Terma, The Most Underrated Member

Memento

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The test that Davis has developped to diagnose CFS patients from immune system cells is based on a observing eletrical properties (impedance IIRC) of these cells when they are subjected to ... hyperosmotic stress.

Can you share a link or more information about this? Thanks!

@Terma , that CFS paper above mentioned mitochondrial fragmentation and you touched at least mitochondrial fusion in the croissant thread. Do you think manipulating the fusion/fission cycle is something to look into or is it just a downstream consequence of metabolic events?
 

LLight

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Can you share a link or more information about this? Thanks!

@Terma , that CFS paper above mentioned mitochondrial fragmentation and you touched at least mitochondrial fusion in the croissant thread. Do you think manipulating the fusion/fission cycle is something to look into or is it just a downstream consequence of metabolic events?

Here is the paper.

"Although the initial hypothesis of this study was that the ATP consumption rate differs in ME/CFS patients’ blood cells compared with healthy control blood cells, our experimental results on 40 ME/CFS individual patients and healthy controls revealed that ME/CFS hyperosmotic-stressed samples (PBMCs in plasma) display a unique characteristic in their impedance pattern, and one that is significantly different than what was observed in the controls. Our work thus far indicates that the impedance signature itself can potentially represent a distinctive indicator of ME/CFS patients versus controls and can potentially establish a diagnostic metric for the disease."
 

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Terma

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Thanks.

The thread with the other video: if this were all in preparation for an ice age, these would be an odd choice of plans because in response to plant closures they're planting more soy (soylent?) instead of investing in housed agriculture and aquaculture? Or will that be happening now?

Aquaculture can keep us alive during a new ice age if fish survive in cold temperatures, sometimes better than mammals, which starve and lose nutrients and hardships. Fish thrive in cold waters with nutrients and then feed the mammals: Salmon run - Wikipedia. Now we have the technology, albeit high populations, as long as the energy is there, but there should be since we'd be hunkered down like northern places.

I imagine this is why you could consider o-3 a conditional requirement for health at best and at worse expected minimum exposure at least part balanced by some beneficial effects. It's in the most nutrient-dense, immunity-preserving food supply that counters the effects of o-6 which otherwise you'd have to counteract with salicylic acid. I'd argue our bodies and foods can be fairly well-equipped to handle o-3. It has some useful effects anyway and nature survives making the best of what it has. Not that warmer climates wouldn't be preferable.

***

With a seafood-based culture you'd expect less inflammation in the population, not incomparable to aspirin, or even could be administered together - not even necessarily for beneficial effects (since side-effects may accrue long term) but to prevent damage from them:
The combination of EPA+DHA and low-dose aspirin ingestion reduces platelet function acutely whereas each alone may not in healthy humans
Healthy Omega-3 Fats and Aspirin Work Together to Fight Inflammation
“Aspirin is able to modify an inflammatory enzyme to stop forming molecules that propagate inflammation and instead produce molecules from omega-3 fatty acids, like resolvin D3, that help inflammation to end," said coauthor Dr. Nicos Petasis of the University of Southern California.
Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Potent Immunoresolvents
Resolvins are a new family of n-3 lipid mediators initially identified in resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited resolving exudates revealed that resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry of RvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte-directed actions, e.g. blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids.
So you can control the usage or balance of o-3 and metabolites, which might be one way or the other depending on the pathology?

In very high o-3 diets you get worse side effects and aging, so it's just a matter of determining a reasonable o-3 (PS) exposure to optimize life and our survival - seemed to be somewhere under 3g/day? It's not mercury and the astaxanthin in seafood might help preserve? Plus rare things like nervonic acid which all the other sources are clearly worse and may not have astaxanthin. Various foods have salicylic acid anyway.

Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes
The dysfunction of oligodendrocytes (OLs) is regarded as one of the major causes of inefficient remyelination in multiple sclerosis, resulting gradually in disease progression. Oligodendrocytes are derived from oligodendrocyte progenitor cells (OPCs), which populate the adult central nervous system, but their physiological capability to myelin synthesis is limited. The low intake of essential lipids for sphingomyelin synthesis in the human diet may account for increased demyelination and the reduced efficiency of the remyelination process. In our study on lipid profiling in an experimental autoimmune encephalomyelitis brain, we revealed that during acute inflammation, nervonic acid synthesis is silenced, which is the effect of shifting the lipid metabolism pathway of common substrates into proinflammatory arachidonic acid production. In the experiments on the human model of maturating oligodendrocyte precursor cells (hOPCs) in vitro, we demonstrated that fish oil mixture (FOM) affected the function of hOPCs, resulting in the improved synthesis of myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein, as well as sphingomyelin. Additionally, FOM reduces proinflammatory cytokines and chemokines, and enhances fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) synthesis by hOPCs was also demonstrated. Based on these observations, we propose that the intake of FOM rich in the nervonic acid ester may improve OL function, affecting OPC maturation and limiting inflammation.

***

About mycoplasma that's something I lost track of ages after candidate for persistent pain, but wanted to read again, because they may be involved in joint deterioration/inflammation or prevention of healing:
Mycoplasma Infections
Mycoplasma pneumoniae infection and arthritis in man.
Tests not always available.

The ME/CFS forums were active about it, then the Garth Nicholson stuff:
Garth L. Nicolson - Wikipedia
Gulf War syndrome and controversy
After the Gulf War of 1990–1991, a number of war veterans suffered from similar illness, popularly dubbed Gulf War syndrome.[24] They indicated symptoms like chronic fatigue, headaches, memory loss, muscle pain, nausea, gastrointestinal problems, joint pain, lymph node pain, increased chemical sensitivities and other signs and symptoms. Nicolson became one of the leading experts in the investigation of the cause and cure of the disease.[25] Initially the US government disregarded the illnesses as the aftermath of the Gulf War, such as exposure to biological or chemical warfare. Nicolson and his wife Nancy became the main voice to raise the problem.[26] They identified the causal pathogen as Mycoplasma fermentans, which was a different strain from the natural pathogen, raising the possibility that it was man-made biological weapon.[27] They successfully treated patients with multiple courses of specific antibiotics, such as doxycycline, ciprofloxacin, azithromycin, clarithromycin or minocycline.[28] Nicolson's "Written Testimony" to the US Senate in 1998 states that: "We consider it quite likely that many of the Desert Storm veterans suffering from the GWI signs and symptoms may have been exposed to chemical/biological toxins (exogenous or endogenous sources of these agents) containing slowly proliferating microorganisms (Mycoplasma, Brucella, Coxiella, etc.), and such infections, although not usually fatal, can produce various chronic signs and symptoms long after exposure."[29] While other researchers found negative results for Mycoplasma infection,[30][31] Nicolson's team found definite high prevalence of Mycoplasma infections.[32]
Soldiers in the gulf were also given fluoroquinolones additionally (!) to try to eradicate mycoplasma. With 4 other options they gave quinolones to extreme intensity athletes.
Relationships between Th1/Th2 cytokine profiles and chest radiographic manifestations in childhood Mycoplasma pneumoniae pneumonia
Th1/Th2 Cytokine Profile and Its Diagnostic Value in Mycoplasma pneumoniae Pneumonia
https://sci-hub.tw/https://www.jimmunol.org/content/198/1_Supplement/131.15
Mycoplasma pneumoniae is a leading cause of bacterial community-acquired pneumonia and is implicated in the initiation and exacerbation of asthma. Over 2 million cases of M. pneumoniae infection occur in the United States each year. However, with no surveillance system in place for reporting infections, the true scope of the problem may be vastly underestimated. One of the hallmark immunological effects of M. pneumoniae infection is an imbalanced Th1/Th2 response. A recently identified M. pneumoniae virulence factor is the Community-Acquired Respiratory Distress Syndrome (CARDS) toxin, an ADP-ribosylating and vacuolating protein produced abundantly during infection that is capable of provoking a Th2 cytokine phenotype in mice. We hypothesize that CARDS toxin is utilized by M. pneumoniae in vivo to dampen the Th1 response and influence the Th2 response in order to establish a strong, persistent infection.

