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Testimony before the House of Representatives Committee on Government Reform Hearing on Dietary Supplements. (HRG Publication #1560)

A former college roommate, now an investment advisor, told me two years ago that herbal/dietary supplement companies were a hot investment item because they do not have to spend money for the research to show that the products are safe and effective. In contrast to the $100 million (some companies claim more) it takes to get a pharmaceutical through the FDA drug review process, several people in the industry have estimated to me that it takes a mere $3 to 5 million to get a supplement to the market. The legal cover for this profitable investment strategy comes from the Dietary Supplement Health and Education Act (DSHEA). I thank you for the opportunity to review the increasing evidence that this 1994 law is dangerous for people in this country.  

The American Association of Poison Control Centers (AAPCC) correctly categorizes herbals/dietary supplements as pharmaceutical products since they do have pharmacologic activity. For drugs, the FDA has two opportunities to collect data on safety: legally mandated pre-market safety studies and post-marketing adverse reports. For dietary supplements, neither of these is required of the industry.  

Scope of the Problem :

FDA has estimated that about 10% of adverse reactions to prescription drugs are reported to the agency, most of which come from the pharmaceutical companies who are required, by law, to report such reactions. For dietary supplements, it is likely that less than 1% of such reactions are reported to the FDA, one reason being that the manufacturers have no legal obligation to report. Based on data collected by the national network of Poison Control Centers, mostly located in hospitals throughout the country, the AAPCC publishes an annual report, in the American Journal of Emergency Medicine, which tabulates the number of adverse reactions reported by its toxic exposure surveillance system.  

The figure below shows, for 1994 through 1999, the number of such reports each year for dietary supplements. The total of such reports for AAPCC is 35,400 for that period, more than ten times higher than the 3000 reported to the FDA. The number of AAPCC reports would be even higher if it included those commercial herbal supplements currently categorized as botanicals/plants. Nor does it capture the non-emergent hospitalizations due to adverse reactions that are more chronic than acute.

*only cumulative FDA data available
** from Annual Poison Control Center Reports
Data compiled by Public Citizen Health Research Group 

Ephedra

The following chart shows the close chemical structures of PPA, ephedrine and amphetamine:                                                      

The well-documented concerns about the cardiac (arrhythmias) toxicity and brain toxicity of ephedrine (also associated with a large number of strokes due to bleeding in the brain), the known brain toxicity of amphetamine and the use of amphetamine as an appetite suppressant confirm that there are pharmacological as well as chemical similarities between all of these compounds.

Randy Sasich, M.D., the son of my colleague Larry Sasich, Pharm D., MPH, is in his third year of internal medicine residency at Barnes-Jewish, the main teaching hospital of Washington University in St. Louis. Within just a 7-month period during his residency, he took care of two patients admitted to the coronary care unit because of ephedra (Metabolife) -induced life-threatening cardiac arrhythmias. He is aware of a third patient, also discussed below, who used Metabolife and experienced an arrhythmia but was not hospitalized:   

Case 1 –April 1999.  This patient, a female in her late fifties, presented at the emergency room in with a dangerously rapid rate of contractions of one of the large chambers of the heart, or ventricles (ventricular tachycardia or V-tach), after using a dietary supplement for weight control containing ephedra.  She was admitted to the coronary care unit for observation.  She was subsequently discharged. 

Case 2 –April 1999.  This patient, a female in her late thirties, suffered a heart attack (acute anterior MI) and cardiac arrest while using a dietary supplement containing ephedra for weight control. She was a smoker but had no evidence of previous atherosclerotic disease of any significance. She suffered brain damage due to a lack of oxygen.  

Case 3 –October 1999.  A female nurse, age unknown, experienced a rapid heart rate while using a dietary supplement containing ephedra.  The rapid rate was documented by her colleagues using an electrocardiogram (ECG or EKG).  She was observed until her rapid rate resolved.           

