HerbalEGram: Volume 13, Issue 12, December 2016

On its cover, the September 2016 issue of Consumer Reports prominently features the title “Supplements: A Complete Guide to Safety.”¹ The magazine promises that the reader will learn about “15 dangerous ingredients to avoid,” “The truth about health claims,” and “Superfoods to eat instead.” The cover story, which reportedly was developed by a panel of medical experts,* was one of several articles^2-5 in the issue that deal with the safety of dietary supplements. They are the latest examples of Consumer Reports articles^6-8 from the past 12 years that regularly proclaim the dangers of supplements.

The September cover story and related articles are mainly a critique of the dietary supplement industry and its regulatory system. The American Botanical Council (ABC) agrees that the quality of some dietary supplement products is questionable, and ABC is actively involved in educational efforts regarding the identity and authenticity of herb raw materials and extracts through its work in the ABC-American Herbal Products (AHP)-National Center for Natural Products Research (NCNPR) Botanical Adulterants Program. One of the primary concerns for health professionals, regulators, and responsible members of the dietary supplements, natural products, and integrative medicine communities is the issue of pharmaceutical drugs, such as the erectile dysfunction drug sildenafil, being inappropriately and illegally marketed as “dietary supplements.” The occurrence of adverse events caused by illegal drugs masquerading as dietary supplements (and other safety problems associated with a lack of adequate quality control in the herb industry) is not acceptable.

“Supplements: A Complete Guide to Safety” is clearly biased, and would have benefited from a more balanced discussion. The notion that supplements should be 100% safe is not based on rational thinking. There is a presumption that, in general, herbal products should be safe for their intended use, but evidence from numerous clinical studies of herbal dietary supplements (in which adverse effects noted in the experimental group often are the same as or similar to those observed in the placebo group) and from cases reported each year to the US Food and Drug Administration (FDA) shows that adverse effects can and do occur.

Physicians understand that each person may react differently to a pharmaceutical drug, and the same is true for conventional foods and dietary supplements. Most people who use green tea (Camellia sinensis, Theaceae) extracts, for example, will not experience any adverse effects, but there have been a small number of cases in which people have developed liver damage. The exact reasons for these incidents are not fully known.

Table 1. Herbal Products Mentioned in Consumer Reports Coverage of "Unsafe" Supplements

Common Name	Adverse Effects Reported by Consumer Reports	ABC Comments
Sichuan aconite	Nausea, vomiting, respiratory problems, heart arrhythmia, death1,3	Aconite has a longstanding use in traditional Chinese medicine. The high toxicity, due to the presence of diterpene alkaloids,9 is known to practitioners; therefore, aconite is treated with heat (boiling, roasting, or pressure-steaming) to reduce the toxicity of the roots.10
Bitter orange	High blood pressure, fainting, increased risk of arrhythmia, cardiac arrest, stroke6,7	The consumption of bitter orange is considered safe – the content of p-synephrine of ca. 0.1% in the raw material is not high enough to cause adverse cardiovascular effects. A review on adverse events (22 reports received by the US FDA, and 10 case reports from the published literature) concluded that causality between the bitter orange extract consumption and the occurrence of adverse effects could not be established. However, the use of concentrated extracts (containing 4-6% p-synephrine) in combination with caffeine is known to increase the risk of heart problems.11,12
Chaparral	Liver damage, kidney damage, death1,6,7	Known to cause liver injury in sensitive patients.11
Coltsfoot	Liver damage, cancer1,6,7	Coltsfoot leaves are known to contain hepatotoxic pyrrolizidine alkaloids (PAs). Products containing PAs cannot be legally sold in the USA since 2001.13 Currently available coltsfoot products for ingestion must be PA-free.
Comfrey	Liver damage, cancer, death1,6,7	Comfrey leaves and roots are known to contain hepatotoxic pyrrolizidine alkaloids (PAs). Products containing PAs cannot be legally sold in the USA since 2001.13 No deaths have been attributed to consumption of comfrey, but a number of cases of hepatic veno-occlusive disease.14 Currently available comfrey products for ingestion must be PA-free.
Germander	Liver damage, death1,6	Known liver toxic herb due to the presence of furano-diterpenes.15
Greater celandine	Liver damage1,7	Known to increase risk of liver injury in sensitive patients.16
Green tea extract	Dizziness, ringing in the ear, reduced iron absorption, exacerbation of anemia and glaucoma, increased blood pressure and heart rate, liver injury, death1	Case reports suggest involvement in liver injury in rare instances. Known to cause adverse events in people sensitive to caffeine.17,18
Heart-leaf sida	Arrhythmia, cardiac arrest, stroke, death7	Banned by the FDA in 2004 due to the contents of ephedrine.19
Kava	Liver damage, death1,6,7	The risks of liver damage are small, and toxicity possibly due to the use of inappropriate plant part, cultivar, and/or extraction method.
Lobelia	Breathing difficulty, rapid heartbeat, low blood pressure, diarrhea, dizziness, tremor, coma, death1,6,7	The toxicity of lobelia due to alkaloids in the plant is well established – use only under supervision of a qualified medical expert.11
Pennyroyal oil	Liver and kidney failure, nerve damage, convulsions, abdominal tenderness, burning of the throat, death1,6	Toxicity of pennyroyal oil, mainly due to the presence of pulegone, is well established. Current uses are mainly as an insect repellent, or in aromatherapy. Reported deaths have been due to attempts for self-induced abortion by ingesting substantial amounts of the oil, or after infants were given pennyroyal tea that was mistaken for another mint.11
Red yeast rice	Kidney and muscle problems, liver damage, hair loss, increased risk of statin drug adverse side effects when using concomittantly1	The listed adverse effects have been reported for conventional statin drugs. However, red yeast rice products that contain monacolin K or other statins cannot be legally sold as dietary supplements in the United States.20
Skullcap	Liver damage6	There is no known toxicity associated with skullcap. Case reports of liver damage were reportedly due to adulteration of skullcap with germander species, which are known to cause liver damage.21
Yohimbe	High blood pressure, heart arrhythmia, respiratory problems, cardiac arrest, death1,6,7	The adverse side effect profile of yohimbe bark is well documented. The most frequent adverse effects are anxiety and increased urinary frequency, but no known deaths due to ingestion of yohimbe bark.18 Other potential adverse effects for products containing yohimbine are increase of blood pressure and pulse rate, palpitation, dizziness, vomiting, gastric complaints, sweating, shivering, allergic reactions, and nervousness.11,22