The clinical isolate strain M. pneumoniae S1 abundantly produces CARDS toxin during infection and causes severe pathology. We utilized S1 as a template to generate a CARDS-deficient mutant we designated M7. M7 and S1 were used in vitro and in vivo to identify Th1- and Th2-specific cytokine changes during active infection. We observed significant differences in pathology between M7- and S1-infected mice, indicating that CARDS toxin directly impacted M. pneumoniae disease and persistence. Our findings provide insights to understand the elusive pathological mechanisms behind M. pneumoniae infection and implicate CARDS toxin as a potentially important target for therapeutic intervention during M. pneumoniae infection.
So altogether given the range and severity of symptoms of ME/CFS, we know some of these are potent, but then ME/CFS overlaps maybe better with fluoroquinolone poisoning. Meaning I could see fluoroquinolones may trigger or worsen ME/CFS as some people reported, whereas the association with mycoplasma I'm not sure was as reported, maybe other studies might show, maybe a candidate in some people or co-infection, and maybe some people even have immune responses geared to clearing them. Not clear:
https://www.me-pedia.org/wiki/Mycoplasma
A small number of published studies have suggested an increased prevalence of Mycoplasma presence in individuals with Chronic Fatigue Syndrome as compared to healthy controls.[4][5][6] These species include Mycoplasma pneumoniae, Mycoplasma fermentans and more.

Independent work by Dr. Garth Nicolson has found similar prevalence and symptom patterns and with Gulf War Illness (GWI) and fibromyalgia (FM).[7]

A later study, by a different group, was unable to detect the presence of Mycoplasma in either patients with CFS or healthy controls. The authors of this study have advised potential limitations of the patient selection and detection methodology of the earlier studies.[8]
Standard Mycoplasma Pneumoniae infections are generally detected using antibody tests. Such tests may be insufficient for chronic Mycoplasma detection and instead PCR tests may be more effective.[9]

The reliability of Mycoplasma testing from specific private laboratories may not be well established. Variation in results may be seen between different labs so discretion may be needed. An example of a private test provider for Mycoplasma PCR is Australian Biologics.
As the link between Mycoplasma and CFS is not well established, there is no standard treatment protocol for suspected cases. Mycoplasma are generally susceptible to antibiotics. There is one published study which suggests long term doxycycline may be effective for CFS patients who are detected with a Mycoplasma infection.[10]

Despite limited evidence, a number of practitioners consider and treat CFS patients who show signs of a chronic Mycoplasma infection. Treatment usually involves long term antibiotics along with supportive measures. Examples of practitioner protocols are those of Dr. Richard Schloeffel, Dr. Greg Emerson and the late Dr. Lerner.
But then one or two people were convinced antibiotics including doxycycline caused their ME/CFS or what they defined that as, so if there's something there maybe it's more like co-infections? I'll admit it's not strong, whereas antibiotics damage people and alternatives welcome.
 

Terma

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Yes good remark about mito fission/fusion, I forgot to write about that. Clearly those are meant to work in cycles. I guess it invokes circadian but maybe we're also talking about longer cycles of food abundance vs restriction, I guess with regulation of things like substrates for ceramides like palmitic acid or serine (partially supplied by kidneys). Will get around. It might be important to understand for how to answer ME/CFS, for those who believe mitochondrial health is a part.
Circadian rhythms in mitochondrial respiration
Many physiological processes are regulated with a 24-h periodicity to anticipate the environmental changes of daytime to nighttime and vice versa. These 24-h regulations, commonly termed circadian rhythms, among others control the sleep–wake cycle, locomotor activity and preparation for food availability during the active phase (daytime for humans and nighttime for nocturnal animals). Disturbing circadian rhythms at the organ or whole-body level by social jetlag or shift work, increases the risk to develop chronic metabolic diseases such as type 2 diabetes mellitus. The molecular basis of this risk is a topic of increasing interest. Mitochondria are essential organelles that produce the majority of energy in eukaryotes by converting lipids and carbohydrates into ATP through oxidative phosphorylation. To adapt to the ever-changing environment, mitochondria are highly dynamic in form and function and a loss of this flexibility is linked to metabolic diseases. Interestingly, recent studies have indicated that changes in mitochondrial morphology (i.e., fusion and fission) as well as generation of new mitochondria are dependent on a viable circadian clock. In addition, fission and fusion processes display diurnal changes that are aligned to the light/darkness cycle. Besides morphological changes, mitochondrial respiration also displays diurnal changes. Disturbing the molecular clock in animal models leads to abrogated mitochondrial rhythmicity and altered respiration. Moreover, mitochondrial-dependent production of reactive oxygen species, which plays a role in cellular signaling, has also been linked to the circadian clock. In this review, we will summarize recent advances in the study of circadian rhythms of mitochondria and how this is linked to the molecular circadian clock.

You see mitochondrial biogenesis in liver going by PGC1A protein levels should be highest at the start of the active period (NAD+):
In human muscle, the marker of mitochondrial biogenesis, PGC1A, was not found to be rhythmically expressed, but in synchronized immortalized human hepatic cells, mRNA levels of PGC1A were found to be rhythmic, with peak levels of expression proximal to peak levels of BMAL1 expression. Animal models also show different results on the regulation of mitochondrial biogenesis by the circadian timing system. In mice, liver protein levels of PGC1A and PGC1B were found to be oscillating with peak levels at the onset of the active phase and in the middle of the inactive phase, respectively (Liu et al. 2007).
Normally you'd expect the later food consumption to drive ceramide synthesis and those drive fission:
Ceramide-induced BOK promotes mitochondrial fission in preeclampsia
It would have to go further but it's argument you could use for longer breaks on the gut from food, hence the occasional 16-hour fasts idea.

