• “We found that serum zinc was significantly lower in the CFS patients than in the normal controls. There was a trend toward a significant negative correlation between serum zinc and the severity of CFS and there was a significant and negative correlation between serum zinc and the subjective experience of infection.” [2006]
• “Serum levels of zinc (P = 0.001) and magnesium (P = 0.002) were significantly decreased by FM groups,” [2008]
• “[IBS]…Finally, the role of zinc in treatment of infectious diarrhea led to studies of its effect on intracellular human enterocyte ion secretion. ” [2010]
• “The aim of our study was to evaluate the oral dietary intake of a group of patients with irritable bowel syndrome and to compare with international recommendations….A low intake of calcium, magnesium, yodo and zinc was detected.” [2004]
• “paper reports a study of 50 patients affected by irritable bowel syndrome. Two subgroups have been identified (Ac and Ad), characterised by reduced blood zinc [correction of zinchemia] and increased fecal excretion of zinc. This finding suggests that the syndrome has a multifactorial pathogenesis and that over time it may follow a different pattern in the different subgroups.” [1990]
• Dryness of eye symptom associated with low zinc levels [2016]

Other Aspects

• “These studies demonstrate for the first time that zinc regulates LPS-mediated immune activation of human macrophages in a ZIP8-dependent manner, reducing IL-10. Based on these findings we predict that macrophage zinc metabolism is important in host defense against pathogens.” [2017]
• “We found no evidence that the use of oral zinc supplementation improves symptoms in adults with tinnitus.” [2016]
• “We can conclude that the food supplement containing α-lipoic acid, L-carnosin, zinc,[ 7.5 mg] and vitamins of group B improved glycemic control, lipid profile, and anti-oxidative stress markers.” [2016]
• “The scientific evidence presented in this systematic review shows that zinc supplementation improves insulin resistance in obese individuals of both sexes.” [2017]
• “35% to 45% of adults 60 years of age or older had zinc intakes below the estimated average requirement of 6.8 mg/day for elderly females and 9.4 mg/day for elderly males. Zinc deficiency may lead to loss of appetite, impaired immune function, weight loss, delayed healing of wounds, eye and skin lesions, and smell and taste disturbances” [2016]
  • “Zinc supplementation at 30 mg/d for 3 mo is effective in increasing serum zinc concentrations in nursing home elderly; however, not all zinc-deficient elderly reached adequate concentrations.” [2016]

Missing Diet on what is an effective level of supplementation

Above we see low levels across the board. There have been no reported studies on the effect of supplementation in the above conditions. What is level and duration needed to be effective!

• Human study used
  • ” daily supplementation of zinc (9 mg elemental Zn/d; ” [2017]
  • “25 mg of zinc” [2017]
  • 40 mg day [2017]
• Interactions of iron with manganese, zinc, chromium, and selenium as related to prophylaxis and treatment of iron deficiency [2017].
  • “human data on the interplay between Fe and Zn especially in terms of Fe-deficiency and supplementation are contradictory, demonstrating both positive and negative influence of Zn on Fe status.”

Bottom Line

This [2016] study seems the best match for CFS/FM/IBS and used 30 mg/d for at least 3 mo. “Tolerable Upper Intake Levels (UL) of zinc for people who are not receiving zinc under medical supervision: … adults 19 years and older (including pregnancy and lactation), 40 mg/day.” WebMd

A reader requested to review the most recent literature on CoQ10 and summarize my conclusions.

Fibromyalgia and Migraines

“CoQ(10) level in plasma samples from FM patients was doubled compared to healthy controls and in blood mononuclear cells isolated from 37 FM patients was found to be about 40% lower….The protection caused in mononuclear cells by CoQ(10) would indicate the benefit of its supplementation in FM patients. ” [2009]

” Coenzyme Q(10) (CoQ(10)) levels in salivary cells (SCs) and mononuclear blood cells (BMCs) from Fibromyalgia (FM)..were reduced in both cell models. Oral supplementation showed an improvement in clinical symptoms and restored levels.” [2012]

” In this report, we show the effect of CoQ10 treatment on clinical symptoms, blood mononuclear cells, and mitochondrial and oxidative stress markers from a woman with FM. After CoQ10 treatment, the patient reported a significant improvement of clinical symptoms.” [2012]

“A placebo-controlled trial of CoQ10 in FM patients has shown a reduced NLRP3 inflammasome activation and IL-1β and IL-18 serum levels.” [2014]

• “300 mg/day CoQ₁₀ divided into three doses”
• This study did not describe any symptom improvements seen — it was focused on lab results.
• [2011] study cites: “Patients with CoQ(10) deficiency showed a statistically significant reduction on symptoms after CoQ(10) treatment during 9 months (300 mg/day).”