Clarifications Regarding Herbs and Other Dietary Ingredients

The Consumer Reports “guide” makes a number of statements about the following botanicals and other ingredients used in dietary supplements that are misleading or warrant clarification and qualification.

• Aconite, Germander, and Pennyroyal Oil. Aconite (Aconitum carmichaelii, Ranunculaceae), germander (Teucrium chamaedrys, Lamiaceae), and pennyroyal (Mentha pulegium, Lamiaceae) are examples of botanical ingredients that are toxic. Neither aconite nor germander was listed as an herbal dietary supplement ingredient in sales data provided to ABC by the market research company SPINS, although processed aconite (in which the toxicity is reduced or altogether eliminated) is used in some traditional Chinese medicine formulas. Pennyroyal dietary supplements had sales of $1,517 in all combined market channels in 2015 (K. Kawa [SPINS] email, July 11, 2016), indicating its relatively low level of distribution and demand. The essential oil distilled from this plant is primarily used as an insect repellent, a fragrance, or in aromatherapy, but not as a dietary supplement ingredient (i.e, not for ingestion).
  
• Chaparral, Coltsfoot, Comfrey, Greater Celandine, Lobelia, Yohimbe, and Usnic Acid. The adverse event potential of chaparral (Larrea tridentata, Zygophyllaceae), coltsfoot (Tussilago farfara, Asteraceae), comfrey (Symphytum officinalis, Boraginaceae), greater celandine (Chelidonium majus, Papaveraceae), lobelia (Lobelia inflata, Campanulaceae), yohimbe (Pausinystalia johimbe, Rubiaceae), and usnic acid has been documented, and ingestion of these ingredients is not recommended. Taking lobelia or yohimbe supplements is advised only under supervision by a qualified expert. There is one case report of a man suffering a hypertensive crisis after ingestion of a yohimbe-containing herbal product, but there have been no deaths attributed to yohimbe bark to date.^11,22 The main uses of comfrey extracts are in topical formulations (ointments, creams and gels) to treat pain, inflammation and swelling of muscles and joints. According to Staiger, only pyrrolizidine-depleted or pyrrolizidine-free extracts are used in these products.²³ There is ample evidence of the safety of low-PA comfrey extracts in these external preparations.^23-25
• Bitter Orange. Traditional indications of bitter orange (Citrus × aurantium, Rutaceae) include the lack of appetite, fullness, or flatulence.²⁶ Extracts have also been marketed as ingredients in weight loss supplements. The peel contains trace amounts of the alkaloid p-synephrine. ²⁶ The concentrations of this alkaloid are not high enough to cause safety concerns. Indeed, a majority of adverse event case reports linked to bitter orange received by the US Food and Drug Administration (FDA) implicated products that contained other stimulant ingredients such as caffeine or ephedra (Ephedra sinica, Ephedraceae).²⁷ Some authors have mistakenly reported the occurrence of m-synephrine (phenylephrine) rather than p-synephrine in bitter orange.^28,29 Phenylephrine is used as an over-the-counter ingredient in nasal decongestants; it has different pharmacological actions and potential adverse events include high blood pressure and slow heart rate.³⁰ Another alkaloid that is chemically similar to p-synephrine, methylsynephrine (see below), has also been claimed to originate from bitter orange. However, natural occurrence of this compound could not be confirmed in authentic bitter orange peels.^31-33 The listing of these alkaloids as synonyms for bitter orange, e.g., on the WebMD website,³⁴ is misleading and adds to the already existing confusion about the composition, benefits, and adverse side effect potential of this ingredient.
• Methylsynephrine. Methylsynephrine is not a legal dietary ingredient. The question if the component could be derived from bitter orange was raised by the FDA in warning letters to seven companies selling what FDA stated was pure methylsynephrine in their supplement products,³⁵ but a search of available data do not provide evidence that methylsynephrine occurs naturally in bitter orange.
  