***

I'd say it could be a valid form of treatment to attempt because almost all ME/CFS therapies have been downstream therapies but they allow some to function. Exception if the behavior is some kind of protective response, but I think it's past that.
 
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Terma

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This is in response to this post, but it complements the above:
I Keep Seeing Coronavirus EVERYWHERE (lounge)
It is particularly unsettling in a way to me how there's this seemingly odd campaign about staying indoors and staying safe. "Stay Home. Stay Safe." You see this reminded nonstop on TV, stores, internet, etc. "We're in this together. We'll get through this." I feel like we're in a pseudo, bizarre rift of some sort in a sense maybe.

I think it should be serotonin-related if you consider it's a similar reaction to a startle response. It communicates "the danger is real", like antilope on the lookout, or meerkats, who have complex social and danger alert systems, like state machines/systems. Like bombers flying above (lol no), or eagles circling.
Serotonin Causes The Startle Response, And Likely PTSD As Well

But it's also that alien threat again that invokes team playing and protective behavior, reminiscent also of certain hormones: oxytocin, vasopressin (receptors), testosterone/DHT/estrogen? I think it probably has a meaningful social effect that populations are on SSRIs and other drugs. You're either more attuned to danger, more aggressive (together with norepinephrine/other), more passive or even possibly experiencing some forms of relief (due to temporary effects of post-synaptic 5-HT1a receptor without downregulation), depending on the time period and patterns of post-synaptic 5-HT stimulation.

Together with hibernation those are the responses to threats, and serotonin receptors releasing vasopressin suggests they help implement these social programs/responses, besides acting on individual pro-survival - the distinction probably influenced by oxytocin, vasopressin and hormones. Also they release dopamine, cholinergic receptors, ... Since cortisol is self-sacrificial in nature it could be associated to oxytocin release, and the post-synaptic 5-HT1a receptor releases both so it pinpoints its pro-social part of the danger response (like relief experienced when re-locating your lost herd after adrenaline anxiety and 5-HT2/3, drive toward it).

5-HT1A receptor - Wikipedia seems like a group (especially infant/family) huddle program if you imagine animal prey families, but given oxytocin/endorphins the social contact and physical contact should be involved with:
5-HT1A receptor activation induces the secretion of various hormones including cortisol, corticosterone, adrenocorticotropic hormone (ACTH), oxytocin, prolactin, growth hormone, and β-endorphin.[63][64][65][66] The receptor does not affect vasopressin or renin secretion, unlike the 5-HT2 receptors.[63][64] It has been suggested that oxytocin release may contribute to the prosocial, antiaggressive, and anxiolytic properties observed upon activation of the receptor.[30] β-Endorphin secretion may contribute to antidepressant, anxiolytic, and analgesic effects.[67]
GH? Groups mean safety which means time for rest and regeneration - even in the presence of cortisol, which it sort of offsets at the expense of FFAs. Then you get melatonin. The confounder is cortisol which is damaging to sleep. So that suggests its pro-cortisol effects either have to be antagonized into the evening/night - either though epigenetics, steroids/conversions, receptors, etc. - or for optimal health post-synaptic 5-HT1a can't be agonized into the night, or must be followed by a significant (melatonin) period where GH can act alone to recover from damage.

I'd suggest both, for maximum effect; the other hormones like ALLO/oxytocin can get triggered other ways to make up for diminishing serotonin post-synaptic 5-HT1a agonism, and I'm guessing 5-HT7 especially (8-OH-DPAT - Wikipedia) and maybe others are involved as well as the absence of inappropriate 5-HT2/3 stimulation.

The serotonin system seems to help determine environmental/social/energetic prerequisite signals/states for transitioning into paralysis and unconsciousness, again a state machine. So you'd expect to see a circadian influence on these receptors:
Circadian rhythm in the response of central 5-HT1A receptors to 8-OH-DPAT in rats. - PubMed - NCBI
8-OH-DPAT - Wikipedia

A corollary of this is that you probably don't want to be stimulating post-synaptic 5-HT1a all the time. This is why you need circadian rhythm, so the body has time to recover from catabolism and hormetic stress. So the more plastic your neurocircuitry and the better you adapt to stressors is determined by your ability to enter effective cycles of regeneration and amplify circadian rhythm/NAD+. At some point you can't avoid stressors and even need hormesis so the focus is predominantly recovering from them. Amplified NAD+ also means higher NAD+ availability for NADPH synthesis for steroid synthesis, KMO, etc. Mostly NAD+ represents metabolic capacity so would be expected to be a marker for regenerative capacity later during the night.

Because hormesis exists, we/nature find ways to exploit stressors. But this is also true for socially and intellectually beneficial stressors, meaning post-synaptic 5-HT1a activation with oxytocin along with others can be and are likely exploited for developmental, regenerative, targeted recovery, therapeutic purposes. This involves catabolism but together with some neurogenesis might more rather redistribute brain/body resources and abilities/priorities of an individual? This is the behavior of GH liberating fatty acids while promoting tissue regeneration, but generally most nighttime processes involve reversals of roles or sacrificing tissues to benefit others. During the day the liver feeds (but then gets endoxing exposure...).

Development of human intelligence was driven by social behavior - again think sailors forced to cooperate at sea, or island life, remote communities, sleeping together for warmth - so this is how they get to say that serotonin- or fear-driven behavioral responses have beneficial therapeutic and evolutionary hormetic effects.

The role of 5-HT₁A receptors in fish oil-mediated increased BDNF expression in the rat hippocampus and cortex: a possible antidepressant mechanism. - PubMed - NCBI

Except: SSRIs are prescribed and have effects that far prolong a sane circadian rhythm, with eventual post-synaptic receptor re-regulation, so although mitigated by ALLO/BDNF/GH/GR/oxytocin, these treatments take unnecessary risks, and often don't work at all unless accompanied by adjuncts like methylfolate (deplin). You'd expect methylfolate (15-30mg/day) to increase melatonin synthesis, NADPH, purines, ATP.

Meaning: there's a highly conditional part of the serotonin system that has beneficial/regenerative properties but only if exploited stress-minimizing situations and with very limited exposure - basically UVB - and with adjuncts. Basically fishing in warm coastal regions.

