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St. Johnís Wort -Herbs and Dietary Supplements -Ephedra-Part II

(5/12/14)- For all our readers interested in the latest recommendations about vitamins and supplements, we suggest that you check the following references:
Moyer VA et al. Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014 Apr 15; 160:558.

(7/23/05)- Even though a federal judge struck down the ban on the sale of ephedra that was imposed by the FDA in April 2004 Cytodyne Technologies of Manasquan, N.J, one of the companies that manufactured the supplement filed for bankruptcy in October 2003. In its filing the company cited the numerous pending lawsuits as the main reason for the bankruptcy.

Nutraquest Inc. of Wall Township, N.J. became the successor company to Cytodyne. Nutraquest was in the news lately in connection with the settlement of a lawsuit brought by the State of New Jersey. In the lawsuit it was alleged that the company made false and misleading statements and that the company's ads in connection with the marketing of its weight loss drugs Xenadrine RFA-1 and Xenadrine EFX (which did not contain ephedra).

The state also alleged that the company understated the risks associated with taking of the supplements. In a statement that accompanied the settlement for about $1 million the company said they were settling the case "to avoid the uncertainty and cost of litigation."

(10/1/04)-The FDA said that it would start to enforce its ban on dietary supplements containing ephedra after U.S. District Judge Joel Pisano in Newark, N.J. refused to grant a temporary restraining order in connection with the pending court action brought by manufacturers of the drug. Two companies requested the temporary block of the ban, NVE Pharmaceuticals Inc. of Newark, N.J., and the National Institute for Clinical Weight Loss of Atlanta, Ga.

The two manufacturers claimed that the FDA lacks proof ephedra is dangerous and that the agency was simply reacting to all the negative publicity in connection with the supplement that has appeared in the media. HHS Secretary Tommy Thompson said that Judge Pisano's decision does not affect medicines containing ephedrine, a synthetic version of ephedra.

Judge Pisano said that the government had submitted 133,000 pages of documents in support of the ban, and that there was little likelihood that the matter could be resolved quickly. The judge ruled against the two manufacturers on the matter of there being irreparable harm done to them if the temporary stay was not granted. He noted that the agency had received 18,000 reports of harm associated with ephedra, including 164 deaths.

The FDA has published its final rule banning the sale of ephedra since it poses "an unreasonable risk to the public health". Sales of ephedra become illegal 60-days after the rule are published. This will be the first time that the FDA has banned a dietary supplement since 1994, when Congress enacted a law to restrict the agency's ability to do so in connection with herbal products. Tommy Thompson, the secretary of the Department of Health and Human Services said that he fully expects a court challenge to the ban from the manufacturers of ephedra.

The consumer group Center for Science in the Public Interest said Congress needs to give the FDA more power to ban the sale of dangerous supplements much quicker than it has been able to do up to now. The FDA took more than seven years to ban ephedra according to Bruce Silverglade, the consumer group's director of legal affairs. Mr. Everglade went on to say: "This shameful track record points to the need for fundamental reform."

Dietary supplements are not subject to FDA review before they come to market. Manufacturers can market dietary supplements as long as they do not make claims that their products affect the "structure or function" of the body. California, Illinois and New York have already banned ephedra as does the National Football League.

The federal act of 1994 requires that the FDA must be able to prove that a dietary supplement poses an unreasonable risk to the public health before it can be banned. The FDA does not have the power to require that the manufacturers of dietary supplements conduct safety studies before bringing the product to market.

The burden of proof is on the FDA to prove scientifically that a product is unsafe. In order to make its case against ephedra, the agency reviewed 16,000 reports of adverse reactions to the supplement. The agency commissioned a study to be done by the RAND Corporation, a nonprofit research agency. The FDA invited comments from the public on this matter. The RAND study found about 20 "sentinel events", including heart attacks, stroke and sudden death.

The ban will take effect 60 days after the FDA publishes a regulation stating its reasons for withdrawing ephedra from the market. Publication is not expected for several months but the agency has advised all manufacturers of the supplement that they will have to stop manufacturing the product shortly.

Governor George E. Pataki, the Republican governor of New York signed into law a ban on the over-the-counter sales of ephedra in the state. The law includes a fine of up to $500 for each sale of the supplement. Ephedra can still be legally sold in the state if a doctor prescribes it. The Ephedra Education Council, an industry-financed group continues to claim that the supplement is safe when used correctly. New York State became the second state in the U.S. to ban ephedra. The New York City Council is also considering such a ban. The FDA has reported 123 deaths associated with ephedra since 1993.

Tommy G. Thompson, Secretary of Health and Human Services, has delayed action in declaring whether or not ephedra, the popular weight-loss supplement is dangerous or not. He said the RAND Corporation, a research organization, would finish a "comprehensive review" of the studies that have been done on the supplement. The Rand report would be the basis for further study of ephedra, which is also known as ma huang, by the National Institutes of Health.

Dr. Mark B. McClellan, commissioner of the FDA in reference to ephedra, told a House subcommittee that: "I think professional sports leagues like baseball teams should take action to protect their players." The commissioner testified that there is little proof that the drug does enhance performance and can pose a serious risk to the user's health.

The FDA is considering whether or not to ban the herbal supplement, which was linked to the death of the Baltimore Oriole pitcher Steve Bechler in the spring of 2003. Baseball owners have banned the use of ephedra in the minor leagues. The National Football League, Major League Soccer and the NCAA have also banned ephedra. McClellan said that the FDA would rule shortly on whether or not to ban ephedra nationwide or restrict its sales.

In a ruling made by Judge Ronald L. Styn of the San Diego Superior Court, in a class action suit against Cytodyne Technologies of Manasquan, N.J., the company must return $12,5 million in profits on sales of ephedra in California. The case involved the plaintiff's allegation of false and fraudulent advertising by the company.

The class action suit accused the company of deceiving consumers with claims of uniquely effective and substantial weight loss. The verdict represents all of the profits the company made in California from 1997 to 2001 on its ephedra product, Xenadrine RFA-1. Illinois passed a ban on ephedra and the California State Assembly is considering a similar ban. Tommy G. Thompson, the administrator for the Centers for Medicare and Medicaid Services said that he is also considering banning the substance, pending a review of public comments.

The death of the Baltimore Oriole pitcher Steve Bechler has brought the dietary supplement ephedra back into the limelight again, The coroner's autopsy report attributed the supplement as one of probable leading causes of his death. American poison control centers have reported 1,178 adverse reactions to ephedra in 2002. The FDA has reports of nearly 100 deaths of people who had taken the supplement. Ephedra can quicken a person's heart rate and cause the blood vessels to constrict. The FDA has ordered 24 companies to stop advertising ephedra use as a way to build muscles or enhance athletic performance, saying there is no scientific evidence for the claim. The industry estimates that 12 million to 17 million Americans consume more than 3 billion doses, or "servings" of ephedra products each year.

Ephedra accounted for 64% of all adverse reactions involving herbs, even though it is found in less than 1% of all herbal products. The American Medical Association has advised people not to use ephedra. The Bush administration ordered a review of ephedra back in June 2002 but the report has not been issued yet. The supplement, which is also known by its Chinese name of ma huang, was originally used in the U.S. as a decongestant and asthma treatment. Doctors stopped prescribing it in the 1930s.

The 1994 Dietary Supplement Health and Education Act put the burden of proving a supplement as being an "imminent hazard" or at least a significant unreasonable risk of injury on the FDA. Dietary supplements are classified as food under the law and not as drugs. As we point out later in this article the FDA lacks the resources to properly monitor many of the dietary supplements. Many of the dietary supplements contain hundreds of ingredients so it is difficult to pinpoint which one it is that causes the problem. Oftentimes the labels of dietary supplements do not accurately reflect what is in the bottle. Herbal remedies do not meet the standards of safety and purity specified in the Federal Food, Drugs and Cosmetics Act. The same applies to vitamins and minerals sold as dietary supplements. None of them have to be tested to define their medicinal effects or how they would react if the user is taking other supplements or medications.

Twinlab Corp., a maker of nutritional supplements announced that it would stop selling dietary supplements containing ephedra beginning March 31, 2003, citing escalating insurance costs and regulatory uncertainty surrounding the product. The AMA urged the FDA to ban supplements containing ephedra in October 2002.

General Nutrition Centers will begin requiring that customers who buy certain dietary supplements have proof that they are over 18 years of age. The proof will be required if the customer is purchasing products containing ephedra, kava, androstenedione (a steroid used in performance-enhancing products) or synephrine (a substance similar to ephedra also used for weight loss).

General Nutrition is the country's largest chain of vitamin and herb stores. California will ban the sale to minors of products containing ephedra starting January 2003. Sales of dietary supplements reached $17.8 billion in 2001, but the industry's growth rate has been slowing because of concerns over the safety and quality of the products being sold.

The Justice Department announced that upon request of the FDA, it was conducting a criminal investigation of Metabolife International, a leading manufacturer of the herbal stimulant ephedra, to determine whether executives of the company lied about what they knew about the safety of the supplement. Officials of the FDA said that it was unclear as to what sort of warning label was justified, or even possible, for that matter since the FDA has limited power to regulate dietary supplements.

