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Common Oversights and Shortcomings in the Study and Implementation of Nutritional Supplementation

By Alex Vasquez, ND, DC, Editor

An impressive discrepancy often exists between the low efficacy of nutritional interventions reported in the research literature and the higher efficacy achieved in the clinical practices of clinicians trained in the use of interventional nutrition (i.e., naturopathic physicians).

This discrepancy is dangerous for at least two reasons. First, it results in an undervaluation of the efficacy of nutritional supplementation, which ultimately leaves otherwise treatable patients untreated. Second, such untreated and undertreated patients often are forced to use dangerous and expensive pharmaceutical drugs and surgical interventions to treat conditions that could have otherwise been easily and safely treated with nutritional supplementation and diet modification. Consequently, the burden of suffering, disease and health care expense in the U.S. is higher than it would be if nutritionally trained clinicians were more fully integrated into the health care system.

Obstacles to Efficacy in the Use of Nutritional Supplementation

Listed below are some of the most common causes of the underachievement of nutritional supplementation in practice and in published research. While this list is not all-inclusive, it will serve as a review for clinicians and an introduction for naturopathic students. In both practice and research, the problems listed below often overlap and function synergistically to reduce the efficacy of nutritional supplementation.

  1. Inadequate dosing (quantity): Many clinical trials published in major journals and many doctors in clinical practice use inadequate doses of vitamins (and other natural therapeutics), and thus fail to achieve the results that would easily have been obtained had they implemented their protocol with the proper physiologic or supraphysiologic dose of intervention. The best example in my experience centers on vitamin D, where so many of the studies are performed with doses of 400-800 IU per day, only to conclude that vitamin supplementation is ineffective for the condition being treated. The problem here is that the researchers failed to appreciate that the physiologic requirement for vitamin D3 in adults is approximately 3,000-5,000 IU per day,1 and that therefore, their supplemental dose of 400-800 IU is only 10 percent to 20 percent of what is required. Subphysiologic doses generally are subtherapeutic. In this regard, I have had to correct journals such as The Lancet,2 JAMA3 and British Medical Journal4 from misleading their readers (many of whom are major policy-makers) from concluding that nutritional supplementation is impotent. Rather, their researchers and editors were not sufficiently educated in the design and review of studies using nutritional interventions. These journals should hire naturopathic physicians so they have staff trained in natural treatments and who can thus provide an educated review of studies on these topics.5

  2. Inadequate dosing (duration): The effects of long-term nutritional deficiency often are not fully reversible and/or may require a treatment period of months or years to achieve maximal clinical response. For example, full replacement of fatty acids in human brain phospholipids is an ongoing process that occurs over a period of several years. Thus, studies using fatty-acid supplements for a period of weeks or two-to-three months generally underestimate the enhanced effectiveness that can be obtained with administration over many months or several years of treatment. Relatedly, recovery from vitamin D deficiency takes several weeks of high-dose supplementation in order to achieve tissue saturation and subsequent cellular replenishment. Studies of short duration are destined to underestimate the results that could have been achieved with supplementation carried out over several months.6

  3. Failure to use proper forms of nutrients: Nutrients often are available in different forms, not the least of which are “active” versus “inactive” and “natural” versus “unnatural.” Most vitamin supplements, particularly high-potency B vitamins, are manufactured synthetically and are not from “natural sources,” despite the marketing hype promulgated by companies that, for example, mix their synthetic vitamins with a vegetable powder and then call their vitamin supplements “natural.” The simple fact is that production of high-potency supplements from purely natural sources would be prohibitively wasteful, inefficient and expensive. Thus, while it is not necessary for vitamins to be “natural” in order to be useful, it is necessary that the vitamins are useable and preferably not “unnatural.”
    The best example of the use of unnatural supplements is the use of synthetic DL-tocopherol in the so-called “vitamin E” studies; DL-tocopherol is, by definition, 50 percent comprised of the L-isomer of tocopherol, which is not only unusable by the human body, but actually is harmful in that it interferes with normal metabolism, and can exacerbate hypertension and cause symptomatic complications (e.g., headaches). Further, tocopherols exist within the body in relationship with the individual forms of the vitamin, such that supplementation with one form (e.g., alpha-tocopherol) can result in a relative deficiency of another form (e.g., gamma-tocopherol). One final example of the failure to use proper forms of nutrients is in the use of pyridoxine HCl as a form of vitamin B6. While this practice itself is not harmful, clinicians need to remember that pyridoxine HCl is ineffective until converted to the more active forms of the vitamin, including pyridoxal-5-phosphate. Since this conversion requires co-nutrients such as magnesium and zinc, we easily can see that the reputed failure of B6 supplementation when administered in the form of pyridoxine HCl actually might be due to untreated insufficiencies of required co-nutrients, as discussed in the following section.

