14 January 2001
SWINacs.MS--
3,275 words

Dietary supplements for reporters:
ACS road show comes to NYC

(Note: Varro Tyler died on 22 August 2001 at age 74)

NEW YORK--The American Chemical Society (ACS) plucked some legitimate, science-based stories about dietary supplements out of all the hype. They presented talks by 3 reliable scientists, highighting a promising new product, rules for evaluating herbal claims, and a regulatory overview, at a meeting of the Science Writers in New York (SWINY) this January. But there's plenty of fraud, "scams," hypocrisy, and incompetence left to write about.

As New York Times investigative reporter John Hess pointed out after his nursing home expose, every newspaper scandal repeats after a few years. Now quack nostrums are back.

A century ago, charlatans were selling ineffective, adulterated, and dangerous drugs, until finally, in 1927, the U.S. Food and Drug Administration was established to regulate them.

Then, in 1994, the Dietary Supplement Health and Education Act established a category of "dietary supplements," with a loophole that brought us back to 1927 again. *Anything* can be a dietary supplement, and the Act places a virtually impossible burden of proof on the FDA to demonstrate that a substance is harmful before the FDA can order it off the market. Even substances like vinpocitene, which is marketed as a prescription drug in Europe and not approved in the U.S., can be sold as a dietary supplement, as Richard Harris reported in his 1999 National Public Radio series on dietary supplements.

The Act was sponsored by the conservative Sen. Orren Hatch (R-UT), and the liberal Sen. Tom Harkin (D-IA). The Act was passed after the supplement industry told its customers, falsely, that new FDA regulations would prevent them from buying high-dose vitamins, creating a storm of protest. (Schiff Products, a major supplement distributor, is in Hatch's state. Harkin acted at the urging of his friend Berkeley Bedell, a former Iowa congressman, multimillionaire fishing tackle manufacturer, and advocate of alternative medicine.)

Debarked watchdog

While Congress will tolerate a few deaths from a dietary supplement, they will not tolerate euphoric use, and they panicked at reports of gamma-butyrolactone and gamma-hydroxybutyric acid used as a "date rape drug." Since the FDA couldn't regulate them any more, Congress ordered the Drug Enforcement Administration to regulate them as Schedule II drugs.

In order to roll back some of the harm he did with the Dietary Supplement Act, Sen. Hatch submitted the "Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 1999," which became law.

So it's time for Upton Sinclair to write The Jungle again. The dietary supplement industry has grown exponentially, up to $14 billion in 1998. Symbiotically, a huge publishing industry has grown, of books and magazines uncritically promoting these products, with many well-paid opportunities for writers (such as yourself). Dietary supplements have become a major advertiser for health and general-interest magazines, which, except for those few with strong separation between advertising and editorial content, have joined the fashion of promoting drugs based on preliminary studies, often in animals and sometimes in vitro. On the Internet, which is even more dependent on advertising and self-promotion, the line between advertising and editorial blurs and disappears. Web searches for information on a product like DHEA or linoleic acid can be useless, since they merely turn up hundreds of hits from commercial sellers with fraudulent claims.

So the search for information about dietary supplements is a problem of finding the valid information in a surfeit of frequently-deceptive promotional claims.

Chemists to the rescue

A stolid, responsible, objective report of an 18 August 2000 presentation at the ACS' 220th National Meeting last year can be found at the EurekAlert web site ("ACS Master Class for Journalists: Dietary Supplements: Genie in a Bottle?"). So I won't repeat their efforts.

The New York class had 3 prominent scientists, who gave background on their work and advice to journalists on how to cover dietary supplements:

1. Michael W. Pariza, PhD, director of the Food Research Institute, at the University of Wisconsin. Pariza, wearing a tie with a pattern of little cows, is developing a fatty acid, conjugated linoleic acid, which, in well-designed randomized human studies, actually does seem to help dieters lose fat and build lean muscle, in addition to inhibiting cancer in mice. (Press Release, "First human studies promising for popular nutritional supplement CLA could help control weight, fat, diabetes and muscle loss"). Pariza gave an earlier presentation in the class that was summarized on EurekAlert. When he first announced his results at an American Chemical Society meeting in Honolulu, he was bombarded by press attention, which gave him some experience, generally favorable, in dealing with the press. (They usually do a good job, he said, and he realizes that editors, not reporters, write the headlines.) For a good general source of information, he recommended Food and Chemical News. He's at (608) 263-6955 .

2. Varro E. Tyler, PhD, ScD, dean emeritus, Purdue University, Lilly distinguished professor of pharmacognosy, which is the study of pharmacologically active substances in plants. Tyler, who was not at the earlier class, is one of the few scientists studying this field. Tyler defended herbal compounds against what he felt were frequent unfair and inaccurate attacks, and criticized the industry itself for its frequent irresponsible marketing. Tyler had the best handout, his article from Health Notes review: "A Guide to Clinically Tested Herbal Products in the U.S. Market," HNR 7(4);279-287 (Winter 2000) which summarized all the clinical trials he was aware of. Another good handout was "The Quality of Herbal Products in the United States Today," HNR 6(3)178-181 (Fall 1999), which criticized the variable, and occasionally poor, quality of herbal products on the market. If you missed the meeting, ask Tyler to send you the papers, particularly the summary of clinical trials (but not by fax; the footnotes won't come out). (765) 463-5326, (765) 463-7202 (fax) (he doesn't use email).