TPH2 + 5-HT1a seems promoted by vitamin D + omega 3 while methylfolate+B12 provides methylation to melatonin. However, NaCl is plentily available for SERT with variable effects on cortisol.
Salt loading affects cortisol metabolism in normotensive subjects: relationships with salt sensitivity. - PubMed - NCBI
This study clearly demonstrates changes in cortisol metabolism in response to dietary sodium in normotensive subjects. Interestingly, the sum of urinary cortisol metabolites,which can be considered as an estimate of cortisol elimination, was on average increased in sr, but decreased in ss subjects after salt loading. Likewise, the excretion of UFF, UFE, and each of the individual cortisol metabolites (THF, allo-THF, and THE) was higher after salt loading in sr sub-jects but was unaltered or lower in ss subjects. Of note, these changes in cortisol metabolite excretion after salt loading were accompanied by a decrease in plasma cortisol concentration, particularly in sr individuals. Taken together, it can be envisaged from these data that salt loading induces an increase in cortisol elimination and hence a decrease in circulating cortisol in sr subjects, whereas these effects of salt loading on cortisol metabolism are blunted in ss individuals.

If vitamin D can increase TPH2, then besides SERT and the 5-HT1a autoreceptor then clearly a transient increase in serotonin is required to go from dopaminergic/norepinephrine activity to melatonin. The goal is to make the serotonin spike as small as possible while endogenous melatonin synthesis as high as possible instead.
Optimal vitamin D spurs serotonin: 1,25-dihydroxyvitamin D represses serotonin reuptake transport ( SERT ) and degradation ( MAO-A ) gene expression in cultured rat serotonergic neuronal cell lines
Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. - PubMed - NCBI
1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D. - PubMed - NCBI
https://raypeatforum.com/community/...ut-increases-brain-serotonin.3300/#post-38864

This argues in favor of high B9/B12-driven methylation, with low cortisol or cortisol antagonism, with the last meal of the day which is typically the highest in Trp, which it complements as well as His. The methylation is what helps drive Trp toward melatonin and histamine toward methylhistamine, cooperating with GABA/glycine/Cl- channels and eNOS to allow GH/IGF-1/SAMe and amino acids to work on tissues, which greater fat oxidation necessitating ROS handling.

In order to make melatonin you must synthesize serotonin, so what vit D with cofactors/regulation really seem to do is determine an amount of serotonin synthesis representing the amount of sleep needed based on the amount of (UVB) light exposure accumulated in the day (as opposed to light levels at the moment of melatonin release, since that influences melatonin itself). If you assume you want to convert as much serotonin into melatonin as possible while lowering peak serotonin levels, serotonin seems to be part of the damage response to a form of light stress invoking sleep.

Effectively vitamin D is closely tied to methylation. The period when vitamin D increases TPH2 highest would be better time to consume most methylation precursors notably methionine/B12 and some B9/serine/B6. Combine with sensory deprivation and SAMe synthesis and so melatonin, and avoiding prolonged exposure to estrogen.

Again since GH lowers GNMT it helps support the methylation process and melatonin, so vitamin D, melatonin and GH (of course) should work together, with T3/thyroid controlling the metabolic rate between them so the healing rate and targeted tissues, nutrient partitioning, GABA/endocannabinoids/oxytocin/eNOS/Cl-/Mg2+/steroids relaxing tissues.

High-protein meals toward the end of the day via GSH synthesis, taurine and others also help prevent the ROS problems associated with vitamin D through UVB exposure and disease. Dinner is also the meal before the longest fast of the day, so naturally you'd want substantial calories to see you through the night and for recovery. Toward the morning liver NAD+ is high and things turn toward autophagy and ketogenesis, offsetting the negative effects of the meal (gut/endotoxin), shifting the metabolic burdens in neurons and astrocytes (like body and liver). It's best if food not too close to sleep or the time of GH release so that the intestines have time to settle down before growth and recovery processes take hold, otherwise you impede them and cause inflammation and unnecessary immune activity which may impair tissue healing and pathogen clearance (when incorrect arm of immune system invoked).

If high NAD+ as well as growth/recovery are desirable then you want to amplify the circadian rhythm as much as possible. Daily 16 hour fasts seem excessive due to time exposed to higher cortisol, but may have other benefits on occasional use, while 10 hour fasts sound like the minimum if leave bare mininum 1 hour eating before bed, maybe something highly digestible. If you say 12 average it comes out to yin/yang. This is basically a rehash of previous posts but trying to integrate the serotonin response, mostly post-synaptic 5-HT1a/5-HT7 and vitamin D with heavy generalizations.
 

Memento

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Clearly those are meant to work in cycles. I guess it invokes circadian but maybe we're also talking about longer cycles of food abundance vs restriction

Thanks for the link, super educational. It helped to explain some success with keto + forced excercise too.

I was surprised to learn that mitochondria are so swift to adapt. I was thinking earlier in terms of longer cycles combined with long water fasts for mitophagy. I guess you could get results just by reinforcing natural daily cycling with occasional longer fasts for mitophagy.

I guess with regulation of things like substrates for ceramides like palmitic acid or serine (partially supplied by kidneys).

ROS for fission and GSSG for hyperfusion:

Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

Is it that simple, fragmented mitochondria need a longer cycle of mitophagy - refeed with low ROS diet, support GSH heavily + other ROS scavengers. What am I missing? Going back to read page 1 it seems and shopping some NAC.
 

Terma

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Thanks, should be interesting.

