoid receptors or non-GPCR CBD targets would help in understanding some of the actions reported for endocannabinoids and for natural cannabinoids such as THC and CBD.
    GPCRs constitute the target of 40–45% of current medicines that act, as agonists or antagonists, via the orthosteric center. The discovery of GPCR allosteric modulators or of modulators of signaling at concentrations 1–2 orders of magnitude below the IC50 values obtained in competing with the binding of orthosteric compounds, opens new perspectives for therapeutic benefit.



    hard to decipher whether or not saturation is even occurring as we imagine it is.
    I think I raised the question of 'saturation,' while Weez had raised the concept of cells developing a resistance to the THC/CBD, and the stronger cells remaining, as the lesser died or vanished, if I understood him correctly.


    Edit: In the same sort of way that Narcan blocks opioid receptor sites, and can not only keep a person from feeling the effects of opiates, but can pull them back from the edge of an OD. That's the image I had in my mind when I mentioned the possibility
    Last edited by moose eater; 01-31-2021, 00:42.

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  • trichrider
    replied
    ...ah, the saturation thingy.
    how long do cannabinoids remain attached to receptors on cells..


    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660261/


    Discussion

    The results reported confirm that nanomolar CBD concentrations are not able to displace the binding of WIN 55,212-2 to the orthosteric center of the CB2R in radioligand binding assays. The binding data using the non-radioactive homogeneous method performed in living cells showed, however, that the binding of the fluorescent orthosteric ligand to HEK-293T cells expressing CB2R was slightly but consistently modified by nanomolar concentrations of CBD. The most plausible interpretation of these data is an allosteric effect disclosed in HTRF-mediated binding assays and a very small difference in the binding mode of radio-labeled WIN 55,212-2 or fluorescence-labeled CM-157 to CB2R. Unfortunately, WIN 55,212-2 could not be used in non-radioactive assays as it non-specifically interacted (for unknown reasons) with the HTRF probes. We found the same non-specific interaction with the fluorescent labeled CBD (data not shown). Structural differences related to the binding of different agonists that may be revealed by HTRF have been discussed elsewhere (Martínez-Pinilla et al., 2016). In that paper, the extensively studied ligand AM630 displayed a biphasic curve on competing with CM-157 binding to CB2R. The results here presented could fit with CBD binding to the high-affinity sites disclosed using AM630 but not to the low-affinity ones. Alternatively, AM630 reduction of high-affinity binding, which occurred at subnanomolar concentrations of AM630, could be due to the same mechanism than that of CBD. In fact, the two compounds displayed on HTRF-based binding assays two components, one at low concentrations, and another at higher concentrations.
    A further piece of information from results using the selective orthosteric CB2R antagonist, SR144528, was the irreversible-like behavior when performing HTRF-based binding to living cells. In binding or functional assays using isolated membranes or tissue extracts from CB2R-expressing cells, the antagonist acts in a reversible fashion (Rinaldi-Carmona et al., 1998; Griffin et al., 1999). CBD seemingly allosteric action was detectable by functional experiments (cAMP and pERK1/2 assays) in which we show that the effect of a selective CB2R agonist was modulated by CBD at physiologically relevant (nanomolar) concentrations. The participation of a third component, acting as mediator of CBD effects on CB2R signaling cannot be ruled out.
    In the absence of consensus data showing a direct interaction between CBD and cannabinoid receptors, only indirect evidence suggests that CBD could be a modulator of endocannabinoid signaling. Accordingly, CBD was suspected to act as allosteric modulator of cannabinoid receptors (Rimoldi and Bow, 2016). In agreement with this possibility, Laprairie et al. (2015) were the first to suggest that CBD acts as allosteric modulator of CB1R; although no binding studies were performed, the allosteric site in the receptor was mapped to two cysteine residues in the N-terminal end. Therefore, CBD reduces both potency and efficacy of endogenous and exogenous cannabinoids on ERK1/2-PLC?3-dependent signaling in an heterologous expression system, and in cells endogenously expressing the receptor. Authors also reported that CBD affects the kinetics of ?-arrestin recruitment and CB1R internalization.
    Allosteric modulators of natural origin do usually provide negative modulation in both enzymology and pharmacology. Allosteric action was negative in both the results reported by Laprairie et al. (2015) on CB1R-mediated signaling and ours on CB2R-mediated signaling; the allosteric effect in both cases seems to be, at least in part, mediated by a CBD-induced decrease in affinity of the orthosteric agonist (Table ?Table11). One interesting possibility would be that cannabinoids may produce effect of allosteric nature on a variety of GPCRs. In support of this option, Lane et al. (2010) showed that the endocannabinoid 2-AG acts as an allosteric modulator of the human adenosine A3 receptor. Adenosine A3 receptors are coupled to a heterotrimeric Gi protein and the action of 2-AG resulted in a decrease in the potency of agonists and in the basal signaling of this adenosine receptor subtype. Their negative effects on the receptor-mediated cAMP response are similar to those reported here for CBD acting on CB2R. CBD is also described as an allosteric modulator of ?- and ?-opioid receptors (Vaysse et al., 1987; Kathmann et al., 2006). Both ?9-THC and CBD accelerate the dissociation of opioids from the receptors although the function of CBD on opioid receptors was not studied (Kathmann et al., 2006).
    Ligand-gated receptors are also affected by CBD. Indeed, CBD inhibits currents mediated by serotonin 5-HT3A receptors expressed in Xenopus laevis oocytes (Yang et al., 2010). Higher CBD concentrations, in the micromolar range, are able to allosterically modulate ligand-gated glycine receptors impacting on the role of glycine in postsynaptic transmission in the adult spinal cord (Ahrens et al., 2009; Foadi et al., 2010). The interacting motif is mapped to Ser276 of the alpha1 subunit of the receptor (Foadi et al., 2010), thus seemingly different from the binding motif reported for CB1R (Laprairie et al., 2015). Homologous residues to those in the CB1R sequence are not present in the CB2R one and, therefore, the putative binding site may not be located in the N-terminal domain of the CB2R; in fact, the putative N-terminal domain is much shorter for CB2 than for CB1 receptors (33 versus 116 amino acids2). Elucidation of the structure for the CB1R rises hope for a similar achievement for CB2R and, subsequently, for detecting allosteric sites that would help in designing novel drug discovery approaches targeting cannabinoid receptors. The N-terminal domain of the A3 receptor is also too short to be involved in the mode of action of 2-AG. Human ? and ? opioid receptors have longer N-terminal domains, 68 and 47, respectively, but there is no obvious homology between them. The two cysteine residues present in the N-terminal end of CB1R and that putatively conform a CBD binding site are not present in the N-terminal domain of ?-opioid receptors. In summary, further experimental effort is needed to identify common motives for endocannabinoid action on ligand-gated and GPCRs, or to identify molecules interacting with these receptors and acting as mediators of the allosteric-like effect disclosed by CBD. Finding CBD binding motives in cannabinoid receptors or non-GPCR CBD targets would help in understanding some of the actions reported for endocannabinoids and for natural cannabinoids such as THC and CBD.
    GPCRs constitute the target of 40–45% of current medicines that act, as agonists or antagonists, via the orthosteric center. The discovery of GPCR allosteric modulators or of modulators of signaling at concentrations 1–2 orders of magnitude below the IC50 values obtained in competing with the binding of orthosteric compounds, opens new perspectives for therapeutic benefit.



