JAMA posted my comment yesterday on a study reviewing vitamin C and Zinc for Covid-19 patients

JAMA edited my comment and changed the final sentence (adding ‘or some other dose’, which doesn’t make sense), but the gist is there.  

Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial | Complementary and Alternative Medicine | JAMA Network Open | JAMA Network

My original submission:

It is unclear what dose of elemental zinc was used in this study from the text provided. Fifty mg of 'zinc gluconate' is described, but that is 50 mg of a compound that is only about 1/7 elemental zinc. PubChem lists the molecular weight of zinc gluconate at 455.7 and of elemental zinc at 65.4; so zinc gluconate contains about 14.35% elemental zinc (a maximum value since 'as is' measurements include impurities, including moisture). If 50 mg. of ‘zinc gluconate’ was used, as described in the text, it would represent only about 7 mg of actual zinc; not a "high dose" since it would be below the FDA's current (and recently lowered) Daily Value of 11 mg. 

If 50 mg of elemental zinc from a much larger amount of zinc gluconate (typically 350- 400 mg) was used, it should have been described more precisely as that to avoid any confusion. The amount of zinc used was either a low dose erroneously described as a high dose or the authors mistakenly used the compound name (zinc gluconate) in place of the element's (zinc) when describing the 50 mg amount. 

Either way, how the supplement was described in this paper leads inevitably to confusion. The amount of actual zinc should be clearly specified, but the authors did not do so; nor did they relate the amount of this mineral to its RDA, Daily Value, or Upper Limit as a relevant reference point. The implication from the description of a ‘high dose’ is that the amount of zinc was 50 mg, not the amount of zinc gluconate, and that the authors misstated the description of the supplement. But they just as plausibly mistook 50 mg of zinc gluconate for 50 mg of elemental zinc, and then inaccurately described both the supplement and the dosing. 

How did this pass peer review without catching this internal conflict of description that would be obvious to chemists who work with mineral compounds and understand how to appropriately label them by either compound or element? And exactly which dose of elemental zinc was used; 50 mg or 7 mg?

Does zinc supplementation reduce absorption of calcium or magnesium?

In general, no.  While it’s true that zinc can reduce absorption of calcium it would have to be a high level to do so; studies showing such a relationship have primarily been on zinc sulfate supplements containing about 140 mg of elemental zinc.  This is far above the RDA/DV level of 15 mg. typically found in dietary supplements, or even the 30-50 mg. found in some immune or prostate formulas.  One typical study used 142 mg/day of zinc to achieve this; far higher than the amount in supplement formulas.  The study noted that the decrease in calcium absorption occurred when low calcium and high zinc intake was noted, but not with adequate calcium intake, and specifically tested lower doses of zinc along with low calcium intake and did not find a reduced absorption of calcium at commonly supplemented levels:  https://www.ncbi.nlm.nih.gov/pubmed/1452955

 

So the issue is limited to a very high zinc intake combined with a very low calcium intake, not the levels found in common supplements.  One will find zinc and calcium together in multiple vitamins or some mineral formulas, but at typically available levels they are not shown to cause the reduced absorption of calcium found in those studies cited above. 

 

The issue has also been studied for magnesium versus zinc intake.  Likewise, very high zinc intake interfered with low calcium intake (500 mg.) but less likely at higher levels of calcium intake.  Again, the levels of zinc in question (around 140 mg.) are not typically found in over-the-counter zinc supplements or multivitamins. https://www.ncbi.nlm.nih.gov/pubmed/7836627/ 

 

 It is more convenient for people to supplement with combination formulations instead of taking several single ingredient supplements, typically increasing compliance with label instructions and dosing.  Knowing that it's okay to take minerals in combinations that are commonly found in the marketplace is reassuring when some pundits claim that it is inappropriate based on the unusual circumstances of low mineral intake combined with abnormally high zinc intake.  For physicians prescribing the high strength zinc products, this is something to consider, but not something for consumers of dietary supplement formulas to be concerned about.