A fully integrated new paradigm for lithium’s mode of action – lithium utilizes latent cellular fail-safe mechanisms
It is proposed that lithium’s therapeutic effects occur indirectly by augmenting a cascade of protective “fail-safe” pathways pre-configured to activate in response to a dangerous low cell [Mg++] situation, eg, posttraumatic brain injury, alongside relative cell adenosine triphosphate depletion. Lithium activates cell protection, as it neatly mimics a lowered intracellular [Mg++] level.
But lowest Mg2+ availability would be expected to occur in the early day with stressors and no food. If you combine with potential Li+ disturbances on AVP and melatonin (worth supplementing alongside) it suggests moderate Li+ doses seem to make sense in the morning (opposite of mainstream) while Mg2+ is especially needed in evening (except for anxiety), so these might be alternated to support rhythm and lower total excitotoxicity and I've been using it to mild success.
The effect of lithium therapy on arginine vasopressin secretion and thirst in man. - PubMed - NCBI
Sci-Hub | Lithium and bipolar disorder: Impacts from molecular to behavioural circadian rhythms. Chronobiology International, 33(4), 351–373 | 10.3109/07420528.2016.1151026
Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder | Neuropsychopharmacology
Lithium and bipolar disorder: Impacts from molecular to behavioural circadian rhythms. - PubMed - NCBI
Lithium pharmacokinetics in the obese. - PubMed - NCBI
Lithium lengthens circadian period of cultured brain slices in area specific manner. - PubMed - NCBI
NAD+: The Molecule of Youth? + Factors That Increase It - SelfHacked
Neuroprotective action of lithium in disorders of the central nervous system
Some people suggested it helps B12 usage but I didn't get into this:
A little lithium orotate and B12 make the world a happier place... for some people.
Vitamin B12 and folate levels and lithium administration in patients with affective disorders. - PubMed - NCBI
At 1-10mg Li+ from orotate persistently I eventually feel off and slow but with drugs and sugar it adds fluency to thoughts and speech. Lately it had more noticeable effect on 'spiritual' experiences than most minerals, except high Mg2+/salt.
‘I Don’t Believe in God, but I Believe in Lithium’
Pharmacological carbonate is also suggested as single dose, but in the evening:
SAGE Journals: Your gateway to world-class research journals
However doing this with Li orotate even small dose kept awake. Jaminet also suggested morning doses in the book (and less frequent/smaller doses), but don't remember how he backed that up.
Lithium carbonate in the management of cannabis withdrawal in humans: an open-label study. - PubMed - NCBI
Cannabis is the most widely used illicit substance in the world. Estimates suggest that approximately 10-20% of cannabis users meet criteria for cannabis dependence and a significant proportion experience withdrawal discomfort on cessation of use. To date, there has been an absence of any clinically validated treatments to manage withdrawal. The current study is an open-label trial exploring the utility of lithium carbonate for the management of cannabis withdrawal symptoms in treatment seeking adult humans. In total, 20 participants were recruited to the study (19 men). All met DSM-IV cannabis-dependence criteria and had been smoking cannabis daily or almost daily for a mean 9 years. Participants were admitted to an inpatient detoxification facility and prescribed lithium 500 mg b.d. for 7 days. Cannabis withdrawal was assessed daily with the Marijuana Withdrawal Checklist (MWC). Two participants were withdrawn from the trial because of possible adverse effects. Sixty percent of participants completed the 7-day treatment program. Follow-up was conducted at a mean of 107 days following treatment. The mean percentage of days abstinent in the period between treatment cessation and follow-up was 87.57%. Twenty-nine percent of participants (n=5) reported continuous abstinence that was biochemically verified at follow-up. Agreement between self-reported cannabis use and urinalysis at follow-up was moderate (kappa=0.47). Significant reductions in symptoms of depression and anxiety and cannabis-related problems were also reported. This study provides evidence for the potential clinical utility and safety of lithium in the management of cannabis withdrawal. A randomised, placebo-controlled trial is recommended.
 
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Terma

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Fun to remember when consuming orotate supplements:
Orotic acid - Wikipedia
Orotic acid is a pyrimidinedione and a carboxylic acid. Historically it was believed to be part of the vitamin B complex and was called vitamin B13, but it is now known that it is not a vitamin.

The compound is manufactured in the body via a mitochondrial enzyme, dihydroorotate dehydrogenase[1] or a cytoplasmic enzyme of pyrimidine synthesis pathway. It is sometimes used as a mineral carrier in some dietary supplements (to increase their bioavailability), most commonly for lithium orotate.
Dihydroorotate is synthesized to orotic acid by the enzyme dihydroorotate dehydrogenase, where it later combines with phosphoribosyl pyrophosphate (PRPP) to form orotidine-5'-monophosphate (OMP). A distinguishing characteristic of pyrimidine synthesis is that the pyrimidine ring is fully synthesized before being attached to the ribose sugar, whereas purine synthesis happens by building the base directly on the sugar.[2]
It's also in milk and the precursor to UMP/uridine.

This implies safe processing high levels of orotate may depend on the functioning of the pentose phosphate pathway for PRPP precursors. These could place strain on cells since PRPP is critical including in B3/NAD+ synthesis. In the worst case:
A buildup of orotic acid can lead to orotic aciduria and acidemia. It may be a symptom of an increased ammonia load due to a metabolic disorder, such as a urea cycle disorder.

In ornithine transcarbamoylase deficiency, an X-linked inherited and the most common urea cycle disorder, excess carbamoyl phosphate is converted into orotic acid. This leads to an increased serum ammonia level, increased serum and urinary orotic acid levels and a decreased serum blood urea nitrogen level. This also leads to an increased urinary orotic acid excretion, because the orotic acid is not being properly utilized and must be eliminated. The hyperammonemia depletes alpha-ketoglutarate leading to the inhibition of the tricarboxylic acid cycle (TCA) decreasing adenosine triphosphate (ATP) production.

Orotic aciduria is a cause of megaloblastic anaemia.
Pyrimidine metabolism - Wikipedia

Hyperammonia was another of Travis's topics, so you see the risks of high orotic acid may mimic or aggravate hyperammonia. So sugar and things that support the PPP is what helps handle orotate, plus Mg2+ and choline for handling the uridine. The other lesson is that Li orotate should be consumed with sugar especially a minimum for the liver so the orotate can convert to UDP and help glycogen synthesis.

What further suggests sugar is critical with Li orotate consumption which promotes Akt thus glucose usage:
Inhibition of GSK3 by lithium, from single molecules to signaling networks
For more than 60 years, the mood stabilizer lithium has been used alone or in combination for the treatment of bipolar disorder, schizophrenia, depression, and other mental illnesses. Despite this long history, the molecular mechanisms trough which lithium regulates behavior are still poorly understood. Among several targets, lithium has been shown to directly inhibit glycogen synthase kinase 3 alpha and beta (GSK3α and GSK3β). However in vivo, lithium also inhibits GSK3 by regulating other mechanisms like the formation of a signaling complex comprised of beta-arrestin 2 (βArr2) and Akt. Here, we provide an overview of in vivo evidence supporting a role for inhibition of GSK3 in some behavioral effects of lithium. We also explore how regulation of GSK3 by lithium within a signaling network involving several molecular targets and cell surface receptors [e.g., G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs)] may provide cues to its relative pharmacological selectivity and its effects on disease mechanisms. A better understanding of these intricate actions of lithium at a systems level may allow the rational development of better mood stabilizer drugs with enhanced selectivity, efficacy, and lesser side effects.
More important regulating effect on Mg2+ effects:
In 1996, two independent studies (Klein and Melton, 1996; Stambolic et al., 1996) of the effects of lithium on cell signaling and development have identified a direct effect of lithium on the activity of GSK3 both in vitro and in cells. However, the therapeutic relevance of this finding has been unclear mostly because the high Ki values of lithium for GSK3α (∼3.5 mM) and GSK3β (∼2.0 mM) are superior to therapeutic lithium serum concentrations in humans (0.5–1.2 mM) (Phiel and Klein, 2001; Gould et al., 2004; Beaulieu and Caron, 2008; Beaulieu et al., 2008). However, these values can be affected by experimental conditions including the availability of Mg2+ ions in the assay system. Indeed, one hypothesis explaining the inhibition of GSK3 by lithium is that Li+ ions act as uncompetitive inhibitors for the binding of the co-factor magnesium to GSK3 (Ryves and Harwood, 2001). Magnesium and lithium share similar ionic radii (0.072 and 0.076 nm, respectively) and it has been suggested long ago (Birch, 1974) that this may explain several of the biochemical effects of lithium since Mg2+ is a cofactor for multiple enzymes (Figure (Figure1).1). The proposed competitive mechanism of inhibition by lithium predicts that the in vivo inhibition of GSK3 may be greater than inhibition levels observed in vitro at optimal concentrations of magnesium ions (Ryves and Harwood, 2001).
This could mean Li+ orotate (morning) + Mg2+ (most evening) + sugar a likely way to increase glycogen stores well and latter would take burden off kidneys while arranging circadian problems. These are also substrates for sat/monosaturated phospholipid synthesis in the liver so choline/alpha-GPC so you can put more sat/monosaturated into phospholipids at an optimal rate and improve the usage of sugar. This allows more of the orotate to incorporate into PC and useful nucleotides instead of becoming metabolic burden. Extremely elemental mood-regulating and other effect formula.