    hard to decipher whether or not saturation is even occurring as we imagine it is.

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    Originally posted by trichrider View Post
    maybe paranoia wasn't the correct syntax relative to anxiety...bad example...maybe fear would be more accurate.



    What are the symptoms of paranoia?
    Some identifiable beliefs and behaviors of individuals with symptoms of paranoia include mistrust, hypervigilence, difficulty with forgiveness, defensive attitude in response to imagined criticism, preoccupation with hidden motives, fear of being deceived or taken advantage of, inability to relax, or are argumentative.


    some of which you have described of your symptoms. so i may have subbed instead of essentially calling you afraid...which you obviously are. apologies for the misappropriation.
    In my case, trich, some of those traits go back to other issues, long before the THC/CBD experimenting we're into now.

    There are many fears in this; tattered adult family relationships, loss of function, possibility of repeated treatment (especially since the first round sounds clearly less than appealing, but necessary).

    But 'reading persons' fairly accurately, I have been better than pretty good at, was paid well for that ability once upon a time, and there was definitely a distancing by, at least, the surgeon, and I picked up on it; later on he more or less confirmed it (the reluctance, and his comment re. tentative agreement to work on me.. 'If').

    There were other instances in this thread wherein I picked up on things that were bothering someone, without them saying so, and they later shared some of the issues I had sensed before they clarified them.

    The hypervigilance, OCD, and more, are core symptoms of PTSD, managed via OCD for decades, in my case. It becomes a crisis when a primary mode of functioning or coping encounters a circumstance for which those coping mechanisms clearly don't work.

    Cancer is one thing, among many, for which the primary methods of of 'control of variables' goes straight out the window.

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  • trichrider
    replied
    maybe paranoia wasn't the correct syntax relative to anxiety...bad example...maybe fear would be more accurate.



