There were a few landmark studies completed recently that did not find in favor of the nutraceutical ingredients studied. Join us as we take a look at three major studies, the results of which were published in the New England Journal of Medicine.

The last study in this analysis was in fact positive. However, the media pick-up for this information was not nearly as significant as that for the three negative studies.


The New England Journal of Medicine (NEJM) recently released the results of a clinical trial conducted on saw palmetto (Serenoa repens), concluding that it is ineffective for problems associated with benign prostatic hyperplasia (BPH). The study (Bent S. et al. Saw palmetto for benign prostatic hyperplasia. NEJM 354(6):557-566) was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Center for Complementary and Alternative Medicine (NCCAM). According to many of the dietary supplement trade associations, these recent findings are inconsistent with benefits demonstrated by other studies.

Saw palmetto-the third highest-selling herbal dietary supplement in the U.S.-is used by over two million American men for the treatment of mild to moderate symptoms associated with BPH and is commonly recommended as an alternative to drugs. BPH is a non-cancerous swelling of the prostate gland in older men, resulting in various symptoms associated with interruption of normal urinary flow.

The double-blind trial published in NEJM randomly assigned 225 men over the age of 49 years who had moderate-to-severe symptoms of BPH to one year of treatment with saw palmetto extract (160 mg twice daily) or placebo. The primary outcome measures were changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate. Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, quality of life, laboratory values and the rates of reported adverse effects.

The results of the trial showed no significant differences between the saw palmetto and placebo groups in the change in AUASI scores, maximum urinary flow rate, prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen (PSA) levels. Therefore, the study authors concluded that saw palmetto was no more effective than placebo in treating symptoms of BPH.

Various industry groups quickly responded to these findings. They claim that the results of this trial are misleading due to improper controls and other issues. The main flaw many cited was the fact that the study examined men with moderate-to-severe symptoms of BPH, while a majority of previous trials showed positive results and efficacy for saw palmetto among men with mild-to-moderate symptoms.

“Since the study raised the bar from mild-to-moderate symptoms to moderate-to-severe, the researchers should have also had a third arm in the trial testing a higher dosage to see if there was a dose-response relationship at that level,” said Mark Blumenthal, founder and executive director of American Botanical Council (ABC), Austin, TX.

Andrew Shao, PhD, vice president, Scientific & Regulatory Affairs, Council for Responsible Nutrition (CRN), Washington, D.C. also found the results from this study particularly puzzling. “Science is an evolutionary process. Given that more than 20 studies have shown promising findings for saw palmetto in alleviating symptoms commonly associated with prostate problems, such as frequent urination, a low stream of urination, and a feeling of heaviness in the prostate, it is inappropriate to simply discount the benefits previously found.”

Indeed, a recent meta-analysis of 18 clinical trials published in the Journal of the American Medical Association (JAMA) and another on 21 clinical trials carried out on over 3000 men as reviewed by the Cochrane Collaboration have confirmed the safety and efficacy of saw palmetto extract in treating symptoms of BPH, usually of stage 1 and 2 (the mild-to-moderate range of BPH symptoms). The latest meta-analysis also concludes that saw palmetto preparations have shown efficacy and greater safety when compared to conventional pharmaceutical drugs.

ABC pointed out another anomaly of the trial-the significantly higher adverse effect profile in the placebo group. Saw palmetto preparations are known to be safe and very well tolerated, producing few adverse effects. However, there were almost twice as many serious adverse effects in the placebo group (11) as in the saw palmetto group (6), suggesting that the patient population may have had other serious illnesses, possibly interfering in the attempt to treat the BPH symptoms.

Daniel Fabricant, vice president of science and quality assurance, National Nutritional Foods Association (NNFA), Washington, D.C., cited the lack of a positive control (i.e., a conventional pharmaceutical intervention) in the study design as contributing to the questionable outcomes of the study. “If CAM (complementary and alternative medicine) therapies are going to be evaluated with the accepted scientific yard stick, then the accepted tool must be used, which is a randomized, placebo- and positive-controlled clinical trial,” he said.