Since re-adding Li orotate 2-10mg morning only long-time bowel problems improved, after already high Mg2+ (topical/cit). Choline can have vasodilating and relaxing effects through muscarinic receptors and hormones so the calming effects of the others on the nervous system. Not implying high acetylcholine is good but that phospholipid synthesis is so important it's sometimes worth risking sides unlikely to be dangerous but mitigated to do the opposite. Since I'd add cholesterol/steroids to further lessens the risks and through anabolism might increase the usage of orotate and choline, so this is the most elementary 4-ingredient stress glucose-regulating tweakable survival formula I could imagine. This is practically all from studies and personal experience already posted. This all pales against the combined benefits on glucose usage.

I've decided to stop being contrarian every 3rd day. But nearly every day I get a reminder of life-threatening harm inflicted to me and killed 2+ important relatives in 1 year. Someone just told me in response I had a right to be angry at a true injustice, but we gotta show we're better than they are. This leads to complex dilemmas entirely avoidable surrendering to - but changing/mitigating the law. Which no can do so I appreciate those who stand up or you might think it's hypocrisy!

This is what I personally do in that circumstance plus amino acids, steroids and other, but seafood actually feeds all this best and especially might help ensure proper thyroid function during Li+ exposure - or you provide more substrate to handle higher intakes and greater therapeutic effects from Li+ orotate. Stress especially dysregulates the immune system so emotional distress places different strains on resources but generally amino acids and phospholipids also choline for intelligence/neurostimulation. Phospholipid synthesis replaces lipid membranes damaged by inflammation and lipid peroxidation, so basis for both preventing damage and healing. Specifically: during and after a period of inflammation is time the kennedy pathway requires the most support.

This could go on with the high number of [potential] therapeutic or at least migitative effects of each ingredient in liver/brain/gut/etc. disorders. Li+ seems to have a positive gut-relating effect here while topical Mg2+ avoids the gut so the gut has 24h of low exposure to the relatively minor risks of side-effects from these things and better orotate handling. Seafood appears highly digestible and antioxidant (selenium GSH) and choline helps innervate and function gut muscles. So you have this perfect survival combo seafood + pineapples (TR right again!) with vic C bromelain manganese etc.

https://raypeatforum.com/community/...ineapples-and-tomatoes.836/reply?quote=314247
Yeah, haven't you ever heard of George Hackenschmidt? and do you know what he ate? It's in his book if you'd like to know. If I wanted to be bigger then I'd eat more coconut and weight train, but I'm not at all concerned about it; and that doesn't invalidate my original post.

Could you explain this quote you'd posted?

'Low protein diets definitely interfere with the liver’s ability to detoxify estrogen and other stressors.” - Ray Peat
How exactly would an amount of protein shown repeatedly to maintain nitrogen balance interfere with detoxification of estrogen? And did you know that meat and dairy actually contain estrogen? perhaps countering the effects of increased detoxification of that hormone even if it could.. .
Usually Travis was right but but here even though the higher methionine and precursor content will allow more PUFA incorporation into phospholipids by PEMT especially when estrogen levels are already high, the nutrient value of seafood is intense. You can't seriously say people with very low protein/methionine intakes never experience problems, whereas having strong methylation support and GSH is way to healing despite methionine. So the final say depends on whether TR or RP solution leads to lower estrogen since drives PEMT and whether low protein and low PEMT works out depends on choline intake (seafood). The problem is low protein for me personally leads to degradation on all levels and was forced to permanently abandon amino acid restrictions, so I think just seafood+pineapples goes long way.

A temporary pineapple+seafood can be made an extremely low o-6 diet for a period, with high peroxidation support for dealing with existing o-6 and safely eliminating over time + some tolerable vitamins.

My guess is people with arthritis might benefit from the anti-inflammatory effects of improved o-3 and o-6 handling, astaxanthin and bromelain, all contained. Everyone gets a part of the solution in my view. I have to commend Travis for choosing the most ethical solution toward living beings but it appears temporary solution to health problems.

Unfortunately Ray's right: protein or nutrient restriction is hormetic and can be done to point of harm, I can never risk it again in my life, AA restriction, unfortunately, I've made the painful experience repeatedly. Everyone still eats eggs that are worse o-6 for nutrients like choline, selenium, and even cholesterol in sardines and shrimp and even the things they advocate like vitamin D.

Personally learned I have to give the intestine a 24-year break from inflammation and irritants for periods of weeks to possibly years - to mimic convalescence. The thing that provides the sustenance for day and night in such a way: seafood diet + few excellent fruit. Personally the mineral combo helped me turn around some corners and I'm adopting the second slowly, and I know nearly for a fact these diets would be aids in recovery in extreme diet restrictions like those attributed to Travis and Ray who further restrict through fears of supplement quality, mineral seafood + fruit/starch is already plentiful in nutrients especially for things like thyroid. These are the simplest safest most effects therapies I've used outside of THC. Basically Li+ orotate Mg2+ GPC sugar seafood is the basic THC supportive formula - it can increase phospholipases thus trigger o-6 and requires anti-stress, anti-Cortisol, anti-anxiety elements etc.

I'm not sure why Travis and haidut insist more on low protein than me but I'd say objectively it appears a much riskier and comparatively nutrient-restricted for lean tissue preservation diet for growth than seafood+carbs which contains the cholesterol too. Whether Ray's strategy works depends entirely on estrogen or analogs/metabolites/ERa/ERb. Jaminet disagrees on fructose. Meanwhile iirc every one of them at some point recommended coconut but my gut was better off altogether (the soap is nice).