• Powdered caffeine. Caffeine is a natural component of several commonly consumed foods, including coffee (Coffea arabica, Rubiaceae), tea, chocolate (Theobroma cacao, Malvaceae), and yerba mate’ (Ilex paraguariensis, Aquifoliaceae). Powdered caffeine, however, cannot be legally sold in bulk. Various companies selling this material over the Internet have received warning letters from the FDA due to the inherent safety risk with ingesting excessive levels of caffeine. Caffeine can legally be added to dietary supplements when the ingested amount is within the safety margins established by scientific evidence.
  
• Green Tea. Tea is the second-most widely consumed beverage after water, and there is no safety concern in drinking green tea, a beverage made from dried tea leaves that have not yet undergone partial or full oxidation (processes that result in oolong and black tea, respectively). Extracts of green tea have been used for many years as a dietary supplement ingredient, mostly with no occurrence of adverse events. However, there have been case reports of liver damage associated with ingestion of dietary supplements containing green tea extract. The current scientific opinion suggests that there is a low risk of liver toxicity most likely in response to a higher susceptibility by sensitive individuals.^20,36 Since green tea polyphenols are known to chelate iron, the use of green tea extracts should be limited in people with iron deficiency. The link between green tea extract and glaucoma is unclear — study results suggest that there is no association between the intake of caffeinated tea and the occurrence of glaucoma.^37,38 Other adverse effects listed in the article are known for caffeine, a compound naturally occurring in green tea.
  
• Kava. The potential of certain extracts of kava (Piper methysticum, Piperaceae) to cause liver damage is recognized, and a few countries, such as Poland and Australia, currently restrict the sale of kava. (Germany had previously banned kava in food supplements and herbal medicinal preparations, but this ban has been lifted due to a German court ruling that the government did not follow appropriate procedures in its initial 2002 ban.) The causes of kava-associated liver toxicity are unclear, but may depend on the cultivar, the plant part (in particular the use of aerial parts), extraction method, or the presence of contaminants such as aflatoxins.^39-41 The cultivar “Noble,” which is typically used for kava drinking in the nations of the South Pacific, reportedly is not associated with liver damage. Therefore, the island of Vanuatu has restricted exports of kava to this particular cultivar, while other cultivars cannot be legally exported.⁴² According to a recent court decision in Germany, the potential of kava to relieve stress-related anxiety outweighs the relatively small risk of liver damage.⁴³ The decision was made after evaluation of the available scientific data, and after hearings that included testimony from expert toxicologists. In one of the arguments, the court stated that “The therapeutic alternatives proposed by the German Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) in every decision and expert statement, namely the benzodiazepines [e.g., antianxiety drugs like Valium], cannot be regarded as safer remedies.”⁴⁴
  