NNFA also faulted the study’s measurement of only one hormonal marker associated with BPH. “The scientific explanations behind BPH are diverse and evolving,” Mr. Fabricant said. “For instance, research indicates that estrogen may lead to abnormal cell proliferation in the prostate. Also, genetic variations in steroid receptor expression in individuals, as well as the ratios of other hormones such as DHT (dihydrotestosterone), to estrogens are factors that may all play a role in the occurrence of BPH. The authors only provide testosterone as a sole hormonal marker related to BPH, which, in light of current research on BPH, does not present an adequate scientific window to view the whole scene.”

ConsumerLab.com, White Plains, NY, noted that the investigators in the study did not confirm the product they used contained proper amounts of the specific fatty acids and sterols expected in saw palmetto. A deficit in these compounds, the company said, could potentially reduce the potency of the product. The investigators in this trial only evaluated the totaI (combined) amounts of the compounds, not the specific fatty acids and sterols.

According to a letter sent from Tod Cooperman, MD, president, and William Obermeyer, PhD, vice president for research, ConsumerLab.com, to the editor of NEJM: “The results of the study by Bent et al would be more meaningful had the test material been shown to match the full chemical profile of authentic saw palmetto. This should be done in all studies of botanicals, but often is not.”

Two major studies published in the February 16th issue of the New England Journal of Medicine (NEJM) on the role of calcium and vitamin D supplementation in the health of post-menopausal women showed disappointing outcomes inconsistent with the large body of scientific evidence and the prevailing wisdom about the beneficial effects of these two nutrients. The studies, one assessing calcium and vitamin D supplementation on the risk of fractures, and the other on these nutrients’ effects on the risk of colorectal cancer, are part of the Women’s Health Initiative (WHI), sponsored by the National Institutes of Health (NIH) and the National Heart, Lung and Blood Institute (NHLBI).

Commenting on the randomized, double blind, placebo-controlled trials, John Hathcock, PhD, vice president, scientific and international affairs, Council for Responsible Nutrition (CRN), Washington, D.C., said, “Without discounting the value or importance of the studies, we think it is important for consumers not to over-interpret the results, as the authors themselves have noted limitations of the studies that may account for the unexpected results.”

The authors explained that in the hip fracture trial, the 400 IU of vitamin D per day used in the study may not have been enough to demonstrate the positive results on hip fracture risk previously shown to be effective. The majority of other studies reporting a benefit from calcium and vitamin D supplementation involved a vitamin D dose of 600 IU or higher. In addition, the study notes that the subjects may have been too young to detect a beneficial effect on hip fracture.

The colon cancer study authors also noted that the latency period of 10 to 20 years for colorectal cancer could have played a role in the null results, given that the study duration averaged only seven years. The authors will assess the longer-term effect of calcium and vitamin D supplementation in an ongoing follow-up.

But Dr. Hathcock also pointed to some promising news from the hip fracture risk study, stating that “the study showed that calcium with vitamin D supplementation resulted in a modest but significant improvement in hip bone density in postmenopausal women and it’s very possible that if the study continued for a longer duration there would have been a significant reduction in fracture risk.” Noting the consistency of that point with other research, Dr. Hathcock continued, “Giving women an edge by building bone density earlier on helps bolster bones against the possible onset of osteoporosis later. Calcium and vitamin D supplementation can effectively increase bone density to help preserve women’s bone health for the long term.”

The long-awaited results from the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) were published in the New England Journal of Medicine (NEJM) in late February. Following publication, the news was picked up by major media. One headline read “Supplements Fail to Ease Arthritis,” while another touted “No Overall Benefit for Mild Arthritis from Supplements.” The latter headline graced the pages of USA Today for a story that started out by saying, “For many arthritis sufferers, there has been a long and frustrating search for the best and safest pain relief. For some, the quest seemed to lead to a health store for unregulated supplements.”