3. Lori A. Love, MD, PhD, Director Clinical Research and Review Staff, Center for Food Safety and Applied Nutrition, FDA. I have interviewed Love in the past. She has the commitment of a doctor, the intellect of scientist, and the timidity of a government official who saw what happened to Jocylin Elders for simply stating a scientific consensus. She had a habit of saying, "I hope this isn't on the record" even while making the most matter-of-fact statements. Accordingly, everything in this account is a paraphrase. There was no tape. If there is anything in this story that some congressman doesn't like, she was misquoted. Blame it on me. She isn't easy to reach, and you have to go through the FDA press office, (202) 205-4144, although her email address is lori.love@cfsan.fda.gov. You can find additional timid information on the FDA's web site.

Conjugated linoleic acid

The inhibitor turned out to be conjugated linoleic acid (CLA):

Linoleic acid (c9,c12): CH3-CH2-CH2-CH2-CH2-CH=CH-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-COOH

t10,c12 conjugated linoleic acid: CH3-CH2-CH2-CH2-CH2-CH=CH-CH=CH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-COOH

c9,t11 conjugated linoleic acid: CH3-CH2-CH2-CH2-CH2-CH2-CH=CH-CH=CH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-COOH

Linoleic acid, an essential fatty acid found in corn oil, is a chain of 18 carbons, with a COOH or acid group at the end, which is what makes it a fatty acid. The 9th and 10th carbons, and the 12th and 13th carbons, are joined by a double bond, which is what makes them conjugated. (Count them from the COOH group at the right.) In the stomach of ruminants such as cows, bacteria move the double bonds to different positions.

The original form, as found in corn, is called cis-9,cis-12 CLA, and the microbes convert it into 2 useful forms, cis-9,trans-11 CLA, which stimulates the immune system and inhibits cancer, and trans-10,cis-12 CLA, which reduces body fat.

(Carbon atoms can rotate freely when they're joined by a single bond, but when they're joined by a double bond, they're fixed in 1 of 2 positions. In this case "cis" means that both of their single hydrogen atoms are on the same side, while "trans" means that they're on opposite sides, which can give them different properties.)

The immune system, said Pariza in a polished metaphor, is "like having landmines around your house to keep burglars away." Sometimes they go off by mistake.

"CLA is the only dietary substance that can stimulate the immune system and not catabolize muscle," said Pariza. On the contrary, it enhances muscle, in growing animals and after exercise.

Pariza showed a photo of pork chops made from pigs fed 1/2% CLA, which had a dramatically apparent 25% reduction in body fat, and, he said, an increase in protein mass of 5%.

In humans, Pariza described his human randomized double-blind trial. 80 clinically obese subjects, 40 years old (average), were randomized to 40 on Tonalin-90 brand CLA, 2.7 g/day, 40 on sunflower oil placebo, for 6 months. At the end, 71 completed the study, 35 on CLA, 36 on placebo. According to the design of the study, all reduced their calorie intake and exercised. There were no adverse effects. Both groups lost weight. As a result of the exercise, a subset in both groups gained lean body mass, but the CLA subjects were more likely to gain lean muscle mass. The unexpected effect was after the trial, when they stopped dieting and put on weight again: Weight gain post-trial was 74% fat, 26% lean muscle on placebo, and 55% fat, 45% lean muscle on CLA (p<0.02). CLA also improved GI, mood, and cognitive problems associated with dieting.

The University of Wisconsin ("The school that rat poison [Warfarin] built") has arranged commercial licensing.

There is an up-to-date CLA bibliography on the web, said Pariza.

Pariza's advice to journalists in covering such studies is to ask whether there is a scientific database that establishes effectiveness and safety. The FDA has much less authority now, he said. On the other hand, the supplement industry, which was originally a cottage industry, now has major players moving in, "who can't afford lawsuits," he said, so the science is getting better. Even if the FDA has no authority to stop harmful drugs from being marketed, people who are harmed can bring civil actions against the manufacturers for tort liability (although Sen. Hatch has also supported tort reform legislation which would make those lawsuits more difficult to win).

Science of herbal products

The labeling on dietary supplements, said Tyler, is "the most hypocritical statement ever put on a label." Under the Dietary Supplement Act, the labels say, "This product is not intended to diagnose, treat, cure, or prevent any disease." (Apparently the word hasn't gotten to Netrition.com.)

If it's not supposed to diagnose, treat, cure, or prevent a disease, said Tyler, then "what are you taking it for?"

There is no provision for quality assurance, said Tyler, and so there is a "tragic" lack of reliability. Products on the market range from "excellent to junk." Samples of ephedra had 0-150% of the amount stated on the label. In samples of yohimbine, a purported aphrodisiac, "not a single one contained active substance."

"These products are basically scams," said Tyler.