To me that seems like an awful room for error so I play it on the safer side of abundance of nutrients, without the aging load of worse protein sources. So because of the shellfish/seafood and the protein amounts suggested I end up doing Ray without dairy and focus on different inhibitory substances these I find more elemental, but they could match with THC legalization in treatment of depressive/PTSD disorders couldn't be simpler. These are my personal opinions and I share them because it's going to be a decade of serious medical issues I could have turned around 6 years ago with 6 ingredients (Li+ orotate supply gotten problematic - incredible). Li+ orotate might contribute to preventing excitotoxicity from fluoroquinolone poisoning (despite risk of QT prolongation contraindication) as would Mg2+ and seafood despite the contraindications, I'd personally take Mg2+ apart in a fast-absorbed form - and in particular topical chloride/other gel/other might be less likely to interfere with gut absorption. Then maybe take Li+ the rest of the time (morning). Specifically: Li+ seems suited in the morning exactly when people take fluoroquinolones and other antibiotics while subjected to the rigors of exercise and stress, increasing ROS and excitoxicity. Li+ helps use and accumulate glucose during the day for the night protecting from some side effects of fluoroquinolones through effects on excitotoxicity, and Mg2+ is already tied to fluoroquinolones and Li+ helps fill in and they even risk people's thyroids and kidneys because the therapeutic effects are that valuable for some people to warrant the risk and fear of lithium orotate - despite theoretical negative effects on kidney filtration from rodents:
Kidney function and lithium concentrations of rats given an injection of lithium orotate or lithium carbonate. - PubMed - NCBI
but the doses don't seem extremely concerning, and should be mitigating by nutrients supporting orotate.

A simple compound like NAC (GSH/seafood) helps both OCD above and bipolar disorder, as I can personally attest for as well as lithium. Even seafood itself is a minor but probably significant source of Li+ next to milk which also contains some orotate. Here they even suggest NAC to protect from lithium, which seems like a wise precaution.
6 Ways to Protect the Kidneys While Prescribing Lithium
Lithium-induced kidney problems - Harvard Health
Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-d-aspartate receptor-mediated calcium influx

Even according to official evening single-dosing criteria
6 Ways to Protect the Kidneys While Prescribing Lithium
if you switch it around to morning you have a potent drug that can prevent these effects 24h except morning dose makes a better curve following a spike a lithium for daytime glucose utilization taken in the morning. Relative to taking no extra Li+, supplementation of gram amounts should give these levels that still provide a higher amount of Li+ to cells during the night.

And specifically higher Li+ orotate since the start of the day with higher sugar might help glycogen so the storage work of Li+ helps complement its own sedatory effects at night.

That's how it works: to tolerate higher Li+ orotate levels at night you'd logically want higher glucose reserves at night.

Travis made good points for pineapples and he argued quantitatively he wasn't worried the serotonin amounts:
https://raypeatforum.com/community/...s-and-feeling-better.19306/reply?quote=322270
and it's even a realistic alternative to orance juice which some people never tolerated. In my opinion seafood + pineapples should be valuable realistic emergency crops and immune system support against infections while lowering effects of endotoxin and inflammation from gut problems thought by some to aggravate viral infections?

I'd suggest that for people actually doing low-protein, the Li+ orotate Mg2+ GPC sugar/pineapple low-protein seafood might be tissue-sparing in significant ways none the least cortisol, inflammation and liver health. Basically allowing for high choline intake might contribute to its choice in low-protein high-fat liver feeding, which require phospholipids and I want that sat/mono fat going into phospholipids, so all these ingredients are basically essential in stress. You can still vary methionine through seafood protein intake as possible resorts against cancer (I don't disagree but eventually it's catabolism over catabolism).

Also, the requirement of PRPP for orotate metabolism suggest D-ribose (w/AGE inhibitors) and lithium orotate and a few of these, but it's doubtful idea to use in infection and the other 6 things are enough to make a difference.
 
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Pompadour

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Very interesting thread!
Cholesterol/choline/aminos/vitamins seem like decent reasons to think egg yolks and seafood should help heal bile, brain, gallbladder, gut, immunity, liver, lungs, steroids, with some compounds compensating kidneys but some dependency on vegetables - though egg yolks do contain B9/biotin/retinol/Se/I already despite binders.
What can one eat instead of eggs in the case of allergy or so. Is seafood sufficient for choline? I dont tolerate eggs or other fatty food, but low fat fish and seafood seems ok.
 

Terma

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Yeah shrimp has a bit and the others accumulate. But I use alpha-GPC/CDP-choline and pregenenolone/seafood-cholesterol to lower eggs.
choline
 

Memento

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What aminos would you add to EAA / MAP mix? What do you eat for copper? Do you have any recommendations for Cu/Mn/Zn intakes and ratios? NAC didn't do much but I think I was Se deficient despite 100ug+ intakes from food.
 

Terma

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What aminos would you add to EAA / MAP mix? What do you eat for copper? Do you have any recommendations for Cu/Mn/Zn intakes and ratios? NAC didn't do much but I think I was Se deficient despite 100ug+ intakes from food.
The stuff either RP or Jaminet recommend generally makes sense. Cu would be: as much as possible from animal sources besides liver, or just do liver, never found good supplement. Mn is easy to get (pineapple, maple syrup, ...). Se is probably best as selenocysteine and the sea but people made cases for the others and I have to reread Travis's posts. Zn I prefer single doses of 40-100mg 1-3x/week, dinner. Is that dosage regularly healthy? I find it makes some activities including sleep better and supporting immunity happens to be important. Mo I take a supplement once in awhile. Boron did something once. I get a minimum iodine and plan to increase a little (<1mg ~per orig Jaminet). Lithium has been great.

On a desert island one choice I'd take serine, otherwise it depends on case because they all have ranges of dose-dependent effects up to pharmacological. I still take tyrosine, histidine, beta-alanine, serine, taurine regularly but others worked before.
 

Terma

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Man, ok, appreciate the sentiment, but this thread title = posting in a self-worship thread. Can you put something else, like robot cat from hell?
 

Markus

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What can one eat instead of eggs in the case of allergy or so. Is seafood sufficient for choline? I dont tolerate eggs or other fatty food, but low fat fish and seafood seems ok.
An alternative to eggs is fish roe, which also contains high amounts of choline and other phospholipids.
 

Terma

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It's not exemplary. Those are scrawny and underfed and tech gets patented, but we have threads about Elon Musk achieving mind control, meanwhile we're still talking home-grown planting vegetables as if they compare. It works and just needs personal touch to get those things healthy. If I had the investment/time/reputation that's where it'd go.
 

