Draft Monographs of Glucosamine, Melatonin, Saw Palmetto Online

WASHINGTON--The Committee on the Framework for Evaluating the Safety of Dietary Supplements, under the National Academy of Sciences, released three of the four remaining prototype monographs Jan. 15. (The fourth, on chromium picolinate, will be released Jan. 17). These four monographs are the last in a series of six prototypes that were developed to test the principles behind the Proposed Framework for Evaluating the Safety of Dietary Supplements Report, released July 24, 2002.

Within the glucosamine monograph, the alternative forms (D-Glucosamine hydrochloride, D-Glucosamine sulfate, N-Acetyl-glucosamine and Glucosamine hydroiodide), preparations (tablets, capsules, caplets, powders and liquids) and dosages (500 mg/d to 2,000 mg/day) were some of the information discussed.

The incidence of adverse events for glucosamine ranged from none to 94 percent, with the number of adverse events almost identical to those taking placebo. In trials comparing the amino monosaccharide compound to NSAIDs, event rates were consistently higher among those taking NSAIDs.

Other adverse events included those noted in a case series consisting of 10 out of more than 200 patients that were followed while taking glucosamine and/or chondroitin supplements. Clinical syndromes included photosensitization, hypertension and proteinuria (excess excretion of protein in the urine). There was also one case study in which a patient developed renal dysfunction, possibly due to glucosamine interacting with the person's medication (cyclosporine).

Even though glucosamine, as a single ingredient or in combination with other ingredients, is commonly marketed to consumers for joint health, the monograph outlined several in vitro studies demonstrating its beneficial effects on beta cell function and insulin secretion.

In terms of processing issues, the draft monograph's authors reported that the quality of glucosamine may not be consistent from batch to batch, as experienced by investigators at the National Institutes of Health sourcing the supplement for a clinical trial; in the end, they had to manufacture these drugs themselves.

More on this monograph can be found at www.iom.edu/iom/iomhome.nsf/WFiles/Glucosamine/$file/Glucosamine.Draft.monograph.pdf.

Another monograph covered the hormone melatonin, available in a variety of forms, including immediate-release, sustained-release, sublingual and liquid preparations. From an overview of products on the market today, melatonin most often comes in the form of a single-ingredient dietary supplement or in combination with other dietary supplement ingredients (i.e., vitamin B6, zinc picolinate). The typical amount suggested for melatonin intake on manufacturers' labels is between 0.5-10 g/d. However, the monograph authors noted, "Since endogenous melatonin is considered a hormone, a 20-fold range for the amount to be ingested is unusual. Typically, a consumer seeking assistance in falling asleep more quickly might ingest 1 mg of melatonin on a daily basis, being careful to ingest the supplement at the appropriate time of day, usually in the evening (0.5 to 1 hour before bedtime)."

The primary adverse events associated with melatonin intake include headache, confusion/agitation, depression and alterations in the levels of other hormones. However, these effects are most evident with large doses of melatonin (i.e., 5 mg/d to 1 g/d). Less toxicity was noted at lower intake levels (0.5 mg/d to 1 mg/d).

The hormone seems to have drug interactions, including those with the anti-depressant fluvoxamine, and with sedating and antipsychotic drugs such as haloperidol, phenothiazines and benzodiazepines. Melatonin is also an antagonist of calcium channel blockers (used for heart health).

There was evidence that melatonin doses of 10 mg or less per day may cause adverse events of the cardiovascular (i.e., hypertension, hypotension), gastrointestinal (i.e., autoimmune hepatitis, constipation) and central nervous systems (i.e., seizures, nightmares). In animal studies, the hormone has been found to affect testicular health. Melatonin supplementation may also make symptoms of depressive disorders worse.

The monograph authors noted that although the hormone was once animal sourced, dietary supplements use the synthetic form, suggesting "that the consumer should easily be able to obtain safe and consistent products containing melatonin."

Currently, melatonin in single-ingredient products is marketed for jet lag, depression, seasonal affective disorder, cardiovascular disease, hypertension and, occasionally, for migraine and episodic cluster headaches.

More on this monograph can be found at www.iom.edu/iom/iomhome.nsf/WFiles/Melatonin/$file/Melatonin.Draft.monograph.pdf.

The monograph on saw palmetto reported the extracts of this fruit are commonly categorized as hexane-extractable (i.e., phytosterols, phenolic components), ethanol-extractable (i.e., flavonoid components, phenolic glycosides) or water-soluble (i.e., polysaccharides). The monograph's authors noted the hexane extract of saw palmetto fruit is the preparation that has been used most commonly in clinical trials. In data gathered from numerous clinical trials, the monograph indicated a typical dose of saw palmetto for treating benign prostatic hyperplasia (BPH) is 320 mg/d.

Adverse events associated with the herb are mild and occur at a rate similar to placebo. There was one case report of a serious adverse event that may have been associated with saw palmetto; during brain surgery, a patient experienced excess bleeding. However, this appears to be atypical. Also, no significant drug interactions have been reported for use of saw palmetto.

In vitro studies on saw palmetto indicate the herb inhibits muscle contraction, androgen-dependent proliferation and cellular stimulation, and induces apoptosis--which are factors in prostate health and even prostate cancer.

Interestingly, the monograph's authors wrote that several of the substances functionally related to saw palmetto extract are contraindicated for use in women, especially in women who are pregnant or may become pregnant during exposure to the extract. Although the herb has not been extensively studied in women, the proposed biological activities for saw palmetto may have deleterious effects on the external genitalia and internal reproductive organs of the male fetus.

Currently, preparations of saw palmetto fruit are marketed to consumers for prostate and urinary health in men and for urinary function in mature men. Occasionally, saw palmetto is marketed to women (for urinary function, milk production during lactation or, rarely, breast enlargement).

More on this monograph can be found at www.iom.edu/iom/iomhome.nsf/WFiles/SawPalmetto/$file/SawPalmetto.Draft.monograph.pdf.

"At this point, no safety conclusions have been drawn, but these drafts weren't meant to have had any," said Phil Harvey, Ph.D., director of science and quality assurance at the National Nutritional Foods Association (NNFA). "My take on these monographs is that they are preliminary and extensive literature reviews, and quite neutral in balance when pooling all of the information together." He added, "These monographs have information that will benefit suppliers and those in the scientific community."

Written comments regarding these draft monographs can be sent via the Internet no later than Jan. 28 to Marilee Shelton or Allison Yates (www4.nas.edu/iom/fnbcomment.nsf/comment?openform).