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Dietary Supplements: A Framework for Evaluating Safety Appendix E Glucosamine: Prototype Monograph Summary1 V. SUMMARY AND CONCLUSIONS A. Summary Glucosamine is an amino monosaccharide that is derived from cellular glucose metabolism and is also found in the body as a simple component of cartilage macromolecules. Glucosamine is widely used as a dietary supplement for chronic joint pain, often recommended at amounts of 500 to 2,000 mg/day. In humans glucosamine has been tested against placebo or nonsteroidal anti-inflammatory drugs (NSAIDs) in 11 randomized, double-blind, 1 This is a summary of a prototype monograph, prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format described in this report. While it was prepared as a prototype using the processes described in the report, it was not conducted under the auspices of the Food and Drug Administration utilizing all the resources available to the agency. Thus some pertinent information not available to the Committee could be of importance in evaluating safety to determine if use of this dietary supplement ingredient would present an unreasonable risk of illness or injury. Also, the development and review of this prototype was conducted by individuals whose backgrounds are in general aspects of evaluating science and whose expertise is not necessarily focused specifically on this dietary ingredient, although significant additional assistance was provided by consultants with relevant expertise. Therefore, this protoype monograph, while extensive, does not represent an authoritative statement regarding the safety of this dietary supplement ingredient. The full prototype monograph and its data tables on glucosamine may be accessed at http://www.iom.edu/fnb.
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Dietary Supplements: A Framework for Evaluating Safety placebo-control (7 studies) or reference-control (4 studies) clinical trials ranging in duration from 1 to 36 months and including a total of 716 participants (in the glucosamine arms). Many of these trials presented incomplete information about the systematic collection of data on adverse effects, and many did not examine or report clinical laboratory values systematically. Many of the trials relied only on passive reporting. In the placebo-controlled trials, the incidence of adverse effects among the treatment arms was almost identical, while in the NSAID comparison trials, adverse effect rates were higher among those taking NSAIDs (range of 15–35 percent). In general, the adverse effects reported were mild and most often related to gastrointestinal complaints. No data are available on the safety of glucosamine use in pregnant or lactating women or in children. Classical animal toxicity studies for glucosamine have not been published; however, reviewers citing only unpublished data state that no toxicity was observed with glucosamine administered by oral administration or by gavage. These findings are corroborated by findings of only minimal toxicity with glucosamine administered by other routes of administration. For glucosamine, as for other substances endogenous to the body, LD50 values could not be determined due to the lack of toxicity observed except when supraphysiologic amounts were administered. Animal studies using infusion of glucosamine in rats at high doses (approaching 1 mM in blood) and in in vitro studies (using the addition of glucosamine to cell-culture media at high concentrations) found that glucosamine inhibited the ability of pancreatic islet cells to increase insulin secretion in response to an increased concentration of glucose. It should be emphasized that these studies were designed to test hypotheses about the intracellular signaling pathways by which glucose exerts its regulatory effects and were not designed to examine the “toxicity” of glucosamine per se. The pharmacokinetics of glucosamine become important to assessing its risk, as discussed below. Orally ingested glucosamine appears to be rapidly absorbed, but it is largely metabolized before it reaches the bloodstream. The primary source of glucosamine in the United States is chitin, derived from shellfish (e.g., shrimp, crab). There may be a risk for antigen exposure if the product is incompletely purified. There is no systematic surveillance of contaminants of these products, and only a subset of the manufacturers apparently comply with U.S. Pharmacopeia (USP) standards. B. Conclusions and Recommendations About the Safety of the Ingredient Based on the Strength of the Scientific Evidence From the evaluation of the available data, there appears to be no evi-
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Dietary Supplements: A Framework for Evaluating Safety dence that use of 1.5 g of glucosamine per day poses a substantial risk in nonpregnant adults. However, given the uncertainty of the minimum glucosamine exposure required for adverse effects on insulin regulation in individuals who are predisposed to glucose regulation problems, glucosamine may present a risk in individuals with, or at risk for, insulin resistance and/or glucose intolerance who ingest it as a dietary supplement for long periods of time. Notably, the available data do not include sufficient studies powered to evaluate safety parameters (e.g., studies measuring relevant blood chemistry parameters following oral administration to animals and humans). These conclusions are therefore based on (1) interpretation of animal and human data indicating that very little intact glucosamine is found in the bloodstream following oral ingestion and thus the secretion problems observed following millimolar blood concentrations in rats would not occur in humans following ingestion,2 and (2) lack of many consistent overt serious effects reported in clinical trials. However, individuals with shellfish allergy should be cautious about use of glucosamine products, many of which are derived from shellfish. C. Unresolved Issues and Uncertainties in the Available Data As mentioned above, few animal or human studies have been designed for evaluating the safety of glucosamine intake. In some studies, data concerning adverse effects was obtained by passive reporting, which is not optimal. The impact of increased glucosamine intake during pregnancy and lactation, especially in the context of insulin resistance, is unknown. The impact of increased glucosamine intake in the individual with liver disease, especially in the context of insulin resistance, is unknown. The impact of increased glucosamine intake in children is unknown. D. Data Gaps and Future Research Recommended The impact of glucosamine on insulin secretion needs further animal and human study at doses relevant to human oral intake. Details of the metabolism of glucosamine are still unclear and, as mentioned above, the conclusions about glucosamine safety are dependent on glucosamine being only minimally bioavailable in the bloodstream. 2 The highest blood concentration possible from ingestion of 1.5 g of glucosamine per day is 1 mM (assuming 7 liters blood volume), assuming no loss due to lack of absorption or metabolism. However, glucosamine does appear to be extensively metabolized.
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Dietary Supplements: A Framework for Evaluating Safety Long-term safety evaluation of glucosamine as a dietary supplement is needed (beyond 3 years of usage). All future trials should have a systematic collection, evaluation, and reporting of adverse events, and key data relevant to addressing the gaps in knowledge should be collected and reported.
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