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From the Townsend Letter
February 2011

The Merck Manual Welcomes Alternative Medicine
by Stephanie Pina, ND, LAc, MSOM

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Stephanie PinaIt may seem like old news, but the 18th edition of the Merck Manual of Diagnosis and Therapy is the first edition to contain information about alternative medicine. Enter any medical office, medical student lounge, or library, or buy the latest medical iPhone application, and you will find at least a copy of the Merck Manual being used as a reference or paper weight. It is the oldest medical textbook written in English and has been translated into 15 different languages, serving as a tool to bring physicians, students, and the public together in their quest for updated medical knowledge. The 18th edition, published in 2006, became the first edition to include chapters covering complementary and alternative medicine, as well as dietary supplements beyond the basic nutrition review covering vitamins and minerals. This breakthrough was probably not given much attention by the natural medicine community, but the presence of these chapters in the Manual is a signal that the conventional medical community can no longer ignore the presence of other forms of medicine that patients have been seeking and asking questions about for years. The editors of Merck wrote: "The book must change or die," and this is much the same as the current state of medicine, which must reflect the therapies of the time and represent all aspects of health and healing.

The 18th edition of the
Merck Manual introduced these two chapters to serve as a baseline in informing any practitioner about natural medicine therapies and supplements commonly used by the average patient. The inclusion of "Complementary and Alternative Medicine (CAM)," chapter 330, and "Dietary Supplements," chapter 331, spans 12 pages in the 2991-page text. The first chapter briefly covers descriptions on different types of holistic treatments such as alterative medical systems like acupuncture, Ayurveda, and naturopathy; mind-body techniques including guided imagery and meditation; manipulative and body-based methods involving chiropractic care, reflexology, and Rolfing; and energy-based medicine discussing medical qi gong, magnets, and Reiki. The biologically based therapies include dietary therapy, herbalism, and orthomolecular medicine, described as the use of "megavitamin therapy" combined with naturally occurring substances like essential fatty acids for treating ADHD and chelation therapy for removing toxic materials from the blood, precede the section that describes the use of common supplements.

The "Dietary Supplements" chapter begins with an overview of guidelines set by the FDA as to the definition of a supplement as "any product (except tobacco) – in a pill, capsule, tablet, or liquid form – containing a vitamin, mineral, herb, amino acid, or other known dietary substance that is intended as a supplement to the normal diet."1 The chapter goes on to list basic requirements that all supplement manufacturing companies should include on their products, while mentioning the lack of regulation in processing and dosing of supplements. It briefly addresses the problem of the lack of evidence available to support health claims made on certain supplements. The bulk of the chapter lists the most popular and effective supplements at the time of publication. The
Merck also contains a graph reviewing possible dietary supplement–drug interactions, including some information not listed in the brief synopsis of each supplement (pp. 2726–2728). Overall, the chapter reviews 23 supplements: 16 single herbs, 5 dietary substances, and 2 hormones, DHEA and melatonin.
The Merck Manual Then and Now
  The first edition was printed in 1899 under the title of
Merck's Manual of the Materia Medica. Prior to this first edition, The Merck Index was printed in 1889 for the chemist community and for those seeking information about chemical components and substances.2 Robert Berkow, former editor of the Manual, reported that while there was little information about the first few editions until records on sale distribution started in the 1930s to 1950s, his research led him to conclude that there were two original versions. The first version was based on the British Pharmacopeia and printed in German, and another version based on the American Pharmacopeia was printed in America in English.3 Seventeen editions later, the purpose of the book is still to provide up-to-date medical information to the scientific community and public.

Additional publications from Merck include the
Merck Veterinary Manual (1955), Merck Manual of Geriatrics (1990), Merck Manual of Medical Information-Home Edition (1997), and the Merck Manual of Health and Aging (2004). For those who have ever purchased or referenced these books, each manual in itself is a whopping collection of almost rice–paper thin pages with small text font, 9-point Times Roman to be exact. In 2004 the Merck Online Medical Library became available, providing additional resources such as photos and videos not in the printed version. In October 2009 an iPhone application for the professional and home version was made available for those who wanted instant access to the Merck without having to carry around the current 2991-page edition. This goal of the company has always been to provide information while keeping the cost of the printed text at a minimum, and it has sustained that goal in recent years by making the entire manual, plus updated information, available online for free.