Folic Acid and coenzyme q10 ameliorate cognitive dysfunction in the rats with intracerebroventricular injection of streptozotocin [2012].

• “The present results suggest that CoQ10 and folic acid have therapeutic and preventive effects on cognitive impairments in Alzheimer’s disease.”
• [2006] study on mice, found CoQ10 alone had similar effects.

Role of magnesium, coenzyme Q10, riboflavin, and vitamin B12 in migraine prophylaxis. [2004] “

• “The therapeutic potential of magnesium, coenzyme Q(10), riboflavin, and vitamin B(12) can be cautiously inferred from some published open clinical trials; it should, however, be considered that double-blind randomized larger studies are needed to correctly estimate the impact of the placebo effect in these promising therapies.”
• “Treatment with … magnesium, riboflavin and Q10 ..had an impact on migraine frequency which showed a trend towards statistical significance.” [2015] i.e. it looks like it may help, but the effect could be random variation of patients symptoms.
• Oxidative stress correlates with headache symptoms in fibromyalgia: coenzyme Q₁₀ effect on clinical improvement.[2012]
  • “induced a significant improvement in clinical and headache symptoms”

CFS/ME

• “Peripheral blood mononuclear cell showed decreased levels of Coenzyme Q10 from CFS patients (p<0.001 compared with controls) and from FM subjects (p<0.001 compared with controls) and ATP levels for CFS patients (p<0.001 compared with controls) and for FM subjects (p<0.001 compared with controls). ” [2013]
• “Improvements in fatigue were observed for nicotinamide adenine dinucleotide hydride (NADH), probiotics, high cocoa polyphenol rich chocolate, and a combination of NADH and coenzyme Q10.” [2017]
  • “Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? [2015]
    • “oral CoQ10 (200 mg/day) plus NADH (20 mg/day) supplementation “
  • “Our results suggest that CoQ10 plus NADH supplementation for 8 weeks is safe and potentially effective in reducing max heart rate during a cycle ergometer test and also on fatigue in CFS.” [2016]
• Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder [2009].

No Studies Could be found for…

• Small intestinal bacterial overgrowth
• IBS

Bottom Line

A dosages of 300 mg/day of CoQ10 appears to have significant benefits. CoQ10 alone for CFS had no studies, only with NADH (which has benefits for CFS alone). NADH is related to niacin (B3) which may be a more economical supplement than NADH, but this is speculation as no studies have been done. NADH amounts cited in studies with positive effects was 20mg/day – but evidence suggests it benefits will disappear after 3 months.

I discovered a 2010 article finding that grapefruit juice significantly enhances the absorption of CoQ10

NADH Notes

• “Administration of oral NADH was associated to a decrease in anxiety and maximum heart rate, after a stress test in patients with CFS. On the contrary, this treatment did not modify other clinical variables and the global functional performance.” [2010]
• “8 of 26 (31%) responded favorably to NADH in contrast to 2 of 26 (8%) to placebo. ” [1999]
• “The twelve patients who received NADH had a dramatic and statistically significant reduction of the mean symptom score in the first trimester (p < 0.001). However, symptom scores in the subsequent trimesters of therapy were similar in both treatment groups. ” [2004]

After discovering some new facts on B12, I noticed that folate was often cited in the same articles. As with B12 — there are two versions, just like B12:

• methylfolate
• folate

There is no harm in taking methylfolate, but if you have the TT MTHFR genotype then plain folate will have little impact.