At a Senate subcommittee hearing Sen. Dick Durbin (Dem.-Ill.) renewed his call to ban the product because of the number of heart attacks and strokes that users of the product have had. Ephedra manufacturers maintain that the product is safe if used as directed, and that there is no conclusive link between the product and dangerous side effects. Congressional investigators found that in examining the adverse event reports, they found many instances of "significant health effects in healthy consumers taking recommended dosages."

In 1998 the president of the company at that time, Michael Ellis, said in a statement to the FDA that the company "had never received one notice from a consumer that any serious adverse health event has occurred because of the ingestion of Metabolife 356."

Court records however showed that the company had received many reports of adverse reactions to the product. The company now admits that it has about 13,000 complaints about the product, including many that had been received prior to Mr. Ellis' comments. The company feels that just because complaints have been filed against the product does not mean the product was the cause of the problem.

Ephedra is an amphetamine-like stimulant that is widely used for weight loss and also to enhance and athlete's performance. According to the American Botanical Council, a nonprofit group that monitors herbal supplements, about 3 billion doses or "servings" of ephedra were sold in 1999.

The November 7, 2000 issue of the New England Journal of Medicine contains an article on a study of the risks of ephedra. Ephedra is an ingredient that is in natural appetite suppressants. As a natural appetite suppressant it is therefore classified as a dietary supplement, and therefore escapes regulation by the FDA. The article reported on the fact that 140 patients suffered serious side effects, including stroke and seizures, after taking ephedra products. Ten died and 13 % were permanently disabled.

The National Football League, the International Olympic Committee and the NCAA have all placed the ephedra on their list of banned substances. A consumer advocacy group, the Public Citizens Health Research Group in Washington, and a prominent pharmacologist Dr. Raymond Woosley, vice-president of health sciences at the University of Arizona, have filed a petition with the FDA urging the agency to pull the product from the market.

The FDA's attempt to collect data on the herbal market has been criticized by the General Accounting Office as incomplete and unreliable. The agency does not have a system to do anything other than receive reports from patients and doctors, and manufacturers have not cooperated with the agency.

Ephedra has been linked to deaths, strokes, heart attacks and other health problems. It is also used under the Chinese name of ma huang. Ephedra is like amphetamines in that it stimulates the central nervous system, and is used in many weight loss and increased energy products.

The petition cited data from the American Association of Poison Control Centers, that showed that adverse events linked to ephedra in dietary supplements rose to 407 in 1999 from 258 in 1998, and 211 in 1997. In figures compiled by the FDA the total number of deaths and injuries caused by ephedra from January 1993 to February 2001 was 1,398. Those who defend the supplement claim that it is excessive usage that has caused the problem and feel that products containing ephedra merely should state that fact on the label.

The heart of the problem can be traced back to the federal law of 1994 that essentially deregulated the dietary supplements. The law allows companies to make and sell dietary supplements without the same proof of safety and efficacy as is required of drugs. The safety of ephedra was attacked in 1997, but the FDA required only the mandatory warning label and a ban on ephedra's usage in combination with other some other specified stimulants.

"Health Sense" columnist Judy Foreman wrote an article in the Boston Globe on St. Johnís Wort entitled "St. Johnís Wort: Less than Meets the Eye". The Boston Globe hired two companies to independently test (PhytoChem analysis) seven different manufacturerís products of St. Johnís wort. They found "considerable chemical and biological variation among the products, with only one product, Natureís Resource, living up to the standard claim on product labels that the product contains 0.3% of hypericin", the level the industry set as the standard.

The 6 other products that were tested contained much greater variations than the amounts stated on the label. The Boston Globe states that "there is no consensus on our testís value in assessing the quality of St. Johnís wort. Because of this, products that failed this test might still be effective." From our read of this article, it would seem that there is need for greater quality control of products in this field. There is no standard as to method of analysis of herbs and supplements.

Then there is the issue of the claims made by some of the over-the-counter manufacturers. Congress passed the Dietary Supplement Health And Education Act in 1994 which gave sellers of dietary products, vitamins, supplements etc. a freedom to advertise their products without much FDA supervision. The act created a new category called dietary supplements, which unfortunately would not be subject to the regulations required for drugs nor for the manufacturing standards for food products.

New guidelines were established in February 2000 in an attempt to regulate the $14 billion (as of 1999) market for dietary supplements. These guidelines make a distinction between disease cure and functional changes. Examples: manufacturers can say "maintains healthy lung function" but canít say "maintains healthy lungs in smokers" or can state the supplement "supports the immune system" but cannot say "supports the bodies antiviral capabilities".

The Food and Drug Administration does not require manufacturers to prove the safety or efficacy of dietary supplements before they go on the market. Dosages are not standardized. There is no federal quality control to make sure that what is on the label reflects what is in the bottle.

