Low Toxin Diet Grant Genereux's Theory Of Vitamin A Toxicity

[charlie]

What is with that? I can't wait to take it.

I feel incomplete without it. Maybe the body sensing the yuge amount of life being pumped back into it, so it craves it.

"The fact that a taste of chocolate can provoke a wild lust for more chocolate, or that once cigarette renews the addiction, does not mean that the presence of chocolate or nicotine in the blood creates a craving. Rather, it is that an organism in an unstable state perceives the availability of something which promises to partially restore the desired stability." - Sir Raymond Peat

 

[Tarmander]

I feel incomplete without it. Maybe the body sensing the yuge amount of life being pumped back into it, so it craves it.

"The fact that a taste of chocolate can provoke a wild lust for more chocolate, or that once cigarette renews the addiction, does not mean that the presence of chocolate or nicotine in the blood creates a craving. Rather, it is that an organism in an unstable state perceives the availability of something which promises to partially restore the desired stability." - Sir Raymond Peat

I have woken in the middle of the night, popped a couple pills...and gone back to sleep blissfully.

Is it me or did Niacinamide never do this?

 

[Blossom]

Is it me or did Niacinamide never do this?

Niacinamide never did that for me!

 

[charlie]

Is it me or did Niacinamide never do this?

Never, not like this. Like Amazonian et el said, something special about niacin.

 

[gaze]

according to peat the niacin flush is extremely toxic and should be avoided, no?

 

[charlie]

according to peat the niacin flush is extremely toxic and should be avoided, no?

Yes. But what do you do when it brings you out of a crisis situation?

 

[Tarmander]

Yes. But what do you do when it brings you out of a crisis situation?

tbh, other then his big recommendations, the opposite of Peat's advice works a lot of times for me.

Also, the more often you take niacin, the less you flush, suggesting that perhaps it might be "bad" at first, but gets better with time?

 

[gaze]

Yes. But what do you do when it brings you out of a crisis situation?

yea definitely im not educated enough so i have no alternative to offer, just wanted to clarify in case i was missing something.

 

[redsun]

according to peat the niacin flush is extremely toxic and should be avoided, no?

Nicotinamide(niacinamide) also increases histamine and serotonin. The study below was a dose of 100mg. I find that interesting because in the same video he recommends 50 to 100mg of niacinamide multiple times a day for certain inflammatory conditions. Seems the histamine and serotonin effects are probably just a characteristic of niacin supplements or the vitamin itself though niacinamide does not produce a flush only rarely. Personally I dont think the histamine part is a concern.

Excess nicotinamide increases plasma serotonin and histamine levels. - PubMed - NCBI

 

[charlie]

yea definitely im not educated enough so i have no alternative to offer, just wanted to clarify in case i was missing something.

I wrestle with this paradox often.

 

[Blossom]

tbh, other then his big recommendations, the opposite of Peat's advice works a lot of times for me.

Yes, I’ve experienced this too in the last few years especially since menopause. That’s what I blame everything on right now.

 

[Vicecaz]

Would raw goat milk be acceptable if one's trying to be little vit A?
That'd be my only source of retinol. No eggs and B carotene anymore anywhere in my diet, just for a few weeks at first to see.

But since I've found a source of raw goat milk (finally), could someone step in with his experience?

 

[Blossom]

Would raw goat milk be acceptable if one's trying to be little vit A?
That'd be my only source of retinol. No eggs and B carotene anymore anywhere in my diet, just for a few weeks at first to see.

But since I've found a source of raw goat milk (finally), could someone step in with his experience?

I eat some goat dairy. Someone on this forum said it was higher than unfortified cow dairy but I tolerate goat better. I suppose it would depend on how much you consume. I only have about 1 serving per day or two and feel fine with that amount. Your experience may differ from mine.

 

[CDT]

It looks like this summer will be 5 years for Grant according to ETFOH.