• Red Yeast Rice. Red yeast rice has been included in dietary supplements based on its centuries-old use in traditional Chinese medicine and food. The ingredient is made by fermenting rice with the purplish-red yeast Monascus purpureus (Monascaceae). The yeast is known to produce a number of cholesterol-lowering fungal metabolites that are known as statins (e.g., monacolin K [lovastatin]). Lovastatin (as Mevacor, Altoprev, and Altocor) is approved by the FDA as a prescription drug to lower cholesterol; typical dosages range from 10-80 mg per day. The amounts of monacolin K in authentic red yeast rice is approximately 0.2% (1.2-1.38 mg per 600 mg red yeast rice)⁴⁴ while total statin contents have been reported as 0.4%.⁴⁵ Monacolin K contents in dietary supplements ranged from 0.005%-1.83% (0.03-10.99 mg per 600 mg red yeast rice), while total statins were between 0.05-1.85% (0.31-11.15 mg per 600 mg red yeast rice).^46,47 In addition, some of the commercial products contained the mycotoxin citrinin, a contaminant compound known to cause liver and kidney toxicity.⁴⁶ Problems with supplements containing unknown levels of a prescription drug prompted the FDA in 2007 to send warning letters to companies selling red yeast rice dietary supplements.²⁰ Red yeast rice products that contain monacolin K or other statins cannot be legally sold as dietary supplements in the United States.
  

Additional Clarifications

The number of people cited in the article as reporting to emergency rooms every year after taking a supplement — 23,000 — is an estimate based on 3,667 actual cases published in a paper by Geller et al.⁴⁸ The authors of the cited publication evaluated case reports from emergency room visits in 63 hospitals, and extrapolated the number of adverse events linked to dietary supplement use to the total number of emergency room visits in all hospitals in the United States. Adverse events included allergic reactions, excess doses, unsupervised ingestion by children, or other events (e.g., choking on a tablet). More than 90% of these people were discharged without hospitalization.⁴⁸

The authors uncritically write that four out of five herbal supplements tested by the New York Attorney General’s (NY AG’s) office in 2015 did not contain the herbs listed on the labels. However, the authors did not mention that the method used in the test, DNA barcoding, is not suitable for processed ingredients (e.g., botanical extracts, such as those most often contained in finished dietary supplements). Even Dr. Cohen, one of the expert panel members for the Consumer Reports article, stated in an interview, “I think that does not ring true. It’s way, way out there. If you’d said 10% of the products couldn’t be identified, then I’d have believed that, but 80%? That’s unbelievable. If I had been doing the work, and we’d found this, then I’d immediately confirm with a tried and trusted method.”⁴⁹ Unfortunately, the writers and editors at Consumer Reports appear to have taken at face value the NY AG’s non-credible claims stemming from its ill-advised and not-fit-for-purpose testing protocols despite the well-documented accounts to the contrary.^50-52

While the article states that most people do not need a dietary supplement, the authors also state that “according to a Gallup survey of 200 physicians, 94% now recommend vitamins or minerals to some of their patients; 45% have recommended herbal supplements as well.” This seems to indicate that the large majority of physicians (at least of those who were surveyed) are convinced of the potential benefits of using a dietary supplement.

Industry Commitment to Quality Products

Many high-quality dietary supplements are available on the market today, but adulteration and contamination issues, including the illegal sale of pharmaceutical drugs masquerading as dietary supplements, need to be addressed. Resources at the FDA are not adequate to enforce current regulations effectively, but responsible members of the supplement industry have indicated an openness to work with regulators to improve the current system.

For example, in a poll during the conference on laboratory analysis organized in November 2015 by the United Natural Products Alliance (UNPA), a dietary supplement trade organization, 81% of the respondents were in favor of having dietary supplement products registered with the FDA prior to marketing, 80% were in favor of monographs that would provide standard manufacturing processes for botanicals, and 87% agreed that the FDA should have new authorities to remove/suspend sales of dietary supplements in “serious” cases (i.e., when there is an established unreasonable risk). Of the participants, 65% were dietary supplement brand manufacturers, contract manufacturers, or ingredient suppliers.

Finally, better education on the health benefits and risks associated with the use of dietary supplements is needed, and should include not only health care professionals, but also consumers, retailers, and members of the dietary supplement industry. However, Consumer Reports’ recent coverage, with its errors and potential misinformation, does not contribute adequately to identifying and addressing these important issues.

—Stefan Gafner, PhD

* The medical panel included the following individuals: Pieter Cohen, MD, assistant professor of medicine at Harvard Medical School; Philip L. Gregory, PharmD, associate professor at the School of Pharmacy and Health Professions at Creighton University; Arthur P. Grollman, MD, professor of experimental medicine at the Stony Brook University School of Medicine; Donald M. Marcus, MD, professor of medicine at Baylor College of Medicine; Paul A. Offit, MD, professor of pediatrics at the Children’s Hospital of Philadelphia; and Marvin M. Lipman, MD, professor emeritus of clinical medicine at the New York Medical, and chief medical advisor for the magazine.

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