MTHFR Mutations, Cardiovascular Disease, and Riboflavin (B2): Scientists Zone in on a Neglected Ménage à Trois

You can test your MTHFR gene either directly or by plugging your raw data from 23andme, or another provider into evaluation tools such as Genetic Genie.

If you have no idea what #MTHFR means, here's the Reader's Digest version: MTHFR is an enzyme that is affected by a mutation in the MTHFR gene. The latter encodes the enzyme methylene-tetrahydrofolate reductase aka MTHFR effectively unless there's a single-nucleotide polymorphism (SNP) affecting the 677th base pair of the MTHFR gene... not helping?

Well, let's just say if you have a certain variation of this gene, you're having a hard time processing B-vitamins; and it's not totally unlikely that you're affected: According to Marini et al. 2008, this mutation affects 29% of the global population.

Previous studies, however, report much lower estimates for prevalence of the MTHFR 677TT genotype, i.e. 10% worldwide, with values ranging from 4 to 18% in the United States, over 20% in Northern China to up to 32% in Mexico (Wilcken 2003 | see Figure 1).

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Based on observational studies, we've known for quite some time that there is a link between having the TT-allele of MTHFR 677 (henceforth only "MTHFR") and cardiovascular disease. Studies quantify the risk increase for hypertension, a major driver of cardiovascular disease, at 24–87% and report CVD risk increases of up to 40%. In view of the large geographical variation in the extent of excess disease risk, scientists have speculated that there may be gene-environment interaction way before the MTHFR mutation was identified. As soon as its effect on the metabolism of folic acid and the importance of the latter in the methylation of homocysteine (Hcy) was clear, it appeared obvious that the previously specified risk increase was a result of accumulating Hcy levels in the in the blood of people who have TT allele of the MTHFR gene. This theory, however, may now have to be revised or at least expanded in view of recent research.

Figure 1: Prevalence of homozygous TT genotype (two 677C>T alleles) among 7130 newborns of different ethnicities from 16 areas in Europe, Asia, the Americas, the Middle East, and Australia (Wilcken 2003) - Note: Others estimate the global prevalence at almost 30% (Marini 2008).

As McNulty et al. report in their 2017 paper in "Molecular Aspects of Medicine", there's "[e]merging evidence [...] that the relevant environmental factor may be riboflavin". The "yellow" vitamin (B2) you pee out in large quantities if you're still willing to pay for crazily high dosed super-vitamins, is an MTHFR co-factor with a previously largely ignored "genotype-specific effect on blood pressure" (McNulty 2017). And in fact, randomized trials in hypertensive patients (with and without overt CVD) "show that targeted riboflavin supplementation in homozygous individuals (MTHFR 677TT genotype) lowers systolic blood pressure by 6 to 13 mmHg, independently of the effect of antihypertensive drugs" (McNulty 2017) - an effect that could reduce the risk of stroke, infarction and co.

Subgroup analysis for the association between MTHFR C677T genotype frequencies and the risks of NAFLD.

The TT-allele is not the only problematic mutation of the MTHFR gene: Studies like Sun et al. 2016 show that the having the CC-allele (albeit at a different position of the MTHFR gene) is similarly problematic - not in terms of CVD, though, but with respect to your risk of developing non-alcoholic fatty liver disease. In their meta-analysis, the researchers from the Tianjin Union Medicine Center & Tianjin People’s Hospital in Tianjin, China, were able to show that both the TT (~50% increased risk) and the CC genotype (50-180% increased risk depending on the model, the scientists used) of the MTHFR C677T and MTHFR A1298C, respectively, "are more likely to be associated with the susceptibility to NAFLD" (Sun 2016).

The debate about MTHFR on the internet has, just as the discourse in the scientific community, focused almost exclusively on the effects of the genetic mutation on folate/folic acid metabolism. I guess that's because the impaired folic acid metabolism in people who carry the TT-allele of the MTHFR gene increases the risk of neural tube and other birth defects in unborn babies - this and the association of having the TT allele with increased homocysteine (Hcy) levels (0.4-8.8µmol/L) and significantly reduced effects of folic acid supplementation on Hcy levels (Lewis 2005; Fezeu 2018). As previously hinted at, there's yet "no strong evidence [...] to support an association of the MTHFR 677 C→T polymorphism and coronary heart disease in Europe, North America, or Australia" - in other words, the potential increase in homocysteine in TT-allele carriers is not just smaller than previously thought it can, in contrast to what the interwebs may say,  also be ameliorated w/ folic acid supplements | Lewis 2005). Contemporary research does yet suggest that "lowering homocysteine concentrations, through supplementation with folic acid" cannot as of now be linked to significantly reduced risks of "heart disease" (Lewis 2005).

Let's briefly forget the folic acid (B9) <> homocysteine theory of heart disease and turn to the more recent revelations about the modulatory effect riboflavin (B2) seem to play:

With the technological advances in gene-testing and interest in gene-environment interactions, there's an increasing number of studies investigating the role of the genetically determined MTHFR activity in cardiovascular disease - and, as of late, its interaction with riboflavin intake and status. The latest set of studies has been presented at the conference of the Nutrition Society in June 2018 and here are a few sneak peaks on what the scientists found.

• MTHFR & endothelial function: Rooney, et al. (2018) show for the first time that individuals with the MTHFR TT genotype have poorer endothelial function compared to their age-matched CC genotype counterparts.
  

  

  Table 1: Differences between groups were assessed by ANOVA; values within a row with different superscript letters are significantly different, by Tuckey post-hoc test. Abbreviations: AIx, augmentation index; DBP, diastolic blood pressure; PWV, pulse wave velocity; SBP. Systolic BP (Rooney 2018).

  More specifically, they observed in healthy individuals, aged 18–60 years, from Northern Ireland, who were screened for MTHFR genotype, that systolic BP is markedly higher(~9%) in participants with the TT genotype, compared to CC and CT genotypes, with a similar, albeit non-significant, trend for diastolic BP. In conjunction with the significantly elevated pulse wave velocity in individuals with the TT compared to CC genotype, this indicates "poorer endothelial compliance in this genetically at-risk group" (Rooney 2018).
  