Terma

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Several downstream steroids are ERbeta agonists which triggers oxytocin, some only weak ERalpha agonists, like people posted. NADPH should support the downstream steroid conversions and in the absence of conflicting factors increase oxytocin plus allopregnanolone synthesis in theory (but allo is probably important to have a baseline during the day since major part of SSRIs working despite serotonin), finally dopamine. If NAD+/NADH low and electron burden high in the evening, maybe NADPH helps put electrons away from NADH toward inhibitory behavior, evening and nighttime activities, most importantly socializing for nighttime survival (it's in the dark we learn to cooperate the most?). It's just about channeling those electrons properly at the right moment in the day into steroids. So you always make dinner the bigger protein meal with the most glucose/fat/protein and that way most dietary tryptophan spends the least time possible as serotonin and more time as melatonin, kynurenine metabolites for nighttime immune regulation, NAD from niacin, anti-glutamate effects of kynurenic acid and xanthurenic acid. Useful compounds and still allows melatonin synthesis for gut health (B12, Li?) so I don't see the point avoiding dietary Trp much anymore, you eat it at dinner and support its conversion to melatonin including methylation which also supports many inhibitory factors like COMT, HNMT, melatonin, with exceptions like PNMT/NMT there for stress scenarios. I tried to restrict protein for weight loss a few times not once worth it must have written.

In studies, clinical practice and my experience periodic gram doses of methylfolate even less than deplin (7500mcg methylfolate/pill) produce antidepressant effects. Personally it works superbly with THC. They use methylfolate+SSRIs (basically steroids) with positive results so imagine it properly prescribed with THC? I tried to post something like this on reddit once and got laughed off but it literally works. It's central to everything including methylation, but you can also take it earlier while avoiding coadministration of other methylation cofactors including B12 which you take with last meal. You still have to figure out cofactors like P5P, R5P. It supports overall intelligence so I've started to see it as a potent nootropic as do these guys:
Vitamin B9 (Folate) – Nootropics Expert

It's extremely tied to serine through SHMT/others so in the evening on alternating days high grams doses of L-serine helps quite a lot overnight, though you have to reach several grams I've found, up to 7 maybe (double the moderate glycine dose), never every day. The body won't need as much protein in the morning since methylfolate recycles serine which feeds all the others and the carbon cycle and although you'd want NADPH in the evening especially, you have to support some steroid synthesis in the morning for mental stability, I'd imagine (haven't looked) cortisol gets prioritized for NADPH so extra might be free-er to the other uses. In the case you promote methylation too much or you interpret it as such (different things, these things are often safe) you can compensate with tyrosine, histidine (HNMT), B3. It'll end up supporting things like serotonin synthesis unfortunately so you have to avoid the other things that promote TPH pathway in morning like dietary Trp. The point is you only need to restrict Trp or TPH cofactors/promoters in the morning and restricting all these compounds focusing on serotonin may backfire at night with a forest of animals keeping you awake.

How wouldn't a diurnal organism figure out evolutionarily it needs its biggest meal latest in the day, just from glycogen/ketones? I don't have much new to say honestly, I'm really happy there are other people figuring this stuff out. Everywhere THC is legal this could be advertised, I wonder if these guys ever thought to run an ad campaign? If it's too contentious you produce a couple studies pure THC + methylfolate + magnesium (yeah c. interest but I know this works) on people no rats need to die and let people find them on their own, warn for B12. They can't deny it works:
Deplin: A 'medical food' that treats depression
L-serine might be slightly safer (homocysteine, NAD+ so indirectly dopamine) but all these are so easy to dose you stop at the first sign of problems. Is this a plant?
Two months off adderall thanks to deplin (l-methyl folate) : Drugs
Two months off adderall thanks to deplin (l-methyl folate)
I've never had such quality of life! I'm glad it works for you too :)
I combine mine with B12 so I don't have a need to take an antidepressant too. Do you combine with anything else?
Nope just deplin in the morning and cannabis
Need magnesium and you cycle on/off cannabis with (probably morning) Li orotate. I read hundreds of journals of anxiety/depression sufferers, I don't know everything but some people suffer for nothing, they already prescribe all this. Tolerance is real but addiction potential might even drop with the adjuncts (someone will argue increased opioids/oxytocin will fuel addiction).

People have talked about this but with high doses of methylfolate and at least some B12 you can avoid need for TMG which seems to be a pathway induced by stress and maybe choline can be spared for CDP-choline over TMG. For those worried about choline and cancer:
Higher dietary intakes of choline and betaine are associated with a lower risk of primary liver cancer: a case-control study | Scientific Reports
Sometimes I forget the liver deals with the side effects of many compounds so as long as it's healthy you can throw things at it, but many of these compounds can highly benefit the liver compared to the other pharmaceuticals (some risk to kidneys with folate).

I see some people worry about folate/methyl traps which are real, hence I never take a large dose of methylfolate 2 days straight (some people go way beyond) and evening methylcobalamin on some days might be sane prevention, R5P/P5P somewhere, when in doubt a high protein diet with less folate prior to starting:
Methylfolate - the "suicidal" nutrient (don't believe the hype)
But most of them seem to neglect serine, NADPH, steroids and circadian rhythm, instead:
Folates Are Serotonin Reuptake Promoters
Based on comments I got patient compliance is a problem and would be but we have dedicated marijuana clinics and this doses itself. Since THC increases pregnenolone and I'd expect some NADPH it's basically endogenous steroids production at the right cells avoiding legal hassle. There wasn't a human study on NADPH from methylfolate just saying it fits pretty well and supports everything (Quantitative flux analysis reveals folate-dependent NADPH production). Several sources say methylfolate supports serotonin synthesis (everything) so you could even slide it under that hypothesis even if it also had anti-serotonin effects and supported metabolism (several ways to divert/limit TPH). What you can't tell people is you need cholesterol or pregnenolone but try to keep a stoner from sugar. No comment:
Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues - PubMed
Folic acid, but not folate, regulates different stages of neurogenesis in the ventral hippocampus of adult female rats
Methylfolate Side Effects - Dr Lynch
Methylfolate - the "suicidal" nutrient (don't believe the hype)
Deplin (L-methylfolate) dosing, indications, interactions, adverse effects, and more
MTHFR and Depression – The Folate and BH4 Connection (can't remember BH4 was correct or not, basically contradicts the other recommendation, ask this guy who was pretty knowledgeable: Is methylation required for serotonin production?)
Also reserve the right to correct this later since folate making NADPH is a guess based on experience with steroids but this would have saved me a decade still works if it's wrong, and SSRI effects are associated with steroids. You can look at it as harm prevention from legalization of THC which these few probably do. I read one of the similar threads below as "Terma Is Underrated, And Causes Most Issues" please change title to this
 

Korven

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Bump! This thread is awesome... if you want to please keep posting @Terma :) Where and how did you learn all of this stuff?!
 
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