  4. Failure to ensure adequacy of co-nutrients: Vitamins, minerals, amino acids and fatty acids work together in an intricately choreographed and delicately orchestrated dance that culminates in the successful completion of interconnected physiologic functions. If any of the performers in this event is missing (i.e., nutritional deficiency) or if successive interconversions are impaired due to lack of enzyme function, then the show cannot go on; or if it does go on, impaired metabolism and defective function will result. So, if we take a patient with “vitamin B6 deficiency” and give them vitamin B6 in the absence of other co-nutrients needed for the proper activation and metabolic utilization of vitamin B6, we cannot honestly expect the “nutritional supplementation” to work in this case. Rather, we might see a marginal benefit or perhaps even a negative outcome as an imbalanced system is pushed into a different state of imbalance, despite supplementation with the “correct” vitamin. In the case of vitamin B6, necessary co-nutrients include zinc, magnesium, and riboflavin. Deficiency of any of these will result in a relative “failure” of B6 supplementation, even if a patient has a B6-responsive condition. Notably, overt magnesium deficiency is alarmingly common among patients and citizens in industrialized nations.7-9 This epidemic of magnesium deficiency is due not only to insufficient intake, but also to excessive excretion caused by consumption of high-glycemic foods, caffeine and a diet that promotes chronic metabolic acidosis with resultant urinary acidification.

  5. Failure to achieve urinary alkalinization: Western/American-style diets typified by overconsumption of grains, dairy, sugar and salt result in a state of subclinical, chronic metabolic acidosis, which results in urinary acidification, relative hypercortisolemia and consequent hyperexcretion of minerals such as calcium and magnesium.10-11 Thus, the common conundrum of magnesium replenishment requires not only magnesium supplementation, but also dietary interventions to change the internal climate to one that is conducive to bodily retention and cellular uptake of magnesium.12

  6. Use of mislabeled supplements: Even in the professional arena of nutritional supplement manufacturers, some companies habitually underdose their products, either in an attempt to spend less in the manufacture of their products or as a consequence of poor quality control. If a product is labeled to contain 1,000 IU of vitamin D, but only contains 836 IU of the nutrient, then obviously, full clinical efficacy will not be achieved. This was a problem in a recent clinical trial involving vitamin D.1 The problem for clinicians is in trusting the companies that supply nutritional supplements; some companies do “in-house” testing, which lacks independent review, while other companies use questionable “independent testing,” which is not infrequently performed by a laboratory that is a wholly owned subsidiary of the parent nutritional company. Manufacturing regulations that are sweeping through the industry will cleanse the nutritional supplement world of poorly made products, and these same regulations will sweep some unprepared companies right out the door when they are unable to meet the regulatory requirements.

  7. Assurance of bioavailability and optimal serum/cellular levels: Clinical trials with nutritional therapies need to monitor serum or cellular levels to ensure absorption, product bioavailability and the attainment of optimal serum levels. This is particularly relevant in the treatment of chronic disorders such as the autoimmune diseases, wherein so many of these patients have gastrointestinal dysbiosis and often have concomitant nutrient malabsorption.13 Simply dosing these patients with supplements is not always efficacious; often the gut must be cleared of dysbiosis so the mucosal lining can be repaired and optimal nutrient absorption can be re-established.

  8. Co-administration of food with nutritional supplements (sometimes right, sometimes wrong): Food can help or hinder the absorption of nutritional supplements. Some supplements, such as coenzyme Q10, should be administered with fatty food to enhance absorption. Other supplements, such as amino acids, should be administered away from protein-rich foods and often are better administered with simple carbohydrate to enhance cellular uptake. This especially is true with tryptophan.