• “We assayed serum folate levels of 60 patients with chronic fatigue syndrome (CFS) and found that 50% had values below 3.0 micrograms/l. Some patients with CFS are deficient in folic acid.” [1993]
  • “Our findings indicated that the average serum folate concentration in IBD patients was significantly lower than that in control patients, whereas the mean serum vitamin B12 concentration did not differ between IBD patients and controls. ” [2017]
• Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia[2015].
  • “. In ME patients, hypomethylation is seen in a majority of certain immune cells [1] and of DNA in genes associated with immune cell regulation [2]. Although the reason for such hypomethylation can only be speculated upon, for the time being, it is interesting that the combined action of the vitamins B12 and folate (Fig 1) play a fundamental role in providing methyl groups to hundreds of substrates in various elementary cell processes. ”
    • A common genetic variant affecting folate metabolism is not over-represented in chronic fatigue syndrome [1997].
  • ” Good responders (6.7±6.6 mg per day) and Mild responders (1.9±2.0 mg per day). ” –> 6.7+6.6 = 13.3 mg  or 13,000 mcg
• Vitamin D deficiency changes the intestinal microbiome reducing B vitamin production in the gut. The resulting lack of pantothenic acid adversely affects the immune system, producing a “pro-inflammatory” state associated with atherosclerosis and autoimmunity.[2016]
  • “Vitamin D blood levels of 60-80ng/ml promote normal sleep. ” – bad sleep patterns may be an indicator of low Vitamin D levels.
  • “These results suggest that the combination of vitamin D plus B100 creates an intestinal environment that favors the return of the four specific species, Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria that make up the normal human microbiome.”

B12 / Folate Balance

The issue arises when B12 levels are low… from [2007] review: “Simply put, if your vitamin B-12 status is good, folate supplementation is good for you!”

• “Those with a low vitamin B-12 status (serum cobalamin <148 pmol/L) and high serum folate (>59 nmol/L) had an odds ratio for cognitive impairment of 5  [times higher] compared with those whose vitamin B-12 status and folate status were both normal. “
• ” In agreement with current knowledge, they found that a low vitamin B-12 status is associated with macrocytosis, anemia, and cognitive impairment. “
• “The “good news” is that, in subjects with a normal vitamin B-12 status, high serum folate (>59 nmol/L) was associated with protection from cognitive impairment. This finding is remarkable in a population with a much higher mean folate concentration (39 nmol/L) than that seen in countries where there is no mandatory folate fortification. “

Bottom Line

For methylfolate, a dosage between 6,000 mcg and 13,000 mcg have been tried with good results. Unlike Vitamin B12 (cost around $.06/day), looking at Amazon we are looking at a cost of $130+/day. With some brands, the capsules are just 400 mcg which means 15 –> 30 capsules per day. There is one brand that sells in 15mg (15,000 mcg) at $39.00 for a 30 day supply – that’s just one capsule per day.

• A remarkable 81% of CFS patients experienced subjective improvement of their symptoms after treatment with folinic acid” [2006] [Full Text] “Folinic acid should be distinguished from folic acid (vitamin B₉). However, folinic acid is a vitamer for folic acid, and has the full vitamin activity of this vitamin. ” [wikipedia]
• NOTE: folinic acid dosage is much smaller that folate (folic acid) because it is bioactive.

Additionally, adequate Vitamin D3 supplementation (likely 15,000 IU/day for many) may be needed to restore natural B-vitamin production

My gut feeling is that 95% of CFS patients are taking less than the level required for a mild responder.

WARNING: Some people can respond with severe anxiety, see this external post.

The answer starts with — “It depends on your DNA…” If you have night-sweats or unexplained fevers…. B12 may cause an improvement

• “Among individuals with B12 deficiency, the frequency of the TT MTHFR genotype was particularly high. The TT polymorphism was associated with endothelial dysfunction even after 6 weeks of treatment with B12 and folic acid.” [2015]
  • “treatment with 1 mg daily of sublingual vitamin B12 and 5 mg daily of folic acid for 6 weeks “
  • Supplements are sold as mcg  1000 mcg = 1 mg
  • ” received sublingual cobalamin preparation, 1000-mcg sublingual nuggets per day for 1 month. Normalization of serum cobalamin was obtained (790 pg/mL) after 1 month of treatment. ” [2014]
  • “Vitamin B12 treatment, which is simple, inexpensive and low-risk, seems to be effective for patients suffering from recurrent aphthous stomatitis, regardless of the serum vitamin B12 level.” [2009]
• “girl with unusual appearance of periodic fever syndrome. … treatment with sublingual tablets of vitamin B12 (VIT B12). Beyond all expectation, we witnessed complete resolution of attacks during the first 2 months following treatment. After a long episode-free period, the parents withheld the treatment on their own accord, and in a short time the disease recurred. We advised to renew the treatment with VIT B12, and during approximately half year of follow-up there were no recurrences of periodic fever.” [2010]
• “A dose of 500 micro g of cobalamin given either sublingually or orally is effective in correcting cobalamin deficiency.” [2003]
• “Decreased serum vitamin B12 level in patients with type 2 diabetes who are treated with metformin can be corrected through treatment with either hydroxocobalamin injections or methylcobalamin sublingual supplements.” [2016]
• Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia[2015].
  • “Frequent injections of high-concentrated vitamin B12, combined with an individual daily dose of oral folic acid, may provide blood saturations high enough to be a remedy for good and safe relief in a subgroup of patients with ME/FM. Moreover, we suspect a counteracting interference between B12/folic acid and certain opioid analgesics and other drugs which have to be demethylated as part of their metabolism. “
  • ” Some patients can do well from oral treatment, but along the years we have recognized that patients with ME or FM respond best to the injective form of B12 therapy, and most of them require an injection at least once a week.”
  • “methylcobalamin became available, in 2 mL ampoules with 5 mg/mL; ” i.e. 10mg per injection(once a week) –> 1.4 mg or 1400 mcg / day.