Two reviews of 140 adverse reaction cases reported to the FDA involving the use of ephedra alkaloids confirmed the cardiac toxicity of ephedra. The first study found that 47% of cases involved the cardiovascular system (17 cases of hypertension, 13 with palpitations or fast heartbeat, 10 strokes). There were also 7 reports of seizures.[1] The second study found that of the 104 reports in which causation by ephedra was very likely, there were 10 cases of sudden death, nine cardiac arrhythmias, another 23 possible arrhythmic events, three heart attacks, ten cases of chest pain and 15 severe strokes.[2]

The FDA ban on PPA was based on a much smaller number of serious adverse reaction reports in their files than now exists, even with the extraordinary underreporting discussed above, for ephedra.

Bleeding, Blood-clotting  Risks of Herbals

A recent review on the potential effects of herbal medicines on blood clotting in patients being given anticoagulants such as coumadin discussed two sets of potential problems:

Supplements which, by virtue of providing additional sources of vitamin K beyond those in food, could decrease the anti-clotting effects of coumadin, thereby increasing the risks of blood clots in those patients who are already at risk for blood clots. These include Passion Flower, Juniper and Verbena. 

Supplements which can increase the anti-coagulant effects of coumadin thereby increasing the risk of bleeding in such patients. These include Japonicum, ginseng, ginkgo biloba, Papaw, Red Clover and Horse Chestnut and therefore should not be used in patients on either anticoagulant or antiplatelet therapy. [3]

In addition, the standard text on drug interactions, Evaluation of Drug Interactions, lists several supplements, including ginkgo, ginseng, dong quai, vitamin C, and green tea as having interactions with coumadin. [4] 

   Herbal Risks During Surgery

A recent news article in the Journal of the American Medical Association, entitled Herbs and Anesthesia, quoted the President of the American Society of Anesthesiology, Dr. John B Neeld, Jr., who said that because of changes in heart rate or blood pressure in people using herbals such as St. John's Wort, ginkgo biloba and ginseng, patients should stop taking herbal medicines at least 2 to 3 weeks before surgery. He pointed out that “It is very troubling to see our patients use products that they believe will provide a health benefit but, in fact, may jeopardize their lives during surgery if they don't tell us what they are taking.” [5] 

Short-term and Long-Term Remedies

Right now, legislation could be introduced—combined with the right signals during the FDA appropriation process and a strong version of the GMP regulations---to rapidly lessen the damage being done by this dietary supplement industry wish list masquerading as, and having the force of, a Federal Law, DSHEA. These improvements include a mandatory adverse event reporting requirement for all dietary supplement manufacturers, mandatory warnings for risks, requirements for company and product registration, and identification of the raw ingredients and the source (by country) for each of the ingredients in each product. This latter requirement is necessary to ensure that BSE-contaminated recycled cow organs do not appear on the shelves in this country as dietary supplements. In addition, mandated funds are necessary to implement and enforce the Good Manufacturing Practices regulation that will hopefully be finalized soon. In addition, FDA should be appropriated the funds to purchase the entire dietary supplement database of the AAPCC. At present, only the ephedra alkaloid cases have been contracted for by the FDA.

When the first member of this committee or of Congress or their families, has a stroke, a fatal cardiac arrhythmia, or some other life-threatening adverse reaction to dietary supplements, perhaps there will be a belated reconsideration of the damage done by DSHEA. The law will then either be significantly modified or repealed so that pre-marketing safety and efficacy testing become the preferable alternative to post-marketing human experimentation. Until then, trust the snake oil companies. Their only concern is your health.

The following appendix contains very brief summaries from 26 articles concerning dietary supplements published in the last  six years in our monthly newsletter, Worst Pills, Best Pills News.

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Appendix

WORST PILLS, BEST PILLS NEWS
(This monthly supplement to our book Worst Pills, Best Pills, has a circulation of approximately 140,000.) 