Merck Manual is published by Merck Research Laboratories, based in Whitehouse Station, New Jersey. This is a division of Merck & Co. Inc., the large American pharmaceutical company. New editions of the Manual have been published roughly every five to seven years since the great success of its first publication, with a slight delay in printing the fifth and sixth edition due to wartime hardships (1923) and the onset of the stock-market crash that preceded the Great Depression (1934).4 Merck Manual editors have always had their hands full prior to the publication of every edition, reviewing content, quality, and therapies that are constantly changing. Along with editing the actual content comes deciding what is the most pertinent information to be included and how to simplify each chapter while maintaining relevance to the topics. One editor wrote that it was not uncommon for there to be anywhere from 6 to 20 edits per submission.5

The 18th edition was no different, with a group of five main editors, including the late Mark Beers, and an editorial board of 13 to review and process the 278 contributors' pieces that were listed at the beginning of the book. Of those listed two names, John Astin, PhD, of California Pacific Medical Center, San Francisco, and Brian M. Berman, MD, from the Center of Integrative Medicine at University of Maryland School of Medicine, are given recognition for the "Complementary and Alternative Medicine" chapters. Since a majority of these pages cover the actual dietary supplements, this is where the focus of this article will remain.
Making the Grade for the Merck
The use of natural substances and herbs is not completely unfamiliar to the
Merck Manual, proving that what is old can become new again. When Merck published its centennial 17th edition in 1999, it included a copy of the original edition as a memento. That original edition was said to contain a variety of therapeutic poisons such as strychnine and listed some of the first drugs mentioned in the text as colchicine, cocaine, digitalis, and atropine – all active constituents of plants. Keryn Kane of the Merck Manuals Department wrote about how there were more than 100 diseases in which arsenic was a medicament for treating a variety of disease including jaundice, hydrophobia, and impotence.6 What was interesting was the use of what seemed like magical herbal substances like Aletris cordial, or false unicorn horn, and tobacco, then used to treat asthma and respiratory ailments; herbs not uncommon in modern-day herbalism that still maintain similar therapeutic properties.

The herbs and supplements included in the 18th edition spark less awe and wonderment for modern-day practitioners since the information pertaining to their use, health claims, and adverse effects is based on general knowledge and practical applications familiar to most alternative-medicine providers. Basic information in regard to the supplement's origins and current proof of evidence supporting its health claim and safe and effective daily dosage are given if known. It should be stressed that this formatting and information should be used as a baseline and guideline for upcoming information where time and stronger supporting evidence will lead not only to the expansion of this list but to their therapeutic usage, and even the change of the word
Claim to Indication.

Glucosamine and Chondroitin Sulfate
As popular joint support supplements, these two substances are included in the Merck Manual as separate entries but with a mention that they work best when combined. Both descriptions contain dose recommendations, not included with many of the other supplements. The recommendations are similar to those found on over-the-counter preparations. The potential mechanisms of action for these two substances are not indicated; however, improvement in glycosasminoglycan synthesis as a result of sulfate moiety is mentioned with glucosamine.7

Basic claims listed for both these supplements, supported by scientific evidence, deal with their ability to treat mild to moderate osteoarthritis by reducing joint pain and improving mobility. Merck also mentions that the analgesic effects of these two supplements may help in reducing of use of conventional anti-inflammatory drugs when taken for 6 to 24 months.8 Chondroitin has additional information in its online listing that indicates the use of caution for patients with asthma, blood disorders, and prostate cancer. In regard to chondroitin's potential effect on warfarin and blood-thinning disorders, also listed online, this may refer to the supplement's ability to potentiate anticoagulant medications, increasing INR levels; but no further information is listed in the Manual. The online caution of use of chondroitin in patients with known prostate cancer can be traced back to an observation that chondroitin appears higher in both decorin and versican prostatic proteins. Elevations of both proteins have been linked to recurrence of prostatic cancer. Glucosamine has limited cautions, and a potential allergic reaction due to its shellfish source is listed.