Do not use Laughing Gas(nitrous oxide) at the Dentist

• “the use of N2O has become increasingly popular in recent years. Unfortunately, the use of N2O leads to inactivation of vitamin B12. Vitamin B12 plays an essential role in the synthesis and maintenance of myelin, a fatty substance that surrounds nerve cells and is crucial for their functioning. Deficiency of vitamin B12 could typically result in degeneration of posterior and lateral columns of the spinal cord. Treatment with intramuscular vitamin B12 injections and abstinence of N2O generally leads to gradual improvement of symptoms” [2017]

B12 / Folate Balance

The issue arises when B12 levels are low… from [2007] review: “Simply put, if your vitamin B-12 status is good, folate supplementation is good for you!”

• “Those with a low vitamin B-12 status (serum cobalamin <148 pmol/L) and high serum folate (>59 nmol/L) had an odds ratio for cognitive impairment of 5  [times higher] compared with those whose vitamin B-12 status and folate status were both normal. “
• ” In agreement with current knowledge, they found that a low vitamin B-12 status is associated with macrocytosis, anemia, and cognitive impairment. “
• “The “good news” is that, in subjects with a normal vitamin B-12 status, high serum folate (>59 nmol/L) was associated with protection from cognitive impairment. This finding is remarkable in a population with a much higher mean folate concentration (39 nmol/L) than that seen in countries where there is no mandatory folate fortification. “
• “Is it possible that poor vitamin B-12 status influences the metabolism of folic acid or the function of NK cells after high intakes of folic acid?”

Bottom Line

Oral, sublingual or injections are equally effective. If there is a cost for injections, then going to oral or sublingual will get you the same results without the expense.

1000 mcg/ 1 mg seems to be the effective ongoing dosage — especially if you have night sweats or unknown fevers.

Methylcobalamin or cobalamin? This depends on your MTHFR status. This blog post on 23 and me, is worth reading. There is no evidence that methylcobalamin have any adverse risk, then that would be preferred.  On Amazon, you can get 1000 mcg or 5000 mcg for about $0.06 each (cost per day).