HERBAL AND DIETARY SUPPLEMENT ARTICLES

April 1995, Vol. 1 #2 

Herbal Product and Liver Side Effects 
Cases of liver toxicity reported in the November 15, 1994 issue of the Annals of Internal Medicine were reviewed.  These cases involved a Chinese herbal remedy called Jin Bu Huan.  The report describes seven patients, six female and one male, aged 24 to 66, with no history of liver disease, obesity, diabetes, allergy, or excessive alcohol intake or use of drugs known to cause liver toxicity. The Food and Drug Administration (FDA) issued an import alert in an attempt to stop the importation of Jin Bu Huan into the United States. 

February 1996, Vol. 2 #2

Adverse Reactions from Herbal Medicines 
The World Health Organization's (WHO) Collaborating Centre for International Drug Monitoring has received more than 5,000 reports of suspected adverse reactions from herbal medicines.  Serious adverse reactions with unregulated supplements such as royal jelly, chaparral or creosote bush, and Chinese herbal remedies were discussed.   

December 1996, Vol. 2 #12

DHEA (Dehydroepiandrosterone) Safety and Effectiveness Have Not Been Proven 
The editors of The Medical Letter on Drugs and Therapeutics said regarding the dietary supplement dehydroepiandrosterone (DHEA) “Patients would be well advised not to take it.”  Various masculinizing effects of DHEA in women, including acne, hair loss, abnormal hairiness and deepening of voice had been reported.  Substances such as DHEA can stimulate the growth of prostate cancer in men. 

July 1997, Vol. 3 #7 

Warning: Potentially Deadly Chomper Herbal Laxative Recalled 
This laxative was recalled because specific lots were found to be contaminated with a digitalis-like substance.  Drugs derived from digitalis, such as digoxin (Lanoxin), are used to treat heart conditions, but if too much is taken, these substances can cause serious heart rhythm disturbances and death. 

August 1997, Vol.3 #8

Warning: Recall of More Dangerous Dietary Supplements 
The Food and Drug Administration (FDA) advised consumers that the raw material labeled plantain used by various dietary supplement manufacturers may contain digitalis.  Digitalis can cause life-threatening heart rhythm disturbances. 

February 1998, Vol. 4 #2

What Do We Know About St. John's Wort? 
The editors of The Medical Letter on Drugs and Therapeutics evaluated the scientific research regarding St. John's Wort, an herb heavily promoted as an anti-depressant.  The editors concluded “Better, longer studies are needed to establish the effectiveness and safety of St. John's Wort for treatment of depression.  The active ingredient, the potency and purity of the preparations sold in the USA are all unknown.” 

June 1998, Vol. 4 #6

Melatonin and Increased Seizures in Disabled Children 
Researchers from the Children's Memorial Hospital and Northwestern University Medical School published a study in the journal The Lancet of melatonin used  as a sleep aid for six children aged 9 months to 18 years with nervous system damage who also had chronic, severe sleep complaints.  The study was terminated before its completion because of increased seizures in four of the six children.

August 1998, Vol. 4 #8

What We Know About Garlic For Cholesterol-Lowering 
German researchers, writing in the June 17, 1998 issue of the Journal of the American Medical Association, used the scientific “gold standard” to test garlic's effect on cholesterol: a randomized, placebo-controlled, double-blind study.  The researchers found that garlic had no effect compared to a placebo in lowering cholesterol in men who had moderately elevated blood levels of cholesterol. 

October 1998, Vol. 4 #10

FDA Confirms Impurities in the Dietary Supplement 5-Hydroxy-L-tryptophan 
Mayo Clinic researchers reported in the September 1, 1998 issue of Nature Medicine that they had found chemical impurities in the nutritional supplement 5-hydroxy-L-tryptophan (5HTP) from six different undisclosed manufacturers.  5HPT is being hyped as an aid for insomnia, depression, obesity, and in children with attention deficit disorder.  These impurities are similar to those found in L-tryptophan and were associated with a 1989 epidemic of eosinophilia-myalgia syndrome (EMS).  

November 1998, Vol. 4 #11 

Untested "Alternative Medicine" Remedies  
The September 17, 1998 issue of The New England Journal of Medicine was devoted to the dangers of alternative medicine.  The Journal published two studies, three letters-to-the-editor and a strongly worded editorial about this issue. 