Thyroid supplements

People typically seek thyroid support nutrients as a way to enhance their energy levels, enable proper control of their body temperature, and support a strong metabolic rate.  We take these nutrients, both individually and in formulas, in order to assure adequate levels to support optimal thyroid function, since a deficiency or insufficiency of key nutrients could reduce the operational efficiency of the thyroid gland.   Proper thyroid function supports a lean body composition and helps prevent fatigue.  Under the control of complex feedback and signals from the hypothalamic-pituitary-thyroid axis, the thyroid gland regulates body temperature and metabolism rates, playing an important role in weight management and energy states.  By the same token, if any of the important nutrients are not available to the thyroid in sufficient amounts, metabolic rates and energy levels could suffer. ¹

Natural thyroid support supplements work primarily by providing precursors of thyroid hormones, along with various cofactors, in order to encourage proper thyroid function.  In some cases, the lack of adequate nutritional resources prevent the thyroid gland from maintaining optimal efficiencies, and if the gland can’t maintain healthy levels of its important hormones, then it can’t adequately support the body’s metabolism.  Unlike medical treatments, nutritional approaches focus on providing what the body needs in order to assure that the thyroid has its particular needs met and can function optimally. 

The key nutrients for thyroid function are the mineral Iodine and the natural amino acid L-Tyrosine. 

Humans require iodine for cellular metabolism and for normal thyroid function; specifically for the production of thyroid hormones.  Thyroid hormones regulate many important biochemical reactions, including protein synthesis and enzymatic activity, and are critical determinants of metabolic activity.  Iodine is a nutrient that can sometimes be obtained from the soil, but many soils are deficient.  Areas that are mountainous, very rainy, or prone to floods/erosion tend to have soils that are low in iodine, increasing the risk that foods grown in those areas will be iodine-deficient.  Table salt is commonly iodized, but those using non-iodized salt or on low-sodium diets can’t rely on that source.  Multivitamin formulas, thyroid support formulas, kelp and some other seaweeds, and some multimineral formulas provide supplemental iodine.  The U.S. Recommended Dietary Allowance (RDA) is 150 mcg (micrograms) daily for adults ages 18 and older, 220 mcg daily for pregnant women, and 290 mcg daily for lactating women. The Tolerable Upper Intake Levels (UL) for adults ages 18 and older is 1,100 micrograms daily. ^{2-3 ]}

The common sources of iodine in dietary supplements include Potassium Iodide, Kelp, and other seaweeds.  While kelp and some seaweeds are fine for getting the relatively low RDA level of iodine intake, those seeking much higher levels are usually advised to consider Potassium Iodide.  This is because seaweeds typically contain less than 1% iodine, along with a lot of other metals and minerals - including some that we may want to avoid getting too much of - so consuming high doses of seaweeds on a daily basis may not be our safest option.  And iodine is a mineral nutrient that needs to be replenished daily.

L-Tyrosine is an amino acid that is important to the structure of most proteins in the body. It is also the precursor of a number of neurotransmitters and hormones, including the major catecholamines dopamine, norepinephrine, and epinephrine (adrenaline), which are stress hormones made by the adrenal glands.  In addition to these functions, tyrosine also helps produce melanin (the pigment responsible for hair and skin color) and helps in the function of the adrenal, thyroid, and pituitary glands.  Because of these varied responsibilities and the ability of various stresses and dietary deficiencies to reduce tyrosine levels, people sometimes supplement tyrosine (as natural L-Tyrosine) in order to support proper thyroid function. ^4-5   

How do Iodine and L-Tyrosine affect thyroid function?  The thyroid gland’s epithelial cells prepare large quantities of tyrosine into a glycoprotein “scaffold” that is the structural backbone used to form the thyroid hormones thyroxine (T4) and triiodothyronine (T3).  The scaffold and iodine are both secreted into the lumen of the thyroid gland, where an enzyme facilitates the hormone synthesis.  Other enzymes then separate the hormones from the scaffolding in steps, liberating them into their circulating forms.  A few tyrosines are incorporated into these hormones, but most are left in the scaffolding structure’s remains that will be recycled by the body. 

