American Journal of Medicine, internal medicine, medicine, health, healthy lifestyles, cancer, heart disease, drugs

Nutraceuticals: Evidence of Benefit in Clinical Practice?

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Nutraceuticals, according to Wikipedia, are food substances or nutritional supplements that have beneficial effects on health. They are not usually considered to be part of a normal diet, such as fruit, vegetable, fish, and meat. Rather, they are additives, usually derived from plants, which are said to be beneficial at preventing or treating illnesses. The term nutraceutical, derived from a combination of the words nutrition and pharmaceutical, was invented in 1989 by Stephen L. DeFelice, founder and chairman of the nonprofit Foundation of Innovation Medicine. DeFelice is an MD with an extensive academic career in clinical pharmacology. He founded the Foundation of Innovation Medicine as a means to accelerate medical discovery by encouraging the performance of well-designed clinical trials involving various compounds, including those from plants and animals. Compounds to be tested range from isolated nutrients, for example vitamins and/or amino acids, to dietary supplements, herbal products, specific diets, and various processed foods. The aim of these trials would be to define whether some of these products actually have clinically beneficial properties.

The history of Western medicine describes the use of a number of remedies using nutraceuticals, such as herbs, animal parts, and materials from natural sources until last century. Today most prescription drugs contain one active ingredient or one molecular entity, with most of these molecular entities being small molecule organic compounds. Many currently used pharmaceutical agents were first isolated from natural sources after the identification of active ingredients. Examples include aspirin from willow tree bark, digitalis from the foxglove plant, morphine from opium poppies, streptomycin from soil microbes, and daunorubicin from Streptomyces, as well as many others. Although nutraceuticals remain a source of single molecule active ingredients, it is more likely that a combination of molecules within these naturally occurring agents act in synergy if they do indeed have beneficial properties for human health.

A major factor limiting physician enthusiasm for nutraceuticals, in addition to inadequate clinical trial data, is that these agents lack US Food and Drug Administration (FDA) regulation and can be contaminated with toxins and in some cases adulterated with actual prescription drugs. Furthermore, there is the technical challenge of defining qualitatively or quantitatively the components that are contained in a specific nutraceutical. Although the nutritional supplement industry is a very big business in the United States, accounting for billions of dollars per year in sales, it is not a high earning segment of our economy when contrasted, for example, with the major global pharmaceutical corporations. Consequently, funding for evidence-based clinical trials for nutraceuticals is sorely lacking. In the United States, nutraceuticals are not recognized as legitimate pharmacologic agents, and hence are unregulated by the FDA. When sold over the counter in health food stores, supermarkets, and pharmacies, the labeling for these agents must not claim efficacy in treating disease. Labeling is controlled by the FDA to contain the following sentence: “These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.” Unlike vitamin supplements or pharmaceutical products, defining the components and the quantitation of key components in nutraceuticals is a challenge. With improvements in current assay technologies, such as mass spectrometry-based simultaneous measurements of multiple molecules, one would hope that the various molecular ingredients in many nutraceutical products could be defined, thereby aiding investigators in the conduct of evidence-based clinical trials.

Despite the lack of scientific evidence for or against the use of these products, they continue to be widely ingested throughout the world. Traditional Chinese medicine, for example, uses a variety of herbal and animal products to treat or prevent a wide range of diseases. Let us examine one of these products with worldwide sales exceeding 2 billion dollars per year. Lingzhi is a Ganoderma mushroom that contains a number of potential biologically active compounds, including some that resemble steroids and others that are sterols and polysaccharides. This nutraceutical has been widely used in China and throughout Asia for more than 2000 years as a therapeutic agent for enhancing health, strengthening immunity, and increasing longevity. The English translation of its name says a great deal about the respect accorded this product: Ling in Chinese means spirit, spiritual, or soul, whereas zhihas been variously translated as mushroom, fungus, or plant. This plant has been referred to numerous times in ancient and modern Chinese literature where it has, at times, been called the “divine mushroom” and the “immortality plant” among other auspicious names. Because of its rarity in nature, it is considered to be one of the most valuable Chinese medicines, and consumers are willing to pay high prices for pills containing Lingzhi.

There have been a number of basic scientific investigations involving extracts of this mushroom and its effects on mammalian cellular function in tissue culture and in vivo experiments using mice and rats. In cellular and animal models, these extracts have shown anticonvulsant, antioxidant, antitumor, and anti-inflammatory effects, as well as immune system enhancement. The positive nature of these animal and cellular experiments suggests that clinical investigation should be carried out with this ancient herbal remedy.

Clinical studies are unfortunately few in number. The worldwide clinical trial registry (ClinicalTrials.gov) shows a total of 6 clinical trials, with 3 completed for conditions ranging from active pediatric cancers to rheumatoid arthritis and Parkinson’s disease, as well as to support breast cancer patients after chemotherapy. Finally, this agent has been used to improve general physical fitness. However, a Medline title search for Lingzhi found only 3 randomized controlled clinical studies. One trial involved 32 patients with active rheumatoid arthritis who were treated with a combination of Lingzhi and a second herbal agent. The conclusion from this trial was that “no significant antioxidant, anti-inflammatory or immunomodulation effect” was observed. A second controlled clinical trial involved 26 patients with borderline elevations of blood pressure and/or cholesterol. The conclusion from this study was that “Lingzhi might have a mild antidiabetic effect.” The third controlled trial recruited 18 healthy individuals to determine the effect of Lingzhi on a range of biomarkers of antioxidant activity. The authors concluded that there were no significant changes in any of the variables; however, they did observe a slight trend toward lower lipids and increased antioxidant capacity in the urine.

A search of the National Institutes of Health–sponsored PubMed website turned up 2 Cochrane reviews involving meta-analyses performed on the limited number of studies done to explore the therapeutic potential of Lingzhi. There were a modest number of clinical trials that sought to reduce cardiovascular risk factors and a small number of trials assessing this agent as an adjunct to cancer chemotherapy. The meta-analyses of the cardiovascular trials were negative: blood glucose, blood pressure, and blood lipid levels were unaffected. However, the cancer trials did show some modest benefit when the mushroom was administered together with standard chemotherapy. It is difficult to be conclusive with respect to any clinical therapeutic benefit given the small size of the clinical trials performed at this time. In addition, the quality of a number of these clinical trials was not considered to be optimal. Therefore, despite widespread use of Lingzhi, several small randomized, controlled trials or meta-analyses demonstrated no significant health benefits of Lingzhi.

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-Qin M. Chen, PhD, Joseph S. Alpert, MD (Editor in Chief, The American Journal of Medicine)

This article originally appeared in the September 2016 issue of The American Journal of Medicine.

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