  9. Correction of gross dietary imbalances enhances supplement effectiveness: If the diet is grossly imbalanced, nutritional supplementation is less likely to be effective. The best example of this is in the use of fatty-acid supplements, particularly in the treatment of inflammatory disorders. If the diet is laden with dairy, beef and other sources of arachidonate, then fatty acid supplementation with EPA, DHA and GLA is much less likely to be effective, or much higher doses of the supplements will need to be used to help restore fatty acid balance. Generally speaking, the diet needs to be optimized to enhance the efficacy of nutritional supplementation.

In this brief review, I have listed and discussed some of the most common impediments to the success of nutritional supplementation. I hope naturopathic students, clinicians and researchers will find these points helpful in their design of clinical treatment protocols.


  1. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr, 2003 Jan;77(1):204-10.
  2. Vasquez A. “Subphysiologic Doses of Vitamin D Are Subtherapeutic: Comment on the Study by The Record Trial Group.” The Lancet, 2005 Published online May 6.
  3. Muanza DN, Vasquez A, Cannell J, Grant WB. “Isoflavones and Postmenopausal Women” [letter]. JAMA, 2004;292:2337.
  4. Vasquez A, Cannell J. “Calcium and vitamin D in Preventing Fractures: Data Are Not Sufficient to Show Inefficacy” [letter]. BMJ, 2005;331:108-9. Click to view it online.
  5. Vasquez A. “Allopathic Usurpation of Natural Medicine: The Blind Leading the Sighted.” Naturopathy Digest, 2006 Feb.
  6. Vasquez A, Manso G, Cannell J. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers. Altern Ther Health Med., 2004 Sep-Oct;10(5):28-36. Click to view it online.
  7. “Altogether 43% of 113 trauma patients had low magnesium levels compared to 30% of noninjured cohorts.” Frankel H, Haskell R, Lee SY, Miller D, Rotondo M, Schwab CW. Hypomagnesemia in trauma patients. World J Surg, 1999 Sep;23(9):966-9.
  8. “There was a 20% overall prevalence of hypomagnesemia among this predominantly female, African American population.” Fox CH, Ramsoomair D, Mahoney MC, Carter C, Young B, Graham R. An investigation of hypomagnesemia among ambulatory urban African Americans. J Fam Pract, 1999 Aug;48(8):636-9.
  9. “Suboptimal levels were detected in 33.7 per cent of the population under study. These data clearly demonstrate that the Mg supply of the German population needs increased attention.” Schimatschek HF, Rempis R. Prevalence of hypomagnesemia in an unselected German population of 16,000 individuals. Magnes Res, 2001 Dec;14(4):283-90.
  10. Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O’Keefe JH, Brand-Miller J. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr, 2005 Feb;81(2):341-54.
  11. Maurer M, Riesen W, Muser J, Hulter HN, Krapf R. Neutralization of Western diet inhibits bone resorption independently of K intake and reduces cortisol secretion in humans. Am J Physiol Renal Physiol, 2003 Jan;284(1):F32-40.
  12. Vormann J, Worlitschek M, Goedecke T, Silver B. Supplementation with alkaline minerals reduces symptoms in patients with chronic low back pain. J Trace Elem Med Biol, 2001;15(2-3):179-83.
  13. Vasquez A. “Reducing Pain and Inflammation Naturally. Part 6: Nutritional and Botanical Treatments Against “Silent Infections” and Gastrointestinal Dysbiosis, Commonly Overlooked Causes of Neuromusculoskeletal Inflammation and Chronic Health Problems.” Nutritional Perspectives, 2006 Jan. Click to view it online.

About the Author: Dr. Alex Vasquez is a 1999 graduate of Bastyr University, where he later taught rheumatology, orthopedics, and radiographic interpretation. He is the author of two textbooks: Integrative Orthopedics and Integrative Rheumatology. He is also a researcher and lecturer for Biotics Research Corporation and has authored more than 50 articles and letters in various peer-reviewed journals. Dr. Vasquez currently practices in Fort Worth, Texas.

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Date Last Modified - Friday, 17-Oct-2008 12:11:06 PDT