Selenium is an essential mineral nutrient that is necessary for normal thyroid hormone metabolism.  Selenium-containing enzymes control the synthesis and degradation of the biologically active thyroid hormone, T3.  Selenium deficiency may worsen the effects of iodine deficiency on thyroid function, and adequate selenium nutritional status may help protect against some of the neurological effects of iodine deficiency.   Additionally, selenium-based antioxidant enzymes protect the thyroid gland from peroxides produced during the synthesis of these hormones. ^{2, 3, 6}

Zinc, another essential mineral responsible for hundreds of critical chemical reactions in the healthy human, is also important for maintaining normal thyroid homeostasis. Its complex roles include effects on both the synthesis and mode of action of the hormones.  Thyroid hormone binding transcription factors, which are essential for modulating gene expression, contain zinc bound to cysteine-related compounds.   In some studies, low zinc status was associated with decreased thyroid hormone levels.  ³

Copper is believed to have a role in thyroid hormone function, perhaps related to selenium status. ³

Guggul (Commiphora mukul) is an Indian Ayurvedic herb that contains the active compound Guggulsterone, which has been shown to stimulate thyroid activity. ^7-8

 
These ingredients, both singly and as thyroid support formulas, are in demand by consumers wanting to assure adequate thyroid function in times of dietary insufficiencies and various stresses.  Of course, these nutrients and their many functions in the body have a host of potential benefits to those supplementing with them if they may not get adequate amounts from their diet for their individual requirements. 

 

REFERENCES

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1.  Zoeller RT, Tan SW, Tyl RW. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Crit Rev Toxicol. 2007 Jan-Feb;37(1-2):11-53. Review. PubMed PMID: 17364704.
2. http://ods.od.nih.gov/factsheets/Iodine-HealthProfessional/
3. Arthur JR, Beckett GJ. Thyroid function. Br Med Bull. 1999;55(3):658-68. Review. PubMed PMID: 10746354.
4. http://www.umm.edu/altmed/articles/tyrosine-000329.htm
5. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/thyroid/synthesis.html
6. http://ods.od.nih.gov/factsheets/selenium/
7. http://www.drugs.com/npp/guggul.html
8. http://www.peoplespharmacy.com/2005/10/18/guggul/

Functional Doses of Vitamins and Minerals for Bones

• Protein: 0.8 grams per kilogram of body weight

• Calcium: Over 1 gram per day

• Magnesium: 310 – 420 mg per day

• Zinc: 15 mg per day

• Copper: 2.5 to 3 mg per day

• Boron: 3 mg per day

• Manganese: 5 mg per day

• Potassium: 3,500 to 4,000 mg per day

• Vitamin D: over 500 IU daily

• Vitamin K: Levels are not well understood; at least 90 mcg/d for women and 120 mcg/d for men

• Vitamin C: over 500 mg daily

• Vitamin A: 2333 IU in women and 3000 IU in men; avoid low and excessive amounts

Palacios C. The role of nutrients in bone health, from A to Z. Crit Rev Food Sci Nutr. 2006;46(8):621-8. Review. PubMed PMID: 17092827.

Unbalanced Fox news report misleads about vitamin-mineral safety

Unbalanced Fox news report misleads about vitamin-mineral safety By Neil E. Levin, CCN, DANLA I watched the special health report on vitamins and minerals on FOX-32 (How Do Vitamins and Minerals Really Affect Your Body? on 2/12/08, see link below), but was disappointed that the report exaggerated the risks of vitamins and minerals and minimized their benefits without any mention of the common deficiencies that exist in the American population. For example, the report cautioned about vitamin E causing blood thinning, but the Food and Nutrition Board of the Institute of Medicine has set an upper tolerable intake level (UL) for vitamin E (alpha-tocopherol) at 1,500 IU per day, which “is the highest dose unlikely to result in bleeding problems;” though the Institute has also said that the danger of the vitamin inhibiting clotting was not convincing. In other words, taking about four times the most common strength of even a hi-potency vitamin E capsule might be a problem in terms of affecting clotting, but this potency is higher than is available as a dietary supplement and one that people are unlikely to try without specific medical advice. Yet, somehow, the far more common danger of a vitamin E deficiency was completely ignored. This, despite the fact that, according to dietary data from the National Health and Nutrition Examination Surveys, ninety percent or more of the adults studied had usual intakes below the current Estimated Average Requirement. Why is a theoretical overdose problem even mentioned in the report, especially with no balancing mention of known deficiencies and benefits? What happened to fair and balanced reporting? And what are the benefits of vitamin E supplementation? An NIH-supported USDA -Tufts University study published in the medical journal JAMA reported, “…we observed a protective effect of vitamin E supplementation on upper respiratory tract infections, particularly the common cold,” for nursing home patients taking 200 IU of vitamin E daily. And Annals of the New York Academy of Sciences reported that, “The results of this clinical trial show that vitamin E supplementation significantly reduces the incidence rate of common colds and the number of subjects who acquire a cold among elderly nursing home residents.” Zinc was also mentioned in the FOX report as a possible overdose candidate, but levels required to reach the negative side effects mentioned are between 150-450 mg per day, again requiring a consumer to take several capsules to achieve this. The highest potency I have ever seen (in 35 years) was 75 mg, though 15-50 mg products are relatively common. Yet the median intake among American adults is just over 2/3 of the Daily Value, making deficiencies far more common than overdoses. Again, the FOX report ignored the common, greater danger in favor of sensationalizing a remote possibility of overdosing. Zinc is essential for many biochemical reactions in the body, and is most notably associated with immune function and wound healing. Yet isn’t FOX essentially warning people against taking zinc, hinting that they may be in danger but without any hint of the true risks and benefits? A dietician in the report stated that there is no proof that taking extra vitamin C shortens or prevents colds. That should come as news to the researchers at the University of Pittsburgh Medical Center. Publishing results of a Review Study in the medical journal American Family Physician in February 2007, these physicians reported that, “Thirty trials