On the other hand, there are herbal products with demonstrated effectiveness, said Tyler. There are a number of clinical trials of saw palmetto, some in the US, which show that it is "quite effective" for treating benign prostatic hyperplasia, a disease in older men that results in increasing urinary frequency, sometimes requiring several trips to the bathroom at night, and usually treated by anticholinergic drugs and surgery.

Some of the negative publicity has been unfair, and due to ignorance of herbal preparations, said Tyler. In the "hairy baby case," an article in JAMA reported the birth of a baby with unusually dense body hair, which was attributed to the mother taking Siberian ginsing. Actually, he said, they misidentified the herb, to start with. It was Chinese silk vine. A 1998 article in JAMA reported that garlic had no effect on cholesterol, but, he said, they were using steam-distilled garlic oil, which lacks the active substance, allicin. That illustrates one recommendation for journalists, he said: make sure the study is talking about the right product. Herbal products are formulated into tablets that don't even release therapeutic doses into the body. One JAMA paper gave the dose as "4 capsules."

"Good papers get published in good journals," added Pariza, "but not everything that gets published in a good journal is a good paper."

The reason, said Tyler, is that there aren't enough peer reviewers who understand herbal treatments.

Tyler recommended to journalists that they read the original paper and go through the following checklist:

1. Remember that the conclusions of a study are only applicable to that specific preparation.
2. Was the product properly identified? How was it identified -- chemically or botanically? How was it analyzed for quality?
3. How was the product prepared? Did they use the crude herb, a water extract, an alcohol extract?
4. Is it a test tube study, an animal study, a human study?
5. Is it in a respected, peer-reviewed journal?
6. Do the researchers have a financial interest?
7. Do the conclusions agree with other studies and reference sources? He immodestly recommended his own reference book, "Rational Phytotherapy," in which he has a financial interest.

FDA regulation

The general public has misperceptions about dietary supplements, said Love. They believe that "natural equals safe," "historical use equals safe," that the FDA wouldn't let people sell supplements if they weren't safe, and that "more is better." None of these are true.

Take the historical use of ephedra, for example. Historically, ephedra was a prescribed medicine, which was used transiently for fever. Currently, it's used for an extended time, for weight loss, as an energy booster, and other non-traditional indications. So safety in historical use is no reassurance of safety in current use.

Natural does not equal safe. Many of the supplements have adverse effects. Ephedra has cardiovascular and central nervous system effects. St. John's Wort can lead to "serotonin syndrome," said Love. Ginko biloba can lead to bleeding.

There is a "misperception" that L-tryptophan caused serious and fatal side effects a few years ago because of a bad batch with impurities, said Love. "It's very clear that there was something in the tryptophan itself."

Many people told me that, in practice, it's impossible for the FDA to take a substance off the market, even for something as dangerous as gamma-hydroxybutyrate. Is that true, I asked Love.

The FDA sent warning letters to manufacturers, who have voluntarily recalled them, Love said.

But, she acknowledged when pressed, the FDA has never compelled a manufacturer to take a dietary supplement off the market.

The regulations forbid manufacturers from making "disease claims," even when they are backed by legitimate research, unless the claims have been specifically approved by the FDA. ("Dietary Supplement Claim for Saw Palmetto Extract and Benign Prostatic Hyperplasia: Denied" (letter, May 26, 2000) , but see "FDA Announces Decision on Two Health Claims for dietary supplements," FDA Talk Paper, October 11, 2000 . Although now that the FDA has denied permission, they could simply ignore the FDA and make claims without permission, as Netrition.com does.)

Why not simply let manufacturers make disease claims, with the disclaimer that the claims have not been endorsed by the FDA, and let consumers suffer the consequences of their own decisions, if they insist, in the free market? Because, FDA officials argue, if they did that, drug manufacturers would never get FDA approval for any claims.

So dietary supplements will provide a steady stream of stories about adverse effects from the latest dangerous products. The FDA has a monitoring system, "The Special Nutritionals Adverse Event Monitoring System (SN/AEMS)" . Unfortunately, reporting is voluntary, and as of this writing (24 January 2001), the reports were only current to 1998. Furthermore, the FDA can only investigate the most serious reports. As the caveats note, most of these reports are unverified, and they merely say that someone suffered certain symptoms after taking a particular product. As the manufacturers will tell you when you call them for comment, these anecdotal reports do not prove causation. This database only contains summaries of more detailed reports which you will have to get after Freedom of Information requests and long hassles.)

(If you want to check out the product liability lawsuits, try the Association of Trial Lawyers in America, who are big contributors to political campaigns, BTW. The ATLA's PR department is clueless in helping reporters, in my experience, but the trial lawyers they sometimes refer you to usually know their stuff. Another source is Medical Malpractice Verdicts Settlements Reporter, edited by Lewis Laska, Nashville, TN, which gives far more detailed reports than the FDA does.)

For all its limits, you can find intriguing patterns in the FDA SN/AEMS database. Try searching for "death", "stroke", "ephedra", "st. john's wort", "ginko biloba", "saw palmetto", or other nutritional supplements. (I wonder what's happened since 1998.) Since the FDA doesn't have the staff to monitor all these reports, you can sometimes find serious problems that they missed or didn't publicize.

--Norman Bauman