"2014 August-2015 May  The long road to recovery. It has not been exactly a linear and direct recovery. There have been some road bumps and setbacks. But, overall, everything has slowly moved back to normal. Where my health is now:  Thinking is perfectly clear (at least I think so).  I’m totally refreshed and thinking clearly in the mornings.  Fatigue is totally gone (not a trace of it).  Stiffness is totally gone; I mean completely! No stiffness in the morning or after sitting.  Joint pain is totally gone.  Skin nodules—completely gone.  Psoriasis on the elbows—completely gone, not a speck of it.  Skin is almost perfect. Weirdly, other than on my hands, it now very smooth, like that of a kid’s.  Itchiness is totally, completely gone.  Age spots have all but disappeared.
Spoken language is much more fluent; I now immediately notice misspelled words.  I can now hit bumps all I want on my bike; the inflammation in my brain is gone.  The world is brighter (this is not a metaphor or a figure of speech; it’s literally brighter). I bet my cataracts are gone.  My vision is vastly improved and still improving, it’s now crystal clear in the near view, distant view improving too. Some days my vision is remarkable as it was in my 20s. A home self-test is 20/15 (two grades better than 20/20). Yet, it varies from week to week.  I dream every single night now.  I have a much better quality of sleep every night now.  Night sweats are totally and completely gone—not a trace of them.  Overall, I have much more hair on my lower body, especially the legs. The hair on my head is thicker, too.  All other symptoms are slowly resolving.  I still have smaller, random inflammation occurrences and corresponding negative vision changes.  My overall wellbeing has vastly improved from a year prior.  Another oddity is I think my sense of smell has improved.  My ability for tasting sweetness is about 3 times better.  Blue and green neon signs at night are now very clear.  The thick build up of skin I had on the heals of my feet for over a decade is now gone, my heals are now normal and quite smooth."

Those were just his 1 year improvements.

Are you referring to supplemented vitamin A or vitamin A in the form of carotenoids and non-active compounds?

 

[Blossom]

Are you referring to supplemented vitamin A or vitamin A in the form of carotenoids and non-active compounds?

That post is me quoting Grant.

 

[Amazoniac]

Tl;dr: can't blame you, I barely did.

They focused below on RXRs in isolation. As discussed, the shady alternative ligands (if anything) require higher doses to work, and if you decontaminate yourself enough, the body must try to find means of making them work, by increasing their availability, becoming more sensitive, etc. For example, if you consume the RDA of poison A, it can be 0.001 g/d and it may be enough to fullfil functions, whereas pharmacological doses of DHA might be needed to guarantee that it's substituting poisonous metabolites. Also, I'm not sure if the concentrations required would be sustained in the circulation for too long, and if they is, that it's a good trade-off.

- Alternative retinoid X receptor (RXR) ligands

"9-cisretinoic acid (9CRA), formerly widely accepted as the potential physiological RXR ligand, was found to be essentially undetectable under physiological conditions in vertebrates including human serum and tissue samples. We will review evidence indicating that 9-cis-13,14-dihydroretinoic acid (9CDHRA) meets probably best the criterion of a physiological ligand of RXRs. The physiological relevance of 9CDHRA is further supported by its central role in the concept of vitamin A5, identified as a new class of vitamin A, which may depend on a distinct set of nutritionally relevant precursors. This does not exclude the possibility that other endogenous ligands might also be physiologically and nutritionally relevant in specific cell types or in some “challenging” conditions such as nutritional deficits of specific micronutrients, as reviewed below."

"Before discussing different types of ligands, we need first to define concepts of natural vs endogenous and physiological ligands, which are frequently misused. We will thus consider as natural ligands all substances present in Nature that bind with high potency (optimally in the nanomolar range) their receptors leading to conformational changes in the receptor structure, and induce relevant physiological functions. Excluded are all man-made compounds generated de novo, which will be referred to as synthetic ligands. Endogenous ligands, although frequently dependent on natural precursors found in nutrition, are unique in a sense that they are produced in the body and do not need to be introduced into the organism from outside to be detected. Such endogenous production is therefore dependent on dedicated metabolic pathway(s) and availability of nutritional precursors, as in the case of small bioactive molecules like retinoids. Although several endogenous ligands were proposed for RXRs, their physiological relevance is under debate, since the presence of the ligand in the right place, at the right time and at sufficient concentration to activate RXRs is not always met and, in most cases, is unknown. Importantly, manipulation of nutritional precursors, relevant metabolic pathways or natural ligands provides a method for regulation of ligand bioavailability ranging from deficiency through maintenance of physiological levels relevant for organismal homeostasis to supraphysiological levels. In the latter cases, referred to as supraphysiological conditions or nutritional intervention, exogenous ligands or endogenous substances not acting as endogenous ligands, may become relevant for the control of biological processes in an RXR-dependent manner."