• Epigenetics:
  • “Little is known about how micronutrient deficiencies affect the human gut microbiota. A study by Hibberd et al. illustrates how these deficiencies affect the composition and function of gut microbiota, and further, how different species realize changes in gene expression and cellular metabolism to cope with micronutrient shortages”[Src] Connecting gene expression to bacteria (epigenetics impacted by bacteria)
  • ” In particular, bacterial-derived short chain fatty acids have emerged as one clear link between how the microbiota intersects with host epigenomic pathways. Here we review recent findings describing crosstalk between the microbiota and epigenomic pathways in multiple mammalian cell populations. “[2017]
• Brain:
  • “Cognitive impairment by antibiotic-induced gut dysbiosis: Analysis of gut microbiota-brain communication” [src]
  • “For people with IBS research shows for the first time that there is an association between the gut microbiota and the brain regions involved in the processing of sensory information from their bodies. The results suggest that signals generated by the brain can influence the composition of microbes residing in the intestine and that the chemicals in the gut can shape the human brain’s structure.” [src]
  • “Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice” [src]
  • “clinical (low) doses of penicillin to pregnant mice and their offspring results in long-term behavioural changes. These changes include elevated levels of aggression and lower levels of anxiety, accompanied by characteristic neurochemical changes in the brain” [src]
• Probiotics:
  • “Unraveling the Differences between Gram-Positive and Gram-Negative Probiotics in Modulating Protective Immunity to Enteric Infections”[src] “Lactobacilli spp. and Escherichia coli Nissle 1917 are two probiotics that are commonly used in children to treat various medical conditions including human rotavirus diarrhea and inflammatory bowel disease. Although the health benefits of probiotics have been confirmed, the specific effects of these established Gram-positive (G+) and Gram-negative (G−) probiotics in modulating immunity against pathogens and disease are largely undefined…These probiotics modulate the pathogenesis of infectious diseases and protective immunity against pathogens in a species- and strain-specific manner. “
  • “The leading probiotics currently available to consumers are generally drawn from a narrow range of organisms. Knowledge of the gut microbiota and its constituent actors is changing this paradigm, particularly given the phylogenetic range and relatively unknown characteristics of the organisms under investigation as novel therapeutics. For this reason, and because their development is likely to be more amenable to a pharmaceutical than a food delivery route, these organisms are often operationally referred to as next-generation probiotics, a concept that overlaps with the emerging concept of live biotherapeutic products. The latter is a class of organisms developed exclusively for pharmaceutical application. ” [src]
  • “Lactobacillus parafarraginis metabolites hindered the growth of multiple, distantly related bacterial pathogens.”[src]
  • Update studies of Probiotics with Evidence available in the US and Canada. [Site] Download PROBIOTIC GUIDE mobile app for free
     [NOTE There are US and Canada versions — download appropriate one (or both)]
    
    • NOTE: If your favorite probiotic is NOT listed — it is because the strains are unknown and thus it lacks any scientific evidence.
• “New study in mice shows gut microbes are a driver of age-associated inflammation “[src]
• “The gut microbiota can influence immune-cell function by the production of short-chain fatty acids. Mackay and colleagues show that diets enriched for acetate and butyrate protect non-obese diabetic mice from insulitis and diabetes progression.” [src]
• “Intense exercise damages gut bacteria and increases health risks'[src]
• Disease:
  • “However, a marked decrease in the total diversity of microbial communities, an over-representation of Proteobacteria and an under-representation of Actinobacteria has been observed in lesional skin from psoriasis patients compared to corresponding non-lesional skin from the same individual.” [src]
  • “Giardiasis may be a disease of the ecology of the GI tract.
    Colonization by the human and animal parasite, Giardia, changed the species composition of the mouse microbiome in a way that might be harmful. “This shift is generally characterized by more aerobic bacteria and less diversity of anaerobic species” [src]
  • “The long-term dynamic behaviour of the gut microbiome in inflammatory bowel disease demonstrates increased deviation from the ‘healthy plane’ when compared to the normal variation observed in healthy individuals.” [src] – the longer you have it, the worst the shift gets
  • “Researchers report introducing probiotics help reduce yeast infections in men with schizophrenia. “[src]
  • “Accumulating evidence suggests that abnormalities in the composition of the gut microbiota may play a role in the pathogenesis of depression. ” [src]
  • “reater richness in Campylobacteraceae (P = 0.0003), Neisseriaceae (P = 0.0115), Methylobacteriaceae (P = 0.0004), Sphingomonadaceae (P = 0.0221), and Enterobacteriaceae (P = 0.0451) was found in patients with complicated acute viral gastroenteritis  compared with normal controls. The data suggest a significant reduction in intestinal microbial diversity in patients with severe acute viral gastroenteritis , particularly those with rotavirus infection. ” [src]
  • “Bacterial residents of the human body often provide beneficial effects, but some can be harmful. The action of gut bacteria has been found to be tightly linked to neurodegeneration in a mouse model of Parkinson’s disease.”
  • “Alterations in the Microbiome Are Associated with Changes in Bone Quality” [src]
• “Breast Milk Contributes Significantly to Babies’ Bacteria “[src]
• “Women who have unprotected sex with men seem to have more bad types of bacteria in their vaginas, which may make them more prone to infection and disease” [src]
• “A diet rich in whole grains may lead to modest improvements in gut microbiota and immune response in healthy adults”[src]
• “The gut microbes of young killifish can extend the lifespans of older fish – hinting at the microbiome’s role in ageing. It may not be the most appetizing way to extend life but researchers have shown for the first time that older fish live longer after they consumed microbes from the poo of younger fish.” [src]