  What the scientists could not tell at the conference (yet) is whether the increase in blood pressure is modified by the subjects riboflavin intake as it was observed in the studies summarized in the previously cited paper by McNulty et al. (2017).
• MTHFR & gestational hypertension: O'Sullivan et al. (2018) conducted the subset analysis that's (as of yet) lacking for the data from the previously discussed study by Rooney et al. (2018). They found based on data from the ongoing Optimal Nutrition for the Prevention of Hypertension (OptiPREG) project that "women with the TT genotype and low riboflavin status undergo a markedly greater increase in systolic BP from the 14th to the 36th GW". A similar trend was also seen in diastolic BP, but did not reach statistical significance.
  

  

  Figure 2: Changes in systolic and diastolic blood pressure from gestational week 14 to 36 according to riboflavin status of the pregnant subjects | plotted based on data in O'Sullivan 2018.

  If you look at the actual values I've plotted for you in Figure 2 the effect is not as large as one may expect based on the phrase "markedly greater increases", but the important mediating effect of riboflavin intake (high vs. low) is obvious... and, even though this may not be significant - it looks as if it would help everyone, i.e. independent of the MTHFR gene variant.
  
  At this point, it is obviously important to conduct a randomized controlled trial to investigate the effect of riboflavin supplementation on pregnant women's blood pressure levels - needless to say that this RCT is already "underway at [the researchers'] centre with results from the trial expected in early 2019" (O'Sullivan 2018).
• MTHFR & blood pressure in normal people: With Hughes' recent study, the follow-up to the previously discussed study does already exist. However, it was conducted in 18-65-year-old non-pregnant adults, and not mothers-to-be O'Sullivan et al. are interested in. In their study, Hughes et al. (2018) assigned n = 81 adult subjects with the TT-allele of the MTHFR gene randomly (but stratified by baseline systolic BP) to two groups: the B2 group in which subjects received 10 mg/day riboflavin (that's "only" 8x the RDA and much less than I've seen in many multivitamin products) and the placebo (PLA) group which supplemented with indistinguishable placebo pills, both for 16 weeks.
  
  Primary outcomes of the study were the biomarker status of riboflavin, which was measured using the erythrocyte glutathione reductase activation coefficient (EGRac) assay (Graham 2005), and, obviously the subjects' blood pressure (BP), which was measured in form of both clinic BP and ambulatory BP (the latter gives a much better picture of the 'real' blood pressure of an individual and this is the first study to evaluate in the B2 <> blood pressure context)- in accordance with NICE guidelines.
  
  The results are interesting and cannot be summarized solely as "B2 worked" or "B2 failed". That's mostly because the blood pressure response to riboflavin (i.e. whether there was a reduction or not) was "found to be strongly dependent on baseline BP" (Hughes 2018).

  • 

    Table 2: Response to intervention analyzed by repeated measures ANCOVA, adjusting for sex. † Higher EGRac values are indicative of lower riboflavin status. ≠ mean of participant daytime/awake hrs which was personalized for each participant (Hughes 2018).

    Participants with a baseline systolic BP of less than 125 mmHg showed no response to riboflavin supplementation (data not shown).
  • In participants with a baseline systolic BP ≥125 mmHg, B2 supplementation resulted in a significant BP lowering of daytime systolic BP by 3·8 mmHg vs. 0·2 mmHg in the placebo group (see Table 2).
  Is that bad news? No, quite the opposite is the case. A systolic blood pressure of <125mm/Hg is absolutely within the no-danger zone (learn more about optimal blood pressure levels in "Pre-hypertension ain't benign").
  
  But is the effect even relevant? With only -3.8 mmHg, the effect may seem to be irrelevant. You have to keep in mind, however, that it was observed in a healthy study population, not in patients with hypertension, and lowering an already optimal systolic BP at e.g. 110 mmHg by another 10-15 mmHg could actually make the subjects pass out. Accordingly, it seems to be more worthwhile to ignore the effect size for the time being and start speculating about the reasons why the provision of 8-9 times (for men and women respectively) the RDA of B2 failed to increase the riboflavin status of the subjects (see Table 2). I mean, the subjects in the supplement group did, in fact, end up with a lower B2 status than the placebo group.
  
  Before the scientists hope comes true and "these findings [...] offer a personalised approach for BP management in [...] at risk sub-populations", there's thus IMHO still a lot of work to do.
• MTHFR & Messed Up Methylation: The additional studies I asked for towards the end of the discussion of the Hughes study could also deal with the epigenetic effects of riboflavin, as studies like Amenyah et al. 2018 which examine the global and MTHFR gene DNA methylation response to riboflavin supplementation may explain many of the questions we haven't answered yet.
  
  In the corresponding paper, Amenyah and colleagues from the Ulster University point out that, while the "mechanism linking this gene-nutrient [MTHFR <> B2] interaction is currently unknown", it is possible if not likely that it "involve[s] aberrant DNA methylation, which has been implicated in hypertension" (Amenyah 2018) before. To confirm the importance of this interaction and investigate the methylation response, the scientists analyzed blood samples of 120 subjects who had previously participated in a 16-week B2 supplementation trial (1.6mg/d ~1xRDA).  While the scientists found changes in gene-methylation, most importantly a reduction in MTHFR north shore methylation in TT genotype participants, it's not clear how this or the concomitant reduction in LINE-1 methylation are related to the blood pressure lowering effects of riboflavin in genetically at-risk adults. It is possible, though, that the slight changes in MTHFR methylation partly restore its function in TT-allele carriers and thus contribute to significant improvements in their ability to effectively process folate and other B-vitamins - an improvement that could have significant downstream effects on CVD.