    What are the symptoms of paranoia?
    Some identifiable beliefs and behaviors of individuals with symptoms of paranoia include mistrust, hypervigilence, difficulty with forgiveness, defensive attitude in response to imagined criticism, preoccupation with hidden motives, fear of being deceived or taken advantage of, inability to relax, or are argumentative.


    some of which you have described of your symptoms. so i may have subbed instead of essentially calling you afraid...which you obviously are. apologies for the misappropriation.

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    Quick thought occurred a moment ago; if the cancer cells do, in fact, organize some sort of tolerance to this or that, and CBD competes with THC/THC-a, what about a regimen that sticks to THC/THC-a for a week, then another week of straight CBD?? Or make it 2 weeks on, 2 weeks off? Or??

    Would that possibly effectively reduce the competition for the receptor sites, while keeping the cancer cells at least a little confused as to what they're reacting to, and building tolerance?

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    Originally posted by trichrider View Post
    Cancer

    CBD exerts antiproliferative/proapoptotic effects (IC50 in the 5–25 ?M range) in several tumor cell lines, including human breast, prostate and colorectal carcinoma, gastric adenocarcinoma, and rat glioma and transformed thyroid cells (478). In human prostate carcinoma cells, CBD induces apoptosis and expression of PUMA and CHOP, two markers of intrinsic apoptotic pathways (194). The production of ROS is at least in part responsible for the antitumor activity of the phytocannabinoid both in vitro (194, 478, 539, 547) and in vivo (800).
    The ability of CBD to inhibit cancer cell viability and proliferation can be reversed in vitro in the presence of blockers of either CB2, TRPV1, TRPM8, cyclooxygenase-2 (COX-2), or PPAR? (reviewed in Ref. 548), and in vivo in the presence of a PPAR? antagonist (713) ( THC???). Furthermore, CBD is able to inhibit cancer cell invasion and metastasis (478, 548, 715). These actions, in highly aggressive human breast cancer cells, are in part mediated by inhibition of epidermal growth factor (EGF), NF-?B, ERK/AKT, and matrix metalloproteinase 2 and 9 signaling pathways (238). CBD also reduces angiogenesis through actions on both tumor and endothelial cells (809) (Figure 1).
    View Image
    FIGURE 1.

    Schematic representation of the main signaling pathways through which (endo)cannabinoids impact proliferation, apoptosis, migration, and angiogenesis in cancer. Blue arrows indicate pathways initiated by cannabinoid/vanilloid receptor-mediated mechanisms, and red arrows indicate non-cannabinoid/vanilloid receptor-mediated mechanisms. Continuous lines indicate stimulation, and dotted lines indicate inhibition. AC, adenylyl cyclase; CBD, cannabidiol; CBG, cannabigerol; eCBs, endocannabinoids; ER, endoplasmic reticulum; ?9-THC, ?9-tetrahydrocannabinol; PKA, protein kinase A; AKT, protein kinase B; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular regulated kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; ROS, reactive oxygen species; p27/p21, cyclin-dependent kinase inhibitor proteins.


    https://journals.physiology.org/doi/...rev.00002.2016


    ..so if THC antagonizes (imo blocks) sites where CBD might be more effective, then instead of THC blocking the sites responsible for endocannabinoid expression, perhaps a reduction in THC in treatment is required for the CBD to excite immune response in apoptosis and CC proliferation.


    it is shown CBD is anxiolytic, and we all here know or think we know that THC induces paranoia...then reasoning that ingesting THC is anxiogenic and reducing the intake of THC may be a more appropriate treatment for the anxiety.
    Thank you, trich.

    I withheld my comment of frustration this morning, but it's clear that if we had not been suppressing good research in re. to medical efficacy of various cannabinoids over the last 85 years (+/-), we likely wouldn't be chasing or tails at times like these, shadow-boxing with unknowns in re. to variables.

    So we have the research you posted, stating CBD can cause, or be involved in bringing about cell apoptosis/'cell suicide', the June 2020 NIH study stating that THC-a reduced size and weight of tumors in pancreatic cancer tumors in mice, and the conclusion (at least for the moment?) that THC (THC-a, as well?) competes with CBD in re. to receptor sites, and THC causes panic..

    In my case, there wasn't so much any paranoia. It was upon ingestion of the CBD from the suspect flowers (yet to be properly tested), that I experienced a nearly immediate tight chest, telling me it was not likely the CBD itself, or THC, for that matter. Too quick for that.

    Wondering if it might not be wise to go either with a straight THC-a extract, or a straight CBD extract at this point. Though, unlike Weez, I have been less apt to do paced research on myself, and more apt to throw anything at the cancer that promises some sort of benefit; providing one doesn't cancel out another, as it seems might be the case some times..

    Thanks again, trich.
    Last edited by moose eater; 01-30-2021, 23:23.

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