"Using bio-guided fractionation of brain-conditioned medium, de Urquiza and colleagues (de Urquiza et al., 2000) identified a series of FFAs capable of inducing RXR transcriptional activation with different efficiencies. Using sensitive reporter assays in JEG-3 or 293T cultured cells, DHA (Fig. 3) displayed the best transactivation activities starting already at 10 μM (EC50 = 50 μM), whereas docosatetraenoic, oleic and arachidonic acids required higher 100-1000 μM (EC50 > 200 μM) concentrations. Although other studies (Calderon and Kim, 2007; Goldstein et al., 2003) confirmed the requirement of such relatively high concentrations of DHA to induce transcription by RXR, Lengqvist et al. reported an EC50 value of 5-10 μM, by using a different method of DHA application in cultured cells, as well as mass spectrometry evidence for DHA attaching / binding to RXRα-LBD (Lengqvist et al., 2004)."

"There is a substantial amount of data supporting the activity of DHA via RXRs under pharmacological conditions, i.e. after DHA treatment or its nutritional supplementations, e.g. in fish oil. In in vitro experiments, treatment with DHA (free acid form), similarly to synthetic RXR agonists (LG100268 or BMS649), increased the number of surviving neurons in primary culture cells and such effect was RXR dependent since it was prevented in the presence of the RXR antagonist LG100268 (Wallen- Mackenzie et al., 2003)."

"[..]the availability of DHA in its free acid form was essential for such RXR-mediated neuroprotective activities, since a phospholipase A2 inhibitor preventing DHA release from its phospholipid derivatives (the major form of DHA in cells) prevented the neuroprotective effects of DHA treatment."

"The role of RXRs in mediating the diverse effects of DHA under supra-physiological conditions (i.e., after treatment or nutritional intervention) and the capability of vertebrates to synthesize DHA from α-linolenic acid as precursor of plant origin (Rajaram, 2014), may suggest that DHA can act as a physiological ligand. However, such a role is questionable due to the likely limited availability of the free acid form. Although the determination of free DHA levels is not evident because of the multiple forms of DHA, its levels were reported to range from 0.1 μM to 0.01 μM in animal and human serum or tissue samples (Elabdeen et al., 2013; Szklenar et al., 2013). Such endogenous levels of DHA would not be sufficient for transcriptional activation, which requires at best a concentration range of 5-10 μM (Lengqvist et al., 2004). Free DHA levels were not examined under conditions of nutritional or pharmacological interventions, and in particular no data are available on its concentration in the nucleus; therefore, it is uncertain whether such interventions really lead to sufficient increase of endogenous free DHA levels to function as a ligand-dependent switch in the nucleus. Moreover, central nervous system activities of DHA (including e.g. promnemonic and antidepressant effects (see (Wietrzych-Schindler et al., 2011) and references therein) might be also difficult to explain by direct DHA-RXR interactions, since transfer of DHA through the blood-brain-barrier is highly selective and of low efficacy for the free acid form, whereas it might be easier for DHA metabolites or synthetic acetyl derivatives (Lo Van et al., 2016; Picq et al., 2010)."

"The relevance of DHA in modulating RXR signaling needs also to be considered in a context of other RXR endogenous ligands due to potential competitions or cross-talk between metabolic pathways involved in the production of such ligands. For example, in vitamin A-deficient animals, enhanced DHA production was observed (Zhou et al., 2006). Although the mechanism of this regulation is not known, it may involve, in addition to transcriptional regulation of DHA metabolic enzymes, competition for enzymes or binding proteins which might be shared in the biogenesis and metabolism of those fatty acids. For example, some retinol-binding proteins may bind with different efficiencies also to DHA (Tachikawa et al., 2018). This could suggest that FFA and retinoid signaling may cooperate in controlling RXR signaling and that such control may involve transcriptional control and sharing of some proteins involved in ligand metabolism and traffic. Such cooperation could possibly become biased towards one of the ligands in specifically challenging situations, like the deficiency of selected micronutrient(s)."

"Using bio-guided fractionation, Kitareewan et al. (Kitareewan et al., 1996) identified phytanic acid as a natural agonist of RXRs (Fig. 4). Using a CRBPII-CAT reporter system in an epithelial cell line transfected with RXRα, these authors demonstrated the phytanic acid-dependent transactivation of RXRα activities at 10 μM. Although phytanic acid competed with [3H]-9CRA for RXRα binding with a Ki of 4 μM, it remained a 200-fold less efficient ligand than 9CRA. Activation of RXRα, β and γ isotypes, with EC50 of 20 μM, was also confirmed in a Gal4 reporter assay (Zomer et al., 2000). As an important metabolite of chlorophyll, phytanic acid can be produced in ruminating animals by their rumen bacteria. Humans do not efficiently absorb chlorophyll and cannot metabolize it; thus, levels of phytanic acid in the human body are entirely dependent on meat and milk products ingested in the diet. Consequently, phytanic acid cannot be considered as an endogenous ligand in humans, but may potentially act as such in ruminants. Furthermore, its low levels in human questions the physiological relevance of its activities as a nutritional RXR ligand. Thus, in human plasma phytanic acid concentrations ranged around 1.6 μM, which was highly dependent on dietary habits of healthy volunteers, with the highest level (5.8 μM) found in meat eaters and the lowest in vegans (0.9 μM) (Al-Dirbashi et al., 2008; Allen et al., 2008). Phytanic acid levels ranged around 1 μM in mouse plasma, but were approximatively 10-100 times lower in different tissues (Wanders et al., 2011). Such quantities were increased to 10 μM levels under supplementation with high amounts of phytol, a phytanic acid precursor (Wanders et al., 2011). Importantly, disruption of phytanol-CoA hydroxylase, the first enzyme in the α-oxidation in Refsum disease, leads to high accumulations of phytanic acid, which may reach up to 1000 times the level of a healthy person (Verhoeven and Jakobs, 2001), with highest levels found in the liver, heart, adipose and peripheral nervous tissues, and much lower in the brain (Cumings, 1971). Despite the wide range of symptoms, including peripheral neuropathy, retinal degeneration and cerebellar ataxia (see (Verhoeven and Jakobs, 2001) and references therein), no abnormalities relevant to general or even exacerbated RXR signaling were reported like, for instance, decreased thyroid hormone T4 levels, elevated triglyceride levels or reduced food intake. This further questions the relevance of phytanic acid and potential phytanic acid metabolites as RXR ligands."

"Discussing RXR ligands to which human and multiple animal species are exposed in daily life, it is necessary to mention environmental pollutants. The group of compounds which may modulate RXR activities include phthalates, plasticizers, certain herbicides, organotins, biocides, and pharmaceuticals. These have been extensively reviewed elsewhere (Rogers et al. 2013; Delfosse et al. 2014, 2015)."


"To better understand the origins but also the functional relevance of ligand-dependent regulation of RXRs in vertebrates, we need to travel in time a billion years backwards and look into the evolution of RXRs, their ligands and their functions. Phylogenetic analyses identified an RXR ancestral gene in Placozoans (Baker, 2008; Srivastava et al., 2008) and Cnidarians (Fuchs et al., 2014; Kostrouch et al., 1998), the simplest multicellular organisms and most ancient animal lineages. In particular, Trichoplax adhaerens (an ameboid-like multicellular organism, a member of Placozoans present in seawater) is the first organism in the animal lineage to have a well-documented RXR orthologue, the TaRXR (Baker, 2008; Srivastava et al., 2008). This RXR prototype was recently shown to share a number of important structural and functional similarities with mammalian RXRs. First, it displayed high degree of homology with RXRs from several species, which for human hRXRα attains 81% of homology for the DBD and 70% for the LBD (Novotny et al., 2017; Reitzel et al., 2018). This homology is functionally relevant as DNA-binding motif specificity as revealed by protein binding microarrays was conserved up to 85% as compared to hRXRα (Reitzel et al., 2018). Similarly to human RXRs, TaRXR also bound with high affinity 9CRA which modulated its transcriptional activity (Novotny et al., 2017; Reitzel et al., 2018). Importantly, the possibility of ligand-dependent TaRXR-mediated induction of an orthologue of vertebrate L-malate-NADP+ oxidoreductase places this receptor and its ligand(s) as key modulators of an ancestral Krebs cycle, a cornerstone of the evolution of cellular metabolism and central regulator of different metabolic pathways. Such an important function necessitates a high level of precision in the control of TaRXR activities and might have exercised an evolutionary pressure to limit the number of endogenous and/or physiological RXR ligands. Thus, ancestral TaRXR could have acted as the first high-affinity receptor for a limited number of ligand(s), with the main function to enhance global metabolic activity in environmentally favorable conditions to produce energy (e.g. to ensure reproduction), or reduce energy production in unfavorable conditions (e.g. to avoid exhaustion)."

"The remaining question is, what is this mysterious ancestral ligand? Was it produced in Trichoplax adhaerens from nutritional precursor(s) to act as endogenous ligand, or was it originally a nutritional ligand and organisms adopted it as “endogenous” through evolution of dedicated metabolic pathway(s)? Whereas 9CRA was certainly a very valuable experimental ligand to document conservation and high-affinity binding properties of RXR ligand binding pocket across evolution, it does not seem to be a physiologically relevant ligand as it was detected at moderate levels only in arthropod Locusta migratoria (Nowickyj et al., 2008; Palli et al., 2005), but not in other phyla or species. Thus, it is tempting to hypothesize that 9CDHRA, a physiological RXR ligand in vertebrates (Ruhl et al., 2015), could be an ancestral retinoid and prototypic ligand for RXRs. This possibility is supported by the identification of dihydroretinoids or their precursors in non-vertebrates (Foster et al., 1993) and vertebrates (Aydemir et al., 2013; Moise et al., 2007; Moise et al., 2004). Understanding the metabolic origin of 9CDHRA and its nutritional precursors will be the focus of future research, as they could be directly relevant to the diet of Trichoplax adhaerens. To address this theory, studies of representatives of ancestral organisms in the context of their endogenous habitats and food chain are necessary. The obtained data should provide insights into the interplay between genetic and environmental constraints shaping ligand-receptor interactions with RXR as model NR. Of particular interest for such investigations, but also for the identification of new nutritionally or pharmacologic valuable RXR ligands, might be the studies of micronutrient diversity in the oceans, the cradle of animal life (Markov et al., 2018)."

"Free fatty acids, and in particular DHA, were proposed as endogenous ligands of RXRs. However, here again an involvement of DHA in control of RXR signaling under physiological conditions is still not clear, since the endogenous concentration of DHA as free acid available for transcriptional activation of RXRs in the nucleus is unknown, and in few reported cases of plasma levels in human or tissue levels in rodents, such concentration is below the transactivation range. Data on tissue levels in humans under basal conditions and after dietary stimuli are not available. In turn, a larger array of fatty acid metabolites, including those from DHA, were reported to be present endogenously but again, not much knowledge is available on the potential overlap between RXR transactivation properties and endogenous/nutritionally relevant ranges. In this context, identification of 9CDHRA as an endogenous and physiologically relevant ligand of RXRs was an important step in understanding RXR signaling in vivo. Accordingly, this retinoid is present in mice and human at sufficient concentrations to activate RXR transcription and its absence in mice induces cognitive deficits associated with deficient RXR signaling. Although at present 9CDHRA fulfills the best criteria for an endogenous ligand, there are still many questions to be addressed, relating to its nutritional precursor(s), metabolic pathway(s), the biological functions it may control, and more generally its bioavailability in health and disease. Importantly, determination of whether ATROL and ATBC are precursors of 9CDHRA or whether there are other precursors, will clarify the link with the known “canonical” vitamin A1 pathway."

"Among the unresolved challenges in RXR-ligand research is the physiological relevance for coexistence of alternative RXR ligands, like 9CDHRA, DHA and its metabolites or the nutritionally acquired phytanic acid. As discussed above, the relevance of one ligand may potentially become evident in the absence of the other, as in case of raising levels of DHA in vitamin A-deficient conditions. What is the physiological meaning of it? Are the alternative ligands functionally redundant (at least as far as RXR signaling is concerned) or will they activate different physiological programs that are best adapted to homeostatic conditions or adaptation to environmental challenges? Furthermore, such mutual regulations would imply a crosstalk between metabolic pathways involved in the biogenesis of such ligands. Although such mechanisms may potentially involve transcriptional regulation and sharing of some transport proteins, this area of research remains essentially unexplored and will require more holistic nutritional and analytical studies."​

in a few months your going to become a breatharian.

I guess that the issue is what's motivating the search or making him relate to the content, because it's either the diet not being adequate or the approach not working, otherwise the case would be closed and he would move on.

We can also antecipate that not far from now the people invested in denying the importance of poison A will start to point out weaknesses in the original research (which there are, but it applies to all nutrients if you dig enough) and renew the spirit that has been fading as it's suspected that there's more to the story.

 

[Tarmander]

I guess that the issue is what's motivating the search or making him relate to the content, because it's either the diet not being adequate or the approach not working, otherwise the case would be closed and he would move on.

We can also antecipate that not far from now the people invested in denying the importance of poison A will start to point out weaknesses in the original research (which there are, but it applies to all nutrients if you dig enough) and renew the spirit that has been fading as it's suspected that there's more to the story.

Do you realize you are hoping/rooting for a bunch of people who found something that makes them feel more alive and human, to fail, and come crawling back to explanations that were not helping them, but in which you are more comfortable with? Like take a step back and just think about what you are fighting against.

 

[Tarmander]

Yes, I’ve experienced this too in the last few years especially since menopause. That’s what I blame everything on right now.

I think it is because Ray is utopian. He leaves out the contentious nature of life, and idolizes the metabolism of youth. Maybe his lack of family and children, and being so rational, cut him off from something crucial

 

[sunraiser]

So how do you get rid of the bad flora? How do you figure out deficiencies? These are the type of questions and answers I've been dealing with for decades. You people that are anti the Grant diet have all this "research" and statements but do not put forth any real solutions. People are suffering and the Grant diet helps them. Maybe it isn't the best but please provide a list a foods/amount of sun/amount of exercise that will alleve the pain and suffering.

If you want to test for fungal infection (candida) then get some raw coconut oil (virgin) and eat a teaspoon of it.

If you're fine then over the next few days you can slowly ramp up the dose to 2-3 teaspoons. If you have a fungal overgrowth then you'll either get a mega stomach ache, diarrhea, or just general die off symptoms like headache and sick feeling.

Don't overdo it too quickly because you'll feel f***ing awful - some people puke.

I'm starting to feel more convinced it's a candida thing that inhibits calcium absorption, hence retinol creating a calcium/phosphorous imbalance.

Again, it'll only work if the coconut oil is unrefined and raw.

 

[Amazoniac]

Do you realize you are hoping/rooting for a bunch of people who found something that makes them feel more alive and human, to fail, and come crawling back to explanations that were not helping them, but in which you are more comfortable with? Like take a step back and just think about what you are fighting against.

Not true, from the start I has been encouraging others to decrease their intake to tolerance but to be wary if it's extremely low for too long. This is about avoiding distortions and taking things to a delusional level only so that a comfortable ground is set. If something that deviates from the norm is being done, appears to work and it's put together for others to try with risks involved, it's more productive to interpret as such and find accurate explanations based on this premise instead of pretending that there isn't a norm or widening it so that we're all fine and one.

You often skip these: if someone starts doing long fasts or adopts a carnivore diet and feels more alive and human, would you encourage or tell the person to be careful and not push it too far? In case it's the latter, what would you think about encouragers who condemn the others?