Choline, which has become a deficiency nutrient since choline-rich foods like eggs have been demonized is necessary another co-factor in homocysteine metabolism. But that's by no means the only reason why you should keep an eye on your choline intake | learn more in my 2014 article "Choline Deficiency, Its Consequences"

MTHFR is a factor to consider... even beyond heart disease: Heart disease is the #1 killer in the US. According to the CDC, 610,000 people die of heart disease in the United States every year–that's 1 in every 4 deaths. It is, however, not yet clear how many of the 610,000 victims of this serial killer carry the TT-allele of the MTHFR gene. What is clear is that those who belong to the (as of now) elusive group of "MTHFR mutants" are at an increased risk of heart disease - an increase of which the studies discussed in this article suggest that it may be modified by one's riboflavin intake.

The emerging theory, which could provide an alternative to the old "homocysteine-folate"- theory scientists used to refer to when trying to explain increased CVD risks in carriers of MTHFR TT-allele. As of late, this link has yet been increasingly scrutinized.

In fact, many scientists are convinced "that HCY is a marker, rather than a cause, of CVD" (Wierzbicki 2007, my emphasis). Hence, its elevation in MTHFR-mutants would not be causally, but corollary related to heart disease. That's in contrast to hypertension, which is so intricately linked to major cardiovascular disease that an MTHFR TT-allele carrier who reduces his systolic blood pressure by 13 mmHg (the upper range of improvements in the meta-analysis by McNulty et al. (2017)) would experience a significant 20-30% decrease in overall cardiovascular disease risk and a 10-25% decrease in his risk of dying from any form of cardiovascular disease (Bundy 2017).

These figures make the previously discussed ménage à trois (MTHFR mutation <> CVD <> riboflavin) all the more interesting. What we should not forget, though, is that increases in CVD risk are by no means the only side effects of MTHFR mutations: Migraines (Scher 2006; Liu 2014), autism (Rai 2016), colorectal cancer (Chen 1999; Shiao 2017), breast cancer (Sharp 2002; Shrubsole 2004; Zhang 2017), lung cancer (Chen 2015) and a plethora of other, non-communicable diseases have at least initially evidence suggesting that the MTFHR mutants among us are at significantly increased risk of contracting them | Comment!

References:

• Amenyah, S.D., et al. “Epigenetic Effects of Riboflavin Supplementation on Hypertension in Adults Screened for the MTHFR C677 T Polymorphism.” Proceedings of the Nutrition Society, vol. 77, no. OCE3, 2018, p. E62., doi:10.1017/S0029665118000666.
• Bundy, Joshua D., et al. "Systolic blood pressure reduction and risk of cardiovascular disease and mortality: a systematic review and network meta-analysis." JAMA cardiology 2.7 (2017): 775-781.
• Chen, Jia, Edward L. Giovannucci, and David J. Hunter. "MTHFR polymorphism, methyl-replete diets and the risk of colorectal carcinoma and adenoma among US men and women: an example of gene-environment interactions in colorectal tumorigenesis." The Journal of nutrition 129.2 (1999): 560S-564S.
• Chen, Hsiao-Ling, et al. "Abstract A47: Meta-analysis of MTHFR polymorphisms in lung cancer: Population health and mutations in the world." (2015): A47-A47.
• Fezeu, Leopold K., et al. "MTHFR 677C→ T genotype modulates the effect of a 5-year supplementation with B-vitamins on homocysteine concentration: The SU. FOL. OM3 randomized controlled trial." PloS one 13.5 (2018): e0193352.
• Graham, Joanne M., et al. "Erythrocyte riboflavin for the detection of riboflavin deficiency in pregnant Nepali women." Clinical chemistry 51.11 (2005): 2162-2165.
• Haerian, Monir Sadat, et al. "MTRR rs1801394 and its interaction with MTHFR rs1801133 in colorectal cancer: a case–control study and meta-analysis." Pharmacogenomics 18.11 (2017): 1075-1084.
• Hughes, C.F., et al. “A Randomised Controlled Trial to Investigate Ambulatory Blood Pressure Response to Riboflavin Supplementation in Adults with the MTHFR 677TT Genotype.” Proceedings of the Nutrition Society, vol. 77, no. OCE3, 2018, p. E56., doi:10.1017/S0029665118000605.
• Lewis, Sarah J., Shah Ebrahim, and George Davey Smith. "Meta-analysis of MTHFR 677C→ T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?." Bmj 331.7524 (2005): 1053.
• Liu, Ruozhuo, et al. "MTHFR C677T polymorphism and migraine risk: a meta-analysis." Journal of the neurological sciences 336.1-2 (2014): 68-73.
• Marini, Nicholas J., et al. "The prevalence of folate-remedial MTHFR enzyme variants in humans." Proceedings of the National Academy of Sciences (2008).
• Mason, Joel B. "Folate status and colorectal cancer risk: a 2016 update." Molecular aspects of medicine 53 (2017): 73-79.
• McNulty, Helene, et al. "Riboflavin, MTHFR genotype and blood pressure: a personalized approach to prevention and treatment of hypertension." Molecular aspects of medicine 53 (2017): 2-9.
• National Institute for Health and Care Excellence (2011) Hypertension in adults: diagnosis and management nice.org.uk/guidance/cg127.
• O'Sullivan, E., et al. “MTHFR Genotype and It's Interaction with Riboflavin in Relation to Blood Pressure Increase during Normal Pregnancy; Preliminary Findings from the OptiPREG Project.” Proceedings of the Nutrition Society, vol. 77, no. OCE3, 2018, p. E58., doi:10.1017/S0029665118000629.
• Rai, Vandana. "Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility." Metabolic brain disease 31.4 (2016): 727-735.
• Rooney, M., et al. “B-Vitamins, Blood Pressure and Endothelial Compliance in Healthy Adults Stratified by MTHFR Genotype.” Proceedings of the Nutrition Society, vol. 77, no. OCE3, 2018, p. E61., doi:10.1017/S0029665118000654.
• Scher, Ann I., et al. "Migraine and MTHFR C677T genotype in a population‐based sample." Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 59.2 (2006): 372-375.
• Sharp, L., et al. "Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR)." Cancer letters 181.1 (2002): 65-71.
• Shiao, S. Pamela K., Amanda Lie, and Chong Ho Yu. "Meta-analysis of homocysteine-related factors on the risk of colorectal cancer." Oncotarget 9.39 (2018): 25681.
• Shrubsole, Martha J., et al. "MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study." Cancer Epidemiology and Prevention Biomarkers 13.2 (2004): 190-196.
• Sun, Man-Yi, et al. "Associations between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and non-alcoholic fatty liver disease (NAFLD) risk: a meta-analysis." PloS one 11.4 (2016): e0154337.
• Wilcken, B., et al. "Geographical and ethnic variation of the 677C> T allele of 5, 10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide." Journal of medical genetics 40.8 (2003): 619-625.
• Wierzbicki, Anthony S. "Homocysteine and cardiovascular disease: a review of the evidence." Diabetes and Vascular Disease Research 4.2 (2007): 143-149.
• Zhang, Yun, et al. "Cumulative review and meta-analyses on the association between MTHFR rs1801133 polymorphism and breast cancer risk: a pooled analysis of 83 studies with 74,019 participants." (2017): 57-73.