The reality, according to the Council for Responsible Nutrition (CRN), Washington, D.C., is that the combination of glucosamine and chondroitin significantly reduced pain in those suffering the most in the GAIT study. “The clinical trial, sponsored by the National Institutes of Health (NIH), Bethesda, MD, found that using a combination of the two supplements ‘significantly decreased’ knee pain in osteoarthritis (OA) patients experiencing moderate-to-severe pain,” the organization said. OA is the most common form of arthritis.

Indeed, the official release from NIH said that while glucosamine and chondroitin did not provide relief among all patients suffering from mild OA of the knee, the combination of the two did provide significant relief for a small subgroup of patients suffering from moderate-to-severe OA. However, according to Daniel Clegg, MD, principal author of the study, “Because of the small size of the moderate-to-severe pain subgroup, the findings in this group for glucosamine plus chondroitin sulfate should be considered preliminary and need to be confirmed in a study designed for this purpose.” The USA Today article discussing the GAIT results also pointed out that Dr. Clegg received fees or grant support from Pfizer, maker of Celebrex, or McNeil Consumer & Specialty Pharmaceuticals, which produces Tylenol.

The six-month GAIT study was funded by the National Center for Complementary and Alternative Medicine (NCCAM) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), which are both part of the NIH. It involved nearly 1600 OA patients, who were given a placebo or daily doses of 1500 mg of glucosamine hydrochloride and/or 1200 mg of chondroitin sulfate or 200 mg of the common prescription pain medication celecoxib (Celebrex).

On entering the study, a participant’s level of pain was assessed as either mild or moderate-to-severe using standard pain assessment tools and scales, such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Of the 1583 study participants, 78% fell into the mild pain subgroup, while the other 22% percent were considered part of the moderate-to-severe pain subgroup. Level of pain was evaluated at weeks four, eight 16, and 24 using the WOMAC scale and other tools. In addition to taking their daily study treatment, participants could take up to 4000 mg of acetaminophen daily for pain, except for the 24 hours before being assessed by study staff. The use of acetaminophen, however, was low, overall averaging fewer than two 500 mg tablets per day. Participants were not allowed take other non-steroidal anti-inflammatory (NSAID) medicines or narcotic (opioid-based) pain relievers during the study.

Due to the positive results in the small subgroup of moderate-to-severe patients, more analysis is planned. The GAIT team will also continue its research with a smaller study to see whether glucosamine and chondroitin sulfate can alter the progression of OA, such as delaying the narrowing of the joint spaces. About one-half of the participants in the larger GAIT study were eligible to enroll in this ancillary study. The results are expected in about a year.

A recent article in Obstetrics & Gynecology (2006;107:247-255) found black cohosh and St. John’s wort to be effective against menopausal complaints.

A randomized trial was conducted to investigate the efficacy of this fixed combination of black cohosh (Cimicifuga racemosa) and St. John’s wort (Hypericum perforatum) extracts in women with menopausal complaints with a pronounced psychological component.

In the double-blind randomized placebo-control study, 301 women experiencing menopausal complaints with psychological symptoms were treated with ethanolic St. John’s wort extract and isopropanolic black cohosh extract or a matched placebo for 16 weeks. Menopausal complaints were evaluated by means of the Menopause Rating Scale mean score, and psychological complaints were evaluated using the Hamilton Depression Rating Scale sum score.

According to the results, the Menopause Rating Scale score decreased 50% in the treatment group and nearly 20% in the placebo group. The Hamilton Depression Rating Scale total score decreased 42% in the treatment group and almost 13% in the placebo group. According to researchers, the treatment was significantly superior to placebo in both measures. There were no relevant group differences regarding adverse events, laboratory values or tolerability.

It was therefore concluded that this fixed combination of black cohosh and St. John’s wort is superior to placebo in alleviating menopausal complaints, including the related psychological component.