ConsumerLab.com of White Plains, a private company, tests various supplements for quality and potency, and posts the results on its web page. Consumer Reports and the Good House Keeping Institute, which test products for Good Housekeeping Magazine have also begun to evaluate dietary supplements.

An office of dietary supplements has been established within the National Institute of Health to collect facts on various vitamins, minerals and herbal supplements that will summarize what is known about the safety and effectiveness of various dietary supplements. The United States Pharmacopeia, the nonprofit organization that sets standards for potency and dosages of drugs in coordination with the FDA is developing standards for herbal remedies.

It is estimated by the FDA that these new guidelines would cover some 20,000 dietary supplements, which considering the small staff the agency has to review the claims of these supplements, would be an impossible task. The Wall Street Journal quotes Joseph Levitt, director of the FDAís Center for Food Safety and Applied Nutrition, that the dietary supplement program "represents our biggest mismatch between the resources we have available and the job we have to accomplish."

With this in mind, we caution people on the usage of dietary supplements. Determine proper dosages and confirm that what you are taking contains the proper amount of the active ingredient.

Reference:
Foreman J. St. Johnís Wort: Less Than Meets the Eye. Boston Globe, Health/Science Section Monday, January 10, 2000:C1.

Linde K, Mulrow CD. St. Johnís Wort for Depression. Cochrane Review, Latest version 09 July 1998. In: The Cochrane Library. Oxford: Update Software.

The latest guidelines for treatment of depression from the American College of Physicians-American Society of Internal Medicine recognizes St. Johnís wort as a possible treatment consideration for mild-acute depression. It should be pointed out that St. Johnís wort is not approved by the Food and Drug Administration.

Keep in mind that St. Johnís wort affects plasma concentration of all drugs that are metabolized by the cytochrome P450 system. Metabolism of a drug by the cytochrome P450 is often required before the drug can be readily eliminated from the body. The large inter-individual differences observed in the effects of drugs is at least in part determined by the variations of the expression and catalytic activities of cytochromes P450. The sources of interindividual variation in the catalytic activity of cytochromes P450 can be divided into three general areas:

  1. The influence of genetics on the expression of cytochromes P450ógenetic polymorphisms (inherited deficiencies of single drug metabolizing enzymes). Ethnic backgrounds and gender have also been shown to influence the metabolism of certain drugs.
  2. Several of the human cytochromes P450 are inducible, that is, the catalytic activity of these cytochromes P450 is increased by exposure of an individual to particular classes of drugs, endogenous compounds and environmental agents.
  3. Activity of cytochromes P450 can be inherited or the cytochromes P450 can be inactivated by drugs, endogenous agents and environmental compounds.

This is why it is important that you inform your treating physician that you are taking St. Johnís wort.

Our search of the literature has turned up a meta-analysis study (Linde et al 1998) that looked at 27 randomized controlled studies comparing St. Johnís wort with a placebo and with low doses of tricyclic antidepressants (TCAís). Most of these studies were done in Germany where St. Johnís wort is the primary treatment of unipolar depression.

The results suggest that St. Johnís wort is more effective than placebo and is as effective as low-dose tricyclics in the treatment of depression. Side effects were less common using St. Johnís wort. While the method of action is not fully understood, it is assumed that St. Johnís wort acts in a similar fashion as conventional antidepressants and involves inhibition of reuptake monoamines. (See Muller WE, Rossol R. Journal of Geriatric Psychiatry and Neurology 1994; 7:S63-S64 for description of mechanism of action of antidepressants)

Copies of the second Annual Bibliography of Significant Advances in Dietary Supplement Research may be downloaded from the ODS website at
http://ods.od.nih.gov/publications/publications.html.

Single copies may also be requested from ODS by phone (301-435-2920) or email (ods@nih.gov).

 

Please also see our article on Nutraceuticals and the Elderly

Please See: Herbs and Dietary Supplements-St. John's Wort-Part I
Phytomedicine or Herbalist-What is It?-Part III
Herbal Medicine and Botanical Supplements Caveat-Part IV
Treating Osteoarthritis with Dietary Supplements-Part V
St John's Wort: Does It Help Treat Depression-Part VI
Herbal Products: Use With Caution-Part VII
Kava: Safety Alert-Part VIII
Herbal Usage for Hormone Replacement Therapy-Part IX
Latest Research Questions the Effectiveness of Herbal Supplements-Part X

 

FOR AN INFORMATIVE AND PERSONAL ARTICLE ON PRACTICAL SUGGESTIONS WHEN SELECTING A NURSING HOME SEE OUR ARTICLE "How to Select a Nursing Home"

Allan and Harold Rubin, MS, ABD, CRC, Guest Lecturer
Updated May 12, 2014http://www.therubins.com

To e-mail: hrubin12@nyc.rr.com or allanrubin4@gmail.com

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