Vitamins B1, B2, B5 & B6 & Glucose Management | Part VII of the "There is More To Glucose Control Than Low Carb"- Series. Any Real Benefit From Supplementing With "Bs"

Funny or obscene? A woman w/ low vitamin B and thus fortified cornflakes is among the "top images" Google will show you, when you search for B-vits

There is an often overlooked reason I am addressing thiamin (B1), riboflavin (B2), panthotenic acid (B5) and pyridoxine (B6) in one installment of the "There is More to Glucose Control Than Carbohydrates"-Series (read previous installments): They are all necessary to store glycogen in the liver (Supplee. 1942).

In general, a whole foods diet, as recommended in previous SuppVersity articles will easily cover the B-vitamin needs of the average sedentary and physically active individual - in spite of minimally increased requirements for B2 & B6, in particular (Manore. 2000; Woolf. 2008).

You can learn more about this topic at the SuppVersity

Proteins, Peptides & Blood Glucose

SFA, MUFA, PUFA & Blood Glucose

Vitamin D & Diabetes

Glucose Manager Calcium?

Flush & No-Flush Niacin & Diabesity

Vitamin C & Glucose Control

As a SuppVersity reader you do yet know that "adequate" and optimal intakes can differ significantly and the fact that the provision of additional B-vitamins does not have ergogenic effects does not exclude the possibility that it may have beneficial effects on blood glucose management.

The initially mentioned inability to convert glucose to glycogen and to store the latter in the liver, for example, would already set you up to increases in blood glucose levels. The latter will in turn increase the urinary loos of the water-soluble vitamins, so that a deficiency in one of the initially named B-vitamins could trigger a whole "pro-diabetic" cascade that leaves the by then (pre-)diabetic individual deficient even in those of the B-vitamins of which he or she is actually getting enough from his or her diet (+ supplements).

Annual spending Alzheimer patients >65y in the US from 2010 to 2050 (projection, in billion U.S. dollars;  Alzheimer's Association. 2010)

This article is exclusively about the beneficial effects of b-vitamins on glucose control: The conclusions I draw based on the evidence presented in this article do not affect potential cognitive benefits from "optimal" (=within the RDA) intakes of B-vitamins (in particularly folate, and B-12, which are not part of this overview, anyway) in the young (Herbison. 2012) and old , where they are furthermore "confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline" (Douaud. 2013).

Conclusive evidence for anti-diabetic or insulin-sensitizing effects of B-vitamin supplements is yet still scarce. Even the notion that (pre-)diabetics suffer from low levels of the said B-vitamins is still controversial. This does not mean, though, that there were no promising study results I could report. For thiamine, for example, ...

• 

  Figure 1: Effects of lipophilic thiamine on HbA1c (top) and insulin requirements (bottom) of type I diabetics (Valerio. 1999(

  Valerio et al. report that the provision of a lipophilic form of thiamine (benzoyloxymethyl-thiamin) at 50mg/day lead to improvements in HbA1c and reduced insulin requirements in children with type I diabetes (Valerio. 1999) - the difference between the active and the placebo arm of the study did yet not reach statistical significance
• Obrenovich et al. report in a 2003 that thiamine, or rather benfothiamine bocks the oxidative damage due to the presence of excessive amounts of glucose in the blood of a rodent model of diabetes - their results have been replicated in human studies by Stirban et al. an other researchers several times over the past decade (Stirban. 2006)

Corresponding evidence for riboflavin is hard to find. While there are studies that suggest the presence of reduced levels of this b-vitamin in both type I and type II diabetics, direct beneficial effects of vitamin B2 supplementation on glucose management have not been reported.

A very similar picture, i.e. reduced levels in type II diabetics, but no reports of direct metabolic benefits from the provision of supplemental vitamin B5 from randomized controlled human trials, emerges if you do a database search for panthotenic acid.

Figure 1: 2h glucose and insulin response to oral glucose tolerance test before (white) and after 25 days of B5 depletion (red), as well as during B5 refeed (violet) in a healthy male subjects (Bean. 1995)

The results of a study from the mid 1950s, when scientists still put healthy individuals on nutritionally deficient diets still indicate. After 25 days without significant amounts of panthotenic acid in the diet, the subjects' insulin sensitivity was notably compromised (Figure 1, red) and was not normalized within only 10 days on a diet with 133x the normal amount of panthotenic acid (Figure 1, violet).

Mind the vitamin <> vitamin interactions: Even if there is no reason for high dose pantothenic acid supplementation to inhibit the cellular uptake of glucose directly, it's well possible that it messes with glucose metabolism via interactions with other water solube vitamins like vitamin B6 aka pyridoxin, the excretion of which is increasing, whenever the intake of panthothenic acid exceeds an (in humans undetermined) sane threshold.

In fact, the extreme elevation of the insulin levels in the "reload phase" would rather suggest that extreme amount of vitamin B5 will compromise, not improve your insulin sensitivity - contrary to edema, severe fatigue, joint pains, reduced protein metabolism, reduced phosphorus, raised VLDL triglycerides, calcification (from calcium pantothenate), dehydration, gastrointestinal symptoms, and depression, a decreased insulin sensitivity is yet not on the "official list of side effects"* of high panthotenic acid intakes (*by "official" I refer to the lists everyone copies ad pastes from the major health information outlets on the Internet).

And what about B6? It's in all my supplements, so it must be good!

If I had to write the bottom line to today's installment of the "There is More to Glucose Control Than Carbohydrates" series now, it would probably be very short and certainly very disappointing for the various supplement junkies out there. Luckily (?) there is still one of the B-vitamins missing: Pyridoxine or vitamin B6 - and you should expect the only B-vitamin that can produce severe toxic effects when it is consumed in very high amounts chronically (peripheral nerve damage) should be able to bring about at least minimal increases in insulin sensitivity / cellular glucose uptake, as well, right?

Well, unfortunately, that's not the case. In 1980, already, a group of scientists from the Gandhi Medical College Hospital in India were able to show that the provision of 40mg of pyrodixine per day had "did not bring about any significant alterations in either the oral glucose tolerance or the insulin response to glucose" in thirteen adult maturity-onset diabetics - and that in spite of the fact that 7 of them were actually vitamin B6 deficient!

Mind the "hidden" B-sources: If you are still concerned that you may not be getting your Bs in, you are probably an OTC supplement junkie. In that case I suggest you briefly take a look at the pre-workout, post- workout and whatever other products in your stack... what? Oh, they all contain 10x the RDA and more of these B-vitamins - that's surprising, right?

A major disappointment? Although this article focused exclusively on the benefits of the water-soluble B-vitamins on glucose control, the results are still paradigmatic for the overall "potency" of vitamin-B-supplements. They are all the rage, but the benefits are overblown, in many cases simply non-existent.

If we discard the well established beneficial effects of benfothiamine on the side-effects of elevated blood glucose levels, and the highly disputed benefits of pyridoxine in diabetic peripheral neuropathies (alleviation of sympthoms, no change in nerve damage; Bernstein. 1988 & 1990), there is actually no reason to even consider taking extra amounts of any or all of these vitamins if you are (a) no diabetic and (b) no junk food eater - and let's be honest, if either (a) or (b) applies you have got more important issues to deal with than potentially suboptimal B-vitamin intakes and their effects on glucose tolerance.

Reference:

• Bean, William B., et al. "Pantothenic acid deficiency induced in human subjects." Journal of Clinical Investigation 34.7 Pt 1 (1955): 1073. 
• Bernstein, A. L., and C. S. Lobitz. "A clinical and electrophysiologic study of the treatment of painful diabetic neuropathies with pyridoxine." Current topics in nutrition and disease (USA) (1988).
• Bernstein, Allan L. "Vitamin B6 in clinical neurology." Annals of the New York Academy of Sciences 585.1 (1990): 250-260.
• Herbison, Carly E., et al. "Low intake of B-vitamins is associated with poor adolescent mental health and behaviour." Preventive medicine 55.6 (2012): 634-638.
• Manore, Melinda M. "Effect of physical activity on thiamine, riboflavin, and vitamin B-6 requirements." The American journal of clinical nutrition 72.2 (2000): 598s-606s.
• Supplee, G. C., R. C. Bender, and Z. M. Hanford. "Interrelated vitamin requirements. The influence of thiamin, riboflavin, pantothenic acid and vitamin B6 on liver glycogen reserves." Journal of the American Pharmaceutical Association 31.7 (1942): 194-198.
• Valerio, G., et al. "Lipophilic thiamine treatment in long-standing insulin-dependent diabetes mellitus." Acta diabetologica 36.1-2 (1999): 73-76.

Natural Migraine Prophylaxis & Treatment: Riboflavin, ALA, Magnesium, CoQ10, Feverfew, Melatonin, Butterbur & Co.

Natural migraine protection: Even if supps won't cure it, they can at least reduce the number of "bad days" and the severity of the attacks.

In the last installment of the "Short News" you've learned about the enormous costs chronic pain produces on an annual basis: Roughly $300 billion for its treatment and another $300 billion in form of economic damage. No wonder pain killers, Cox inhibitors and & co are among the top selling and drugs in the world.

Now, migraine is unquestionably among the most debilitating forms of chronic or rather cyclic chronic pain and while women are much often hit by the pain from withing (21.8% v.s 10.0% of the US citizens suffer; NHS 2009). And while I cannot tell you how much of the $2,000 bucks each of you is "spending" on an annual base on treating the pain of his / her fellow citizens, I believe that both of you, my dear mal and female readers, may benefit from the information in today's installment of "On Short Notice" with a comprehensive, but probably not all-encompassing list of promising supplemental agents for migraine prophylaxis and "treatment":

• magnesium: I have actually mentioned that in a previous SuppVersity post already (read more), but I guess it's well worth mentioning it again. Low brain magnesium levels have been reported in a whole host of observational studies in migraineurs. There have also been a couple of respective trials with overall inconclusive, but rather positive results for the acute treatment of patients with aura and, possibly, perimenstrual migraine prophylaxis.
  
  The magnesium formulation that has been used in these trials varied, and there is no large(r) scale comparison of different forms and dosing regimen as of now. Corresponding effects have been observed with 250mg of intravenous and 600mg of oral magnesium chelates (Cady. 1998; Mauskop. 1998), for example. Evans and Taylor additionally cite the following four randomized controlled trials (RCTs; my emphases):

  Take a form that does not give you diarrhea! If you look at the success rates it would appear as if  the organic formulas are superior to the inorganic ones. On the other hand, this may be a simple effect of the increased rates in diarrhea reported by many researchers using non-organic formulations. After all, this does not simply reduce magnesium absorption but will also have negative effects on the overall mineral and water balance. Both, dehydration and mineral imbalances could otherwise increase instead of decrease your risk to suffer from migraine attacks.