involving 9,676 cold episodes showed a statistically significant decrease in illness duration with vitamin C taken before onset of symptoms…. Likewise, 15 trials involving 7,045 cold episodes demonstrated a decrease in severity scores and in days confined to the home.” While there is some little evidence (not none) that vitamin C can prevent the incidence of colds, there is significant evidence that it can shorten the duration and severity of colds. Don’t you think that the FOX report is irresponsible by highlighting rare nutrient overdoses while ignoring common deficiencies? Also, why would one person’s opinion that vitamin C is worthless against colds trump the collective evidence of 30 clinical studies that met the strict criteria of a review study? Given these gross errors, I suggest that FOX assigns fact-checkers to review all medical and health reports. Let’s put an end to the flawed practice of naively taking the word of health professionals who appear not be up-to-date on what’s published in the medical literature. This is most important when demonstrably false blanket statements are made that inappropriately dismiss the safety and efficacy of essential nutrients that are known to be deficient in most Americans’ diets. REFERENCES: http://www.myfoxchicago.com/myfox/pages/Home/Detail;jsessionid=BF06BF0BCA71AE327C05A6BA65DEB517?contentId=5757535&version=2&locale=EN-US&layoutCode=VSTY&pageId=1.1.1&sflg=1 Vitamin E Fact Sheet NIH Office of Dietary Supplements Zinc Fact Sheet NIH Office of Dietary Supplements “Thirty trials involving 9,676 cold episodes showed a statistically significant decrease in illness duration with vitamin C taken before onset of symptoms: an 8 percent decrease (95% confidence interval [CI], 3 to 13 percent) in adults and a 13.5 percent decrease (95% CI, 5 to 21 percent) in children. Likewise, 15 trials involving 7,045 cold episodes demonstrated a decrease in severity scores and in days confined to the home. Vitamin C did not decrease the incidence of cold in the general population. However, a subgroup of six trials involving runners, skiers, and soldiers participating in subarctic exercises demonstrated a 50 percent relative reduction in the risk of developing a cold (95% CI, 32 to 62 percent).” Simasek M, Blandino DA. Treatment of the common cold. Am Fam Physician. 2007 Feb 15;75(4):515-20. Review. PMID: 17323712 [PubMed - indexed for MEDLINE]. Hathcock JN, et al. Vitamins E and C are safe across a broad range of intakes. Am J Clin Nutr. 2005 Apr;81(4):736-45. Review. PMID: 15817846 [PubMed - indexed for MEDLINE] Dial S, Eitenmiller RR. 1995. Tocopherols and tocotrienols in key foods in the U.S. diet. In: Ong ASH, Niki E, Packer L, eds. Nutrition, Lipids, Health, and Disease. Champaign, IL: AOCS Press. Pp. 327–342. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000). Institute of Medicine JASPREET K.C. AHUJA, JOSEPH D. GOLDMAN, and ALANNA J. MOSHFEGH. Current Status of Vitamin E Nutriture. Ann NY Acad Sci 2004 1031: 387-390. Erwin RB, et al. Dietary intake of selected minerals for the United States population: 1999-2000. Adv Data. 2004 Apr 27;(341):1-5. PMID: 15114720 [PubMed - indexed for MEDLINE] Meydani SN, et al. Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial. JAMA. 2004 Aug 18;292(7):828-36. Erratum in: JAMA. 2004 Sep 15;292(11):1305. JAMA. 2007 May 2;297(17):1882. PMID: 15315997 [PubMed - indexed for MEDLINE] Meydani SN, Han SN, Hamer DH. Vitamin E and respiratory infection in the elderly. Ann N Y Acad Sci. 2004 Dec;1031:214-22. Review. PMID: 15753147 [PubMed - indexed for MEDLINE]