A Tale of Two Minerals – Chromium and Zinc
Chromium picolinate and zinc are the only two microminerals listed in both the nutritional disorders section, chapter 5 – "Mineral Deficiency and Toxicity," and in the "Dietary Supplements" chapter. The active role that both minerals play in basic metabolic processes is mentioned, more so with chromium since it is claimed to be involved in promoting weight loss, possibly through enhanced insulin function, increased muscle building, and lower triglycerides.8 Information on chromium in the nutrition chapter is brief, but in the dietary supplement chapter is mentioned the key role of the addition of a picolinate chelating agent to help with its absorption.

Just as picolinate helps with chromium absorption, it can also help with zinc absorption. Zinc acetate and gluconate are the only oral forms mentioned for their short-term use as lozenges used to relieve the common cold. Zinc's antioxidant effect is credited for slowing the progression of severe atrophic age-related maculopathy (dry form), which can be seen with its inclusion in numerous supplement formulations used to treat eye conditions that are available on the market.

The Infamous G Herbs – Garlic, Ginger, Ginkgo, Ginseng, Goldenseal
These herbs have been making their presence known in both conventional and alternative medicine for a long time, and there is constant debate on their potential uses and drug–herb interactions, mainly stemming from their interactions with cardiovascular medications. This group of herbs has been used by different medical systems for hundreds of years, and they remain some of the most popular herbs used today. The primary active constituents, allicin in garlic, gingergols in ginger, gingkolides and flavonoids in ginkgo seeds and leaves, saponin glycosides in the many variety of ginsengs, and hydrastine and berberine in goldenseal, all affect circulation and the blood. Many constituents are responsible for giving their respective herbs their distinctive odors and tastes. Improved blood flow to the head, through the blood vessels, to the sexual organs, and to immune organs are common functions in this group. Merck also highlights the potential supplement–drug interactions that each one may have, especially their effect on interfering with warfarin. Reactions between ginkgo and anticonvulsant drugs like phenytoin and ginseng's possible reaction with corticosteroids, estrogen, digoxin, and monoamine oxidase inhibitors (MAOIs) are also mentioned.9 The use of such traditional herbs will perhaps always be of great interest in years to come, perhaps due to their multiple indications according to traditional medicines from around the world. Not taken into account is the variety of species of each of these herbs, especially ginseng, and the difference that the use of the whole plant versus a portion of the plant plays in different medicinal functions.

Healthy Heart Function: Fish Oil and Coenzyme Q10
The Merck Manual describes the use of fish oil and its main component, omega-3 fatty acid, the most accurately in regard to general current knowledge in terms of its usage, dose administration, and overall benefits. Fish oil itself has advanced even more in research since the publication of the 18th edition, which should leave everyone wondering what updated information the next edition will contain. The common adverse reaction of concern is its effect on thinning of the blood; risk of bleeding; and interactions with antihypertensive, antiplatelet medications, and warfarin when taken at high doses, mentioned as above 3 g. Debates on the risk of bleeding continue even as a high-dose, FDA-approved pharmaceutical fish oil medication has entered the market providing 4 g per day to patients to treat high triglyceride levels. Fish oil is mentioning as a successful orthomolecular therapy in the treatment of ADHD, a promising sign that increasing evidence is being reviewed and taken into consideration as to other noncardiovascular effects that it has on the body.

On the opposite end of the spectrum, heart-protecting and antioxidant coenzyme Q10 has very little information presented in its description. The Manual mentions its role in energy metabolism and diminished presence with age and in patients with chronic degenerative diseases. The mechanism of action is not listed. This is another dietary supplement that should be expanded upon in upcoming editions as more evidence is collected on its potential uses.

Of Herbs and Hormones: Saw Palmetto and Black Cohosh
Lately, herbal remedies that affect hormone synthesis and metabolism have received great attention due to rising interest in natural remedies for treating menopausal symptoms, low libido, and hormone-based cancers. