B-complex and or Multi recommendation?

[Corngold]

@GRay said in B-complex and or Multi recommendation?:

I just took a quick look at it, there is citric acid in it.

Can you tell me roughly the danger of citric acid? Is there a Peat article on it?

[GRay]

@Corngold I didn't really retain much info on Citric Acid, I heard Georgi talking about it many times in a negative way as cancer promoter, perhaps Ray Peat has some article or interview about it.

[GRay]

@wester130 I know this company. It looks good, I like it since it doesn't have B12 in it. However it doesn't have the B5 in it though, which I think it can be helpful for adrenal hormone production.

[GRay]

@albion

Since I'm ingesting allot of B12 from food, beside the 8oz of liver I have weekly I also eat 1lb of beef heart as well, plus 3 eggs daily, do you think adding more B12 with a B-complex once or twice weekly can be an issue?

it seems like the products I like they also contain the B12, beside Energin and the B-complex from Forefront

[LucH]

@GRay said in B-complex and or Multi recommendation?:

I heard Georgi talking about it many times in a negative way as cancer promoter

Not at this dose, in a supplement, as an antioxidant (citric acid).
The dual role of citrate in cancer
Excerpt
In this context, targeting citrate and citrate-related metabolism [[6], [7], [8]] may appear to be a novel and hopeful option. Citrate is an intermediate of the tricarboxylic acid (TCA) cycle (also known as Krebs cycle). In the cytosol, it is cleaved by ATP-citrate lyase (ACLY) into oxalacetate (OAA) and acetyl-CoA. The latter is the primary substrate for fatty acid (FA) synthesis (FAS) or protein acetylation (either in the cytosol or in the nucleus for epigenetic modifications). Increased de novo FAS is one of the hallmarks of cancer cells, as well as an increase in aerobic glycolysis, the so-called Warburg effect [9]. Therefore, an adequate citrate supply is crucial to sustain cancer cells growth. However, citrate is also a Ca2+ and Mg2+ chelator, as well as a potent inhibitor of phosphofructokinase-1 (PFK1), the key regulatory enzyme of glycolysis [10], and also of phosphofructokinase-2 (PFK2) [11], which produces fructose-2,6-bisphosphate (F-2,6-BP), the main potent activator of PFK1 [12]. Consequently, proliferative cancer cells need to strictly control their intracellular citrate level to keep their metabolism balanced. Indeed, while a low level of citrate could impair cancer cell growth due to decreased FAS, an excessive level may have detrimental effects on glycolysis, ATP production and cell survival [13,14]. Therefore, such a need for a strict control of intracellular citrate level by cancer cells may offer two strategies potentially valid for cancer treatment, i.e., (1) reducing intracellular citrate levels (for example by inhibiting citrate uptake) and (2) flooding cells with excessive citrate to arrest glycolysis.
https://doi.org/10.1016/j.bbcan.2023.188987
Science Direct 2023. Philippe Icard et al.

[CrumblingCookie]

@albion said in B-complex and or Multi recommendation?:

@CrumblingCookie Would you recommend someone trying to diagnose if they need more Cysteine to take NAC? If yes, just as a diagnostic tool or ok as a regular/intermittent supplement?

IMO both is possible. NAC is much much less excitatory than free cysteine and really good as long as there's no diarrhea from taking it. In the latter case it's better to work up with sulfate. It's difficult to forecast the full circle of interdependencies which depends on individual overall health.
For regular or continuous intermittent use I'd blend the NAC 1:1 with glycine and add a basis of 100mcg molybdenum per day. Lots of vegan protein powders are especially poor in cysteine (and total sulfur amino acids) so adding NAC to them can make them feel much more wholesome and nutritious imo.

[GRay]

@CrumblingCookie

If I'm understanding correctly, NAC is actually beneficial as some studies show, totally different from Cysteine?

I supplemented with NAC for years, but put it aside since in the Peat world.

[CrumblingCookie]

@GRay Yes. In the notoriously and rightly bashed context of free cysteine, NAC is very different.

With NAC:

The combination of slow uptake and a deacetylation step that is not extremely efficient is expected to limit the intracellular delivery of Cys.
.Most likely, uptake rather than deacetylation is the rate-limiting step, as a more lipophilic NAC derivative, NAC ethyl ester, shows enhanced intracellular Cys delivery relative to NAC

From The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species you get these illustrations:

Also noteworthy:

Among the amino acids in protein, cysteine and cystine are well known to be among the poorest absorbed from the upper small intestine (NRC, 1994). Heat treatment of proteins contributes to the poor digestibility of cysteine because heating protein causes cysteine to be oxidized to cystine, a dimer that is poorly absorbed (Miller et al., 2001; Parsons et al., 1992)."
[Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate | Institute of the Medicines]

acetylation of the amino group renders NAC resistant to oxidation, and even when it does get oxidized, ensures solubility of the oxidation product. This explains why NAC solutions do not precipitate over time, even after prolonged storage.

Noteworty especially regarding Coenzyme-A, which is not at all about B5-megadosing, and which also means that more acetaldehyde is allowed to be converted into acetic acid to be used for CoA:

"N‐acetylcysteine, which functions as a cysteine donor. Cysteine is critically important in energy metabolism by contributing the sulfhydryl (SH) group needed for energy generation. For example, coenzyme A (CoA‐SH) is an important component of reactions governing energy generation and depends on the availability of a SH group for its normal functioning."

Then there's a lot like the findings described therein (pigs are most similar to humans regarding GI systems):
N-Acetylcysteine improves intestinal function and attenuates intestinal autophagy in piglets challenged with β-conglycinin
and stuff like

Treatment with NAC significantly reversed the glucose intolerance, fasting glucose concentrations, and gains in body weight and plasma endotoxin in HFD-fed mice.
NAC upregulated occludin and mucin glycoprotein levels in the proximal colon of HFD-treated mice.
NAC promoted the growth of beneficial bacteria (i.e. Akkermansia, Bifidobacterium, Lactobacillus and Allobaculum) and decreased populations of diabetes-related genera, including Desulfovibrio and Blautia.

and hints that it even epigenetically upregulates the CBS pathway:

Maternal NAC therapy prevented the rise in systolic blood pressure (BP) in male SHR [genetically altered Spontaneously Hypertensive Rats] offspring at 12 weeks of age. Renal cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulphurtransferase (3MST) protein levels and H2S-releasing activity were increased in the SHR+NAC offspring. Maternal NAC therapy increased fecal H2S and thiosulfate levels in the SHR+NAC group. Additionally, maternal NAC therapy differentially shaped gut microbiota and caused a distinct enterotype in each group."

and other stuff like:

[...] the study found the drug to be safe and effective at doses of 2.4 and 4.8 g/day in reversing the depletion of glutathione and in improving disease activity and the fatigue level."
[...] profoundly reduced mTOR activity in T lymphocytes
[...] kynurenine’s accumulation plays a role in the activation of mTOR in SLE
[...] Treatment with NAC increased the abundance of NADPH which in turn resulted in increased catabolism by NADPH-dependent kynurenine hydroxylase leading to lower levels of kynurenine which subsequently inhibited the mTOR pathway in those T cells
[...] A higher-than normal mitochondrial transmembrane potential or mitochondrial hyperpolarization (MHP) was found in lymphocytes from SLE patients.
MHP is attributed the blocked electron transport, and it is associated with the depletion of ATP and glutathione and the accumulation of oxidative stress-generating mitochondria due to diminished mitophagy.
"Kynurenine accumulation has been reversed by treatment with NAC but not placebo in the setting of a double-blind placebo-controlled clinical trial of 3-month duration."
oral administration is reported to lead to NAC concentrations below 15 μM in the circulation whereas intravenous injections of NAC achieve serum concentrations between 100 and 1500 μM

Orally, it undergoes rapid intestinal absorption and metabolism by the liver, which directs most of the cysteine released toward GSH synthesis.

Intravenous administration allows rapid delivery of high concentrations of NAC due to the absence of the first-pass intestinal and hepatic metabolism and that is why it is the intravenous route used for the treatment of paracetamol overdose

For oral administration, this seems to be the predominant mechanism, with deacetylation taking place in intestinal enterocytes and Cys being forwarded through the portal vein, leading to a bioavailability of 9 and 4% for total and reduced NAC, respectively.

So only about 9% of oral NAC reaches circulation as NAC. The other 91% of oral NAC get taken up and deacelytated by enterocytes and hepatocytes.

GlyNAC supplementation for 24 weeks in Older Adults corrected RBC-GSH (glutathione) deficiency, oxidative stress, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference

Treatment with laxative or NAC reduced mucus accumulation by 43% and 50%, respectively, as measured histologically as dilation of the intestinal crypts. [...] Laxative and NAC also reduced bacterial overgrowth in the CF intestine by 92% and 63%, respectively.

NAC treatment reduced matrix metalloproteinase-2 (MMP-2) secretion and exhibited a direct effect on the secreted MMP-2 activity.
MMP-2 activity were restored to physiological value.
Compounds able to maintain GSH/GSSG ratio to physiological values can be useful to restore normal MMP-2 levels reducing in CD [Crohn's Disease] patient intestine the dysfunction of epithelial barrier.

MMP-2 info for context:

(Matrix Metalloproteinase-2 (MMP-2) is a neutral, zinc-dependent protease that primarily targets extracellular matrix proteins It's dysregulation has been implicated in a variety of pathologies, including Alzheimer Disease.
.MMP-2 induces breakdown of BBB
.MMP-2 disrupts oxidative homeostasis
./MMP-2 has both proinflammatory/pro-angiogenetic and antiinflammatory/ anti-angiogenetic effects

NAC also restores neuroplasticity after cocain abuse (and from other stimulatory drugs), decreasing addiction and relapses:

N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.

Wherein LTP stands for Long-Term-Potentiation and LTD stands for Long-Term-Depression which has been found to induce brain cell apoptosis and elimination of synapses:

New evidence demonstrates there are similarities between the apoptotic pathway and LTD which involves the phosphorylation/activation of GSK3β. NMDAR-LTD(A) contributes to the elimination of excess synapses during development.
[MDMA] can lead to spatial memory impairments and hippocampal cell death
NAC significantly protected against MDMA-induced apoptosis and the up- and down-regulation of Bax and Bcl-2 [which are pro-apoptotic], respectively.
Attenuation of ecstasy-induced neurotoxicity by N-acetylcysteine

NAC facilitates the release of dopamine (DA):

Dopamine itself is strongly prooxidant, forming hydrogen peroxide (H2O2) and free radicals through autooxidation and normal metabolism, and hence dysregulation of dopamine signalling is thought to be a major contributor to neurotoxicity [20].
[...] Methamphetamine evokes strong dopamine release and drives neuronal apoptosis.
[...] NAC ameliorates the oxidative stress induced by methamphetamine production and prevents the downregulation of the dopamine transporter elicited by excessive dopamine release.
[...] demonstrates the importance of cystine/glutamate transport and GSH regulation of oxidative stress in dopaminergic signalling
[The promise of N-acetylcysteine in neuropsychiatry. 10.1016/j.tips.2013.01.001, 2013]

Noteworthy in the context of Peat's mentioned toxicity of (heterocyclic) biogenic amines by consumption of rotten aka "matured"/"aged"/"ripened" meat:

NAC N-acetylcysteine, alpha-tocopherol and glutathione were protective against N-hydroxylamine-mediated lactate dehydrogenase release into the medium.
N-acetylcysteine was by far the most protective of the agents investigated

In summary, it seems that NAC delivers Cys at such a slow and (presumably) steady pace that it avoids the toxic effects that have been associated with corresponding dosages of unmodified Cys. In other words, N-acetylation of Cys slows down the delivery of Cys, making NAC a Cys-prodrug that feeds cells with a trickle of Cys over a prolonged period of time.
A new conceptual framework for NAC’s mechanism of action is emerging, namely as a Cys pro-drug that leads to modest elevations of H2S and sulfane sulfur species inside cells. The slow release of Cys from NAC allows for sustained sulfane sulfur production, providing protective effects -independently of GSH replenishment (Fig. 9). The sulfane sulfur branch of NAC metabolism opens new perspectives on its therapeutic use.

It's important to consider though,
that NAC annihilates the antioxidant effects of lipoic acid in the NO-pathways on nerve cells, because LA exerts that effect through a mild pro-oxidant raise of Akt / decrease of GSK3-beta,
that NAC exerts anticoagulant and antiplatelet properties so would mess with bleeding disorders and blood thinning medications,
that all H2S-generating pathways require PLP/P5P as a cofactor so it's crucial to supply enough of this active vitamin B6,
that NAC hinders antibiotics, phagocytosis and pathogen elimination - unless its specifically Mtb against which it curiously assists,
that NAC (as well as e.g. melatonin) is a TLR4 antagonist and thus decreases beta-defensin expression of the innate immune system hence it's not a wise thing to take in acutely infected conditions and when tackling intestinal pathogens especially.

@GRay I hope that helps you a little.

[GRay]

@CrumblingCookie

wow, that is amazing. thank you so much for putting this together, this should be a pinned post on NAC vs Cysteine

My anecdote:
Years ago I was having a gut issue, I started taking NAC slow released from Jarrow, and it literally improved the issue substantially in a matter of a day or two.

[GRay]

@CrumblingCookie said in B-complex and or Multi recommendation?:

So only about 9% of oral NAC reaches circulation as NAC. The other 91% of oral NAC get taken up and deacelytated by enterocytes and hepatocytes.

@CrumblingCookie if I'm understanding well, even if most of the oral NAC is deacelytated, the cysteine will go mostly for GSH synthesis correct?, which seems to be a good thing, or this means it would be better not to take oral NAC because the deacelytated process?

did they use an oral or injection form in the studies you attached?