March 1999, Vol. 5 #3

FDA Warns About Products Containing Gamma Butyrolactone (GBL) 
The Food and Drug Administration (FDA) alerted the public in January 2000 not to purchase or consume products, sometimes sold as dietary supplements, that contain gamma butyrolactone (GBL for short).  The agency had received reports of serious health problems – some potentially life-threatening – associated with the use of GBL.  

April 1999, Vol. 5 #4 

The Poor Quality of Some Melatonin Products  
Researchers from the University of Maryland School of Pharmacy reported in the Journal of the American Pharmaceutical Association their results of a study of the quality of melatonin products.  Melatonin is a nutritional supplement that has been hyped as a cure for practically everything from aging to jet lag.  The researchers concluded that poor design and manufacture of melatonin tablets and capsules is another example of a widespread problem with dietary supplements.  These poor quality products can exist in the marketplace because, like other dietary supplements, they are not regulated by the FDA.

August 1999, Vol. 5#8  

Warning! Deaths Reported With the Unregulated Dietary Supplement 1,4 Butanediol (BD) 
The Food and Drug Administration (FDA) warned the public of a new group of dietary supplement products being marketed as sleep aids that have been associated with at least three deaths and several adverse non-fatal reactions.  These products are chemically related to gamma butyrolactone (GBL) and gamma hydroxybutyric acid (GHB), substances that have been determined to pose a significant public health hazard.

October 1999, Vol. 5#10

More Serious Reactions and Deaths Associated with Dietary Supplements Containing GBL, GHB, or BD 
The Food and Drug Administration (FDA) announced on August 25, 1999 that the count had risen to at least 122 serious illnesses, including three deaths, associated with the use of gamma butyrolactone (GBL), gamma butyric acid (GHB), or 1,4 butanediol (BD). 

Fish Oil Protects Against Second Heart Attack but Vitamin E Does Not, Italian Study Reveals 
Italian researchers reported in the August 7, 1999 issue of The Lancet that daily supplements of polyunsaturated fatty acids (PUFA) derived from fish demonstrate a beneficial effect on morbidity and mortality in patients with a recent heart attack, while daily use of 300 milligrams of synthetic vitamin E has no such beneficial effect.  

January 2000, Vol.6#1 

Ineffective and Dangerous Dietary Supplements: S-adenosyl-methionine (SAMe) For Depression and the Diet Pill Tiratricol (Triax)  
The editors of The Medical Letter on Drugs and Therapeutics reviewed the dietary supplement s-adenosyl-methionine or SAMe for the treatment of depression.  The Medical Letter editors concluded “There is no convincing evidence that SAME, a dietary supplement is effective or safe for treatment of depression.”   

In the same article we wrote that the Food and Drug Administration (FDA) was warning consumers not to purchase or use Triax Metabolic Accelerator, a dietary supplement containing tiratricol, a breakdown product of natural thyroid hormone.  Triax was being sold in health food stores and over the Internet as a diet pill.  Excess thyroid hormone may cause serious health consequences including heart attacks and strokes.

February 2000, Vol.6#2 

Hypericum Extract (from St. John's Wort)  in the Treatment of Moderate Depression 
A well-designed clinical trial published in the December 11, 1999 British Medical Journal compared the effect of St. John's Wort to the tricyclic antidepressant imipramine (Tofranil) or an inactive placebo.  The study found that the St. John's Wort was more effective than placebo and at least as effective a imipramine for the treatment of moderate depression.  These findings may be irrelevant for the unregulated products sold in the United States, many of which have much less St. John's Wort than used in the study. 

April 2000, Vol.6#4

Save Your Money: Do Not Use Vitamin E for Preventing Heart Attack and Stroke 
Researchers from the Canadian Cardiovascular Collaboration Project reported in the January 20, 2000 issue of The New England Journal of Medicine that daily supplementation with natural vitamin E had no effect in preventing cardiovascular events such as heart attack and stroke in high-risk patients.   