Response to NPR report on supplements and colds

Stress, Nutrition and Colds By Neil E. Levin, CCN, DANLA, January 11, 2007 The NPR Morning Edition story airing today called “Low-Stress Life May Be Best Way to Prevent Colds” has some contradictions and inaccuracies. While I can’t defend the “Airborne” formula, which has non-standardized herbs and non-natural ingredients and was developed by a teacher rather than a nutritionist, some of the statements about dietary supplements made in the report are simply inaccurate. One is the purported lack of connection between boosting the immune system and preventing or treating the common cold or flu, reporting the views of one skeptical medical researcher. In fact, there are many hundreds of published clinical studies showing specific mechanisms by which various dietary supplements can improve immune cell function. A review of the published science on zinc in the Journal of Environmental Pathology and Toxicology stated that “[zinc] fulfills an immune function.” The Journal of Applied Microbiology and Biotechnology published a review reporting that, “Garlic has a wide spectrum of actions; not only is it antibacterial, antiviral, antifungal and antiprotozoal, but it also has beneficial effects on the cardiovascular and immune systems.” Alternative Medicine Review recently published a review of the literature on the effects of herbs on the immune system, reporting, “The in vitro and in vivo research demonstrates that the reviewed botanical medicines modulate the secretion of multiple cytokines.” [immune cells] And the journal Autoimmunity bluntly reported on Echinacea’s positive effect on Natural Killer immune cells, indicating that Echinacea may even provide a new treatment for Type 1 Diabetes: “the fact that the herb, Echinacea, is a well demonstrated immunostimulant of NK cells in normal mice/humans,” and concluding that “The results revealed that, in NOD mice, dietary Echinacea…actually stimulated NK cell production in their bone marrow birth site.” Another mistaken claim is that “most people get plenty of that [Vitamin C] in their diet. Yet according to dietary data from the National Health and Nutrition Examination Survey, “We conclude that despite NHANES III data indicating a small increase in the median dietary vitamin C ingestion in the USA, a substantial fraction of the population still ingests vitamin C at or below the Recommended Dietary Allowance.” The RDA is only 60 mg a day. This links to another part of the report that links stress to a two-fold increase in colds. Vitamin C aids adrenal function, with that gland being the most prominent player in stress response. Vitamin C levels in the adrenal gland are reported to be as great as 150 times the general levels in the bloodstream. Of course, if people don’t get enough in the diet and are under stress, that easily explains the vitamin C connection. The report also stated that some formulas contain, “herbs such as Echinacea, which, although very popular, has been shown by the best scientific studies not to work.” Yet recent negative reports have been challenged by the non-profit American Botanical Council (ABC) as not using commercially available preparations and using lower doses less frequently than commonly and previously used in positive studies. Another criticism is that some studies used college students that typically have better immune system functioning than elderly people. ABC Executive Director Mark Blumenthal said in response to one recent study that, “This is not a definitive trial on the efficacy of echinacea, nor should the results be generalized to echinacea preparations widely available. Unfortunately, the conclusion that may be drawn by some media who report this study may state that ‘echinacea is ineffective,’ but this would be an incorrect conclusion based on the design of this study and the evidence in the existing literature.” A meta-analysis of previously published studies on echinacea was published in the journal Clinical Therapeutics, with the conclusion, “Based on the analysis, the likelihood of experiencing a clinical cold was 55% higher with placebo than with Echinacea.” Another published review says that, “Numerous clinical trials have been carried out on echinacea preparations: it appears that the extracts shorten the duration and severity of colds and other upper respiratory infections (URIs) when given as soon as symptoms become evident.” The NPR report also questions the ability of the mineral zinc to reduce colds. Yet a report by the physician-reviewed health education group A.D.A.M. (http://www.adam.com/) states, “Several important studies have revealed that zinc lozenges may reduce the intensity of the symptoms associated with a cold, particularly cough, and the length of time that a cold lingers.” Such misleading statements in a health report may lead people to think that there are no dietary supplements that can correct deficiencies and imbalances which, combined with stress, may lead to impaired immune function. But science shows that the opposite may be true: dietary supplements have a solid role in immunity and health. Neil Levin is a board certified clinical nutritionist who is a product formulator and the nutrition educator for NOW Foods, a manufacturer of dietary supplements. His nutrition blog is available at http://www.honestnutrition.com/ REFERENCES: Link to original NPR report: http://www.npr.org/templates/story/story.php?storyId=6797207 Frassinetti S, Bronzetti G, Caltavuturo L, Cini M, Croce CD. The role of zinc in life: a review. J Environ Pathol Toxicol Oncol. 2006;25(3):597-610. Review. PMID: 17073562 Harris JC, Cottrell SL, Plummer S, Lloyd D. Antimicrobial properties of Allium sativum (garlic). Appl Microbiol Biotechnol. 2001 Oct;57(3):282-6. Review. PMID: 11759674 Spelman K, Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M. Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators. Altern Med Rev. 2006 Jun;11(2):128-50. Review. PMID: 16813462 Schoop R, Klein P, Suter A, Johnston SL. Echinacea in the prevention of induced rhinovirus colds: a meta-analysis. Clin Ther. 2006 Feb;28(2):174-83. Review. PMID: 16678640 Block KI, Mead MN. Immune system effects of echinacea, ginseng, and astragalus: a review. Integr Cancer Ther. 2003 Sep;2(3):247-67. Review. PMID: 15035888 Delorme D, Miller SC. Dietary consumption of Echinacea by mice afflicted with autoimmune (type I) diabetes: effect of consuming the herb on hemopoietic and immune cell dynamics. Autoimmunity. 2005 Sep;38(6):453-61. PMID: 16278152 Herbal Science Group Says Dosage Too Low in New Echinacea Trial http://www.herbalgram.org/default.asp?c=echinacea072605 Patak P, Willenberg HS, Bornstein SR. Vitamin C is an important cofactor for both adrenal cortex and adrenal medulla. Endocr Res. 2004 Nov;30(4):871-5. Review. PMID: 15666839 Kurugol Z, Akilli M, Bayram N, Koturoglu G. The prophylactic and therapeutic effectiveness of zinc sulphate on common cold in children. Acta Paediatr. 2006 Oct;95(10):1175-81. PMID: 16982486 Hulisz D. Efficacy of zinc against common cold viruses: an overview. J Am Pharm Assoc (Wash DC). 2004 Sep-Oct;44(5):594-603. Review. PMID: 15496046