  "The first RCT of magnesium for migraine prevention involved only 20 subjects and was positive; the active therapy was 360 mg Mg++ pyrrolidone carboxylic acid divided TID. The second RCT, by Peikert et al, involved 81 adult women and 600 mg magnesium (trimagnesium dicitrate) daily demonstrated a 41.6% improvement with verum versus 15.8% for placebo. The third RCT for migraine prophylaxis, published by Pfafferath et al, involved 69 patients taking 486 mg magnesium; no benefit for magnesium was found; at the end of the 3-month treatment phase, the responder rate was 28.6%in the magnesium group and 29.4% in placebo subjects, according to the primary efficacy endpoint. [...] In a last trial, Wang et al gave magnesium oxide 9 mg/kg divided TID to subjects aged 3 to 17 years. Approximately three-quarters of eligible subjects completed the study, with a significant downward trend in headache days in the active treatment group versus placebo; the lack of any difference in the slope of treatment trends, however, was such that no significant superiority of magnesium over placebo could be documented." (Evans, 2006)

  While magnesium's acute effects are usually ascribed to increases in the circulating levels of Mg++ ions, it's efficacy as a prophylactic treatment is most likely a result of increasing tissue levels and requires a minimum of 3 to 4 months for measurable benefits to occur.
• CoQ10: As a student of the SuppVersity you are well aware of the beneficial (actually vital!) importance of CoQ10 on mitochondrial health. It is an endogenous enzyme cofactor that can be produced by your body. Unfortunately, there are certain conditions and medications that lead to the depletion of CoQ10 and subsequently impair the proton-electron translocation across the mitochondrial membranes.
  
  

  

  No headache, no problem, but not a reason not to consider CoQ10 supplementation. CoQ10 can also help if your exercise performance is what gives you headaches: "300mg CoQ10 Boost Peak Power Increases in Young Elite Athletes. Plus: 140ml of Beet Root Juice, That's all it Takes to Minimize the Oxygen Demands During a Workout" (learn more)

  Against that background and in view of the involvement of mitochondrial malfunction in the etiology of migraine, it is not surprising that Rozen et al. observed in a 2002 open label study in which 61%  of the 31 patients who consumed 150mg CoQ10 daily for 3 months had at least a 50% reduction in migraine days without experiencing any significant adverse events. Interestingly, the supplement took "only" 4 weeks to kick in (a follow up on whether or not it was necessary to stay "on" CoQ10 is not available, but I would consider it likely). In 2005 Sandor et al. conducted one of the few randomized controlled trials: In this particular study, the patients received 100mg of CoQ10 three times daily and saw significant decreases in the attack frequency, the number of headache days, and days with nausea.
  
  Interestingly the highly soluble version of CoQ10 (a liquid formulation of water dispersed nano-particles comprising a supercooled melt of CoQ10 with modified physicochemical properties; GuttaQuinone) that was used in the Sandor study had some side effects (gastrointestinal disturbances and cutaneous allergy that had not been reported in other studies). Overall, CoQ10 is yet perfectly safe (even if it's nano-sized) and may even yield benefits if you don't suffer from migraine.
• Tanacetum parthenium: Also known as Feverfew, the dried chrysanthemum leaves have a long history as an analgesic and one huge problem, according to the only available peer-reviewed report, preparations of feverfew have shown a >400% variation in dosage strength of the known active ingredient parthenolide (Rossi. 2005). According to evens Evans & Taylor, some experts even doubt if it can be generally assumed that parthenolide, which has some very promising research to back up its efficacy even is the active ingredient in the plant leaves.
  

  

  Feverfew does not look exactly, like powerful medicinal plant, right?

  "In a systematic review, Vogler et al reported on randomized controlled trials (RCTs) involving feverfew for migraine prophylaxis conducted prior to 1998. 11-16 Five studies qualified by Jadad score as adequate; 1 has been published in abstract form only, and only 216 subjects in total have been studied. Vogler et al concluded, “In view of the popularity of feverfew, perhaps the most striking finding was the paucity and low average quality of the existing RCTs on the subject.”

  If you wanted to cut it short you could thus say. It's popular, people swear by it, but according to our current knowledge it may as well be the placebo effect that keeps people coming back to this natural remedy for headaches.
  
  The latter would be nasty, since Feverfew does actually have a handful of side effects that range from a sore mouth and tongue (including ulcers), over swollen lips, loss of taste, abdominal pain, and GI disturbances, up to the occasional report of what Evans & Taylor call the "post-feverfew syndrome" of joint stiffness and aches that were accompanied by (guess what) increasing headaches! In the MIG-99 trials, which used an isolated and highly standardized 6.25 mg dose of parthenolide the number of adverse events were similar. It would thus seem very likely that many of the side effects are brought about either by the initially mentioned natural fluctuations in the active or - and this is even more likely - by other agents in the feverfew leaves.
• Riboflavin: Also and probably better known as vitamin B2, riboflavin has only few quality trials to support its efficiency with its importance in the mitochondrial energy chain and its role in the electron transport within the citric acid cycle, it does, however, appear to be likely that the otherwise often overlooked "yellow-green pee"-vitamin may actually help reduce the number of migraine attacks by >50% (that's 35% more than w/ 25mg/day; Schoenen. 1998), when it is consumed in doses of 400mg/day.

  

  This table shows the nutrient combination of a supplement that has been found to optimize mitochondrial function in a 2011 study (learn more) and it has not just riboflavin, but also lipoic acid and coQ10, both of which are also on the list of "anti-migraine supplements" - certainly no coincidence! Migraine is after all about mitochondrial health and disease.

  The only known side effects researchers observed in the few available randomized controlled trials were diarrhea and polyuria - and those were pretty rare. Evans & Taylor do yet point out that despite its non-toxicity and the non-existence of a tolerable upper intake level they wouldn't recommend high-dose riboflavin consumption to pregnant women, simply because the possible health effects on the unborn child are not known yet.
• Alpha lipoic acid: Certainly less known and not well-researched are the potential benefits of ALA (it is thus not necessary to buy R-ALA, which was in the formula of the supplement mentioned on the label of the table above). A double-blind, placebo-controlled trial by Magis et al. from the year 2007 was yet able to show a reduced monthly attack frequency with alpha lipoic acid at dosages of 600 mg daily after 3 months. It must be said, though that these results were not significantly different from those in the placebo group. Within-group analyses did yet reveal a significant reduction in attack frequency, headache days and headache severity in patient treated with alpha lipoic acid, but not in the placebo group (Magis. 2007)
• Buttebur:
  A note of caution: The Butterbur plant contains pyrrolizidine alkaloids which are
  hepatotoxic and carcinogenic, these compounds have to be removed before you can safely use this plant from the genus of Asteraceae  to counter / prevent headaches.
  Petasites hybridus or rather extracts of its root have gotten some attention as a potential migraine treatment, as well. Petasites is thought to act through calcium channel regulation and inhibition of peptideleukotriene biosynthesis. These cells are thought to play an important role in the inflammatory cascade associated with a migraine (Sheftell. 2000; Pearlman. 2001). A randomized, double-blind, placebo-controlled trial by Grossman & Schmidrams (2000) found that the consumption of 50 mg of butterbur twice daily yielded significantly reduced number of migraine attacks and migraine days per month. Similar results with 50mg of Petasites extract were also reported by Lipton et al. (2004). Finally, a multicenter prospective open-label study of butterbur in 109 children and adolescents with migraine resulted in 77% of all patients reporting a reduction in migraine frequency of at least 50% (Pothmann. 2005).
  
  Serious adverse events were not observed in any of the few hitherto published studies. Overall, butterbur was well tolerated and the most frequently reported adverse reactions were mild gastrointestinal events, predominantly eructation (burping). 
• Melatonin: Yep, you will be hard pressed to find anything melatonin the pineal sleep hormone is not good for. So it is probably not very surprising that it is on the list or rather the end of a list potential natural(*) anti-migraine supplements (some critics will probably say that supplementing with melatonin is not "natural").
  

  • 

    Sleep is good for everything and if you look back at the past SuppVersity articles on the pineal hormone this seems to apply to melatonin, as well.

    1999, Leone et al. were among the first to report beneficial effects of 10mg of melatonin on cluster headaches; yet while this worked magically in some, other patients did not appear to benefit at all (Leone. 1999)
  • melatonin appears to be an effective alternative for indomethacine in idiopathic stabbing headache (Rozen. 2003)
  • cluster migraine which often goes hand in hand with a lack of melatonin secretion has been shown to respond to 9 mg melatonin taken at bed time (Peres. 2001)
  In a 2005 review of the literature Peres does yet point out a multitude of mechanisms by which melatonin could help alleviate headaches, including "its anti-inflammatory effect, toxic free radical scavenging, reduction of proinflammatory cytokine up-regulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, serotonin modulation, and the similarity of chemical structure to that of indomethacin" (Peres. 2005). Despite the fact that large(r) scale randomized controlled trials are absent, up to know. I personally would certainly give it a try.

Aside from "real medications" (I wonder where you can make the distinction between a supplement like thiotic acid aka ALA and a medicinal agent like aspirin?), there is also a "consistent level of evidence"for the usefulness of acupuncture, which has proven to be superior to no or placebo treatment and works as an adjunct to conventional treatment (Schiaparelli. 2010).

There is one thing left to mention that may even work better than any of the previously enumerated supplements: Prevention! While many people don't really know the cause of their migraine attacks there are a couple of known food triggers you may want to avoid or even test (Peatfield. 1984; Scharff. 1995):

• 

  MSG in fast food is a problem (learn more about MSG)

  Alcohol -- 29-35% of people with migraine are sensitive to mankind's most consumed poison
• Chocolate -- 19-22% of the migraine sufferers worldwide are sensitive to the sweet superfood
• Cheese -- 9-18% don't tolerate the tyramine which can also be found in other fermented foods
• Caffeine -- 14% of the patients report that the vasoconstrictive effects of caffeine make the headaches significantly worse
• MSG -- 12% of the migraine sufferers report that eating high mono-sodium glutamate foods gives them the "Chinese Restaurant Migraine"

Theoretically, each and every food item could trigger migraine attacks, therefore I would not suggest relying on this list all too much. Instead of just testing those 5 and resigning, when you are unable to trigger/avoid migraines by consuming/abstaining from them, I'd strongly advise to start a food diary, in which you log everything you eat, drink and supplement (nitrates are by the way notorious for triggering headaches, as well) + your migraine symptoms. Once you go through the notes you should be able to identify what causes the problem, if it has any dietary cause at all.

References:

• Cady RK, Farmer K, Altura BT, et al. The effect of magnesium on the responsiveness of migraineurs to a 5-HT1 agonist.Neurology.1998;50(suppl 4):A340. 
• Evans RW, Taylor FR. "Natural" or alternative medications for migraine prevention. Headache. 2006 Jun;46(6):1012-8. Review.
• Grossman M, Schmidrams H. An extract of Petasites hybridus is effective in the prophylaxis of migraine.Int J Clin Pharmacol Ther.2000;38:430–435.
• Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia. 1996 Nov;16(7):494-6.  
• Lipton RB, Gobel H, Einhaupl KM, et al. Petsites hybridus root (butterbur) is an effective preventive treatment for migraine.Neurology.2004;63:2240–2244.
• Magis D, Ambrosini A, Sándor P, Jacquy J, Laloux P, Schoenen J. A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis. Headache. 2007 Jan;47(1):52-7.
• Mauskop A, Altura BM. Role of magnesium in the pathogenesis and treatment of migraines.Clin Neurosci.1998;5:24-27.
• Pearlman EM, Fisher S. Preventive treatment for childhood and adolescent headache: role of once-daily montelukast sodium.Cephalalgia.2001;21:461
• Peatfield RC, Glover V, Littlewood JT, et al. The prevalence of diet-induced migraine.Cephalalgia.1984;4:179–183.
• Peres MF, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia. 2001 Dec;21(10):993-5.
• Peres MF. Melatonin, the pineal gland and their implications for headache disorders. Cephalalgia. 2005 Jun;25(6):403-11. 
• Pothmann R, Danesch U. Migraine prevention in children and adolescents: results of an open study with a special butterbur root extract.Headache.2005;45:196–203.  
• Rossi P, Di Lorenzo G, Malpezzi MG, et al. Prevalence, pattern and predictors of use of complementary and alternative medicine (CAM) in migraine patients attending a headache clinic in Italy.Cephalalgia.2005;25:493-506. 
• Rozen TD, OshinskyML, Gebeline CA, et al. Open label trial of Coenzyme Q10 as a migraine preventive. Cephalalgia. 2002;22:137–141.
• Rozen TD. Melatonin as treatment for idiopathic stabbing headache. Neurology. 2003 Sep 23;61(6):865-6. 
• Sandor PS, DiClemente L, Coppola G, et al. Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology. 2005;64:713–715.
• Scharff L, Turk DC, Marcus DA. Triggers of headache episodes and coping response of headache diagnostic groups. Headache.1995;35:397–403. 
• Schiapparelli P, Allais G, Castagnoli Gabellari I, Rolando S, Terzi MG, Benedetto C. Non-pharmacological approach to migraine prophylaxis: part II. Neurol Sci. 2010 Jun;31 Suppl 1:S137-9.
• Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial.Neurology.1998;50:466-470 
• Sheftell F, Rapoport A, Weeks R, et al. Montelukast in the prophylaxis of migraine: a potential role for leukotriene modifiers.Headache.2000;40:158–163. 
• Srivastava KC, Mustafa T. Ginger (Zingziber officinale) in rheumatism and musculoskeletal disorder. Med Hypotheses.1992;33:342–348.
• Sun-Edelstein C, Mauskop A. Foods and supplements in the management of migraine headaches. Clin J Pain. 2009 Jun;25(5):446-52.

Mitochondrial Super Food: R-ALA, Acetyl-L-Carnitine, Biotin, Nicotinamide (B3), Riboflavin (B2), Pyridoxine (B6), Creatine, CoQ10, Resveratrol & Taurine Optimize Mitochondrial Function.

From China, the biggest (and cheapest) producer of raw materials for dietary supplements comes a study (Sun. 2011) on the effectiveness of a mitochondrial nutrient combination on performance and mitochondrial biogenesis in exhaustively exercised rats, which may well have consequences on the number of items on your next supplement shopping list.

For 4 weeks, Sun et al. supplemented exhaustively exercising rats with a combination of R-a-lipoic acid, acetyl-L-carnitine, biotin, nicotinamide, riboflavin, pyridoxine, creatine, CoQ10, resveratrol and taurine (cf. table 1)

Table 1: Ingredients of the "mitochondrial nutrient supplement";dosage used in rat study (data adapted from Sun. 2011); and calculated human equivalent doses 

This nutrient combination had beneficial effects on standard markers of exercise induced oxidative stress and muscular breakdown. Specifically, it "significantly inhibited the increase in activities of alanine transaminase, lactate dehydrogenase and creatine kinase". The supplementation protocol also had beneficial effects on antioxidant status reversing increases in malondialdehyde and inhibiting the decrease in glutathione S-transferase and total antioxidant capacity in plasma. It also suppressed the elevation of reactive oxygen species in the spleen and thus protected splenic lymphocytes from apoptosis [cell death].

These effects were accompanied / mediated by significant increases mitochondrial biogenesis, evidenced by increases in

[...] the protein expression of mitochondrial complexes I, II and III, mtDNA number and transcription factors involved in mitochondrial biogenesis and fusion in skeletal muscle.

Taken together these results underline that proper nutrition, not only on a macroscopic, but also on a microscopic level, is of paramount importance to exercise performance and metabolic health. Interestingly, the amount of the supplemental "mitochondrial nutrients" used in this study is not even exorbitantly high. In fact, the human equivalent doses (cf. table 1) would be easily attainable by a nutrient-rich diet and some cheap and readily available supplements.

B-Vitamins & Diabetes: Protective or Causative?

In a very interesting study, scientists from China and Japan (Zhou. 2010) found that "long-term exposure to high level of the B vitamins may be involved in the increased prevalence of obesity and diabetes in the US in the past 50 years". At first this appears to be counterintuitive, since we have been told over and over that B-Vitamins are not only good for our health, but that we could not even "overdose" them. While the latter has been questioned for years and certainly is not the case for e.g. B6 and niacin, even the former seems questionable, if you read the results from the above mentioned study:

The prevalences of diabetes and adult obesity were highly correlated with per capita consumption of niacin, thiamin and riboflavin with a 26- and 10-year lag, respectively (R2 = 0.952, 0.917 and 0.83 for diabetes, respectively, and R2  = 0.964, 0.975 and 0.935 for obesity, respectively). [...] The relationships between the diabetes or obesity prevalence and per capita niacin consumption were´similar both in different age groups and in male and female populations. The prevalence of adult obesity and diabetes was highly correlated with the grain contribution to niacin (R2 = 0.925 and  0.901, respectively), with a 10- and 26-year lag, respectively.

These results (especially those referring to the detrimental effect of niacin) confirm test-tube studies conducted by a group of scientists from South Korea earlier this year (Choi. 2010), who found that

NA [nicotinic acid] alters gene expression in insulin-sensitive tissues by various mechanisms. Some of the NA-induced changes in gene expression are discussed as potential mechanisms underlying wanted and unwanted effects of NA treatment.

Just anecdotal: My personal perspective on B-vitamins has changed since my overall energy and well being, as well as my physique have largely improved after stopping to take those B-vitamin (over-)loaden mulit-vitamin preparations like Now ADAM, CL Orange Triad, Animal Pak, ON Opti-Men etc. But remember: it is mere speculation that this could in fact be related to their high B-vitamin contents - could be any other constituent, as well.