California Health Director Warns Consumers About Prescription Drugs in Herbal Products
California health authorities warned consumers to immediately stop using five specific herbal products because they were adulterated with two prescription diabetes drugs.  An investigation was begun after a diabetic patient in Northern California suffered from several episodes of low blood sugar (hypoglycemia) after consuming one of the products. 

May 2000, Vol.6#5  

New Warnings! Clinically Important Drug Interactions With St. John's Wort 
The British equivalent of our Food and Drug Administration (FDA), the committee on Safety of Medicines, warned doctors, pharmacists and the public about of a number of significant drug interactions between the herb St. John's Wort (Hypericum perforatum) and prescription drugs. 

The Health Research Group wrote FDA Commissioner Jane Henney on March 2, 2000 urging the agency to warn American physicians and patients about all (more than 25) drugs listed in the British warning, rather than only the AIDS drugs. 

June 2000, Vol.6#6

'Gold Standard' Study Shows No Detectable Benefit Derived From Coenzyme Q10 For Congestive Heart Failure Patients  
Researchers from the University of Maryland School of Medicine and the Veterans Affairs Medical Center in Baltimore publishing in the April 18, 2000 issue of the Annals of Internal Medicine, concluded that adding the dietary supplement coenzyme Q10 to standard treatment was of no benefit to patients with congestive heart failure.

Shoddy Manufacturing and Labeling Practices Found in Dietary Supplements Containing Ephedra  
Reinforcing the need for tighter control of dietary supplements, researchers at the University of Arkansas College of Pharmacy found serious problems with some products containing  the Chinese herbal supplement ephedra.  The research, reported in the May 15, 2000 issue of the American Journal of Health-System Pharmacy, compared the amounts of ephedra listed on the labels of 20 products to the actual content of the substance in the tablets and capsules of these dietary supplements. 

Not surprisingly, the amounts listed on the labels often differed sharply from the scientifically determined contents, both over-and understating by substantial percentages ranging from 0 to 154 percent. 

July 2000, Vol.6#7 

More Reports of Serious Drug Interactions Between St. John's Wort and the Anti-organ Rejection Drug Cyclosporine (NEORAL, SANDIMMUNE)
Additional reports of this dangerous drug interaction were published in May 27, 2000 issue of The Lancet, from doctors at an organ transplant service in Hannover, Germany.  These doctors identified a group of patients whose cyclosporin blood levels had decreased by an average of 49 percent after starting to use St. John's Wort.

Warning!  Do Not Use!  Chinese Herbal Supplements Containing Aristolochic Acid  
The Food and Drug Administration (FDA) asked lobbying groups representing the herbal supplement industry to ask their members to test and not sell herbal supplements containing aristolochic acid.  This herb has been used in Chinese medicine in products sold for weight loss and skin problems.  In Belgium, in 1993, at least 70 cases of kidney failure were reported in association with the use of products containing aristolochic acid.  

February 2001, V7#2

Kidney-toxic and Cancer Causing Chinese Herbal Supplements are Recalled
A recall was issued on November 21, 2000 of Chinese herbal supplements produced by a Eugene OR firm containing aristolochic acid.  Aristolochic acid is known to cause kidney failure and urinary tract cancer.

Ginkgo Biloba is Found Ineffective for Dementia and Age-Associated Memory Impairment in the Elderly
Researchers from The Netherlands reported in the October 2000 issue of the Journal of the American Geriatrics Society that a standardized extract of the widely hyped herb ginkgo biloba was found ineffective for older adults with dementia and age-associated memory impairment.  The results of this study contrast sharply with those of previous ginkgo biloba trials.

[1] Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. New Engl J Med 2000;343:1833-8.

[2] Letter from Ray Woosley, M.D., Ph.D, Georgetown University School of Medicine, August 18, 1999 to the FDA.

[3]  Argento A, et al. Oral anticoagulants and  medicinal plants. An emerging interaction. Ann Ital Med Int 2000; 15(2):139-43.

[4] Evaluation of Drug Interactions, October, 2000. First Databank, Inc.

[5] R Voelker. Herbs and anesthesia. JAMA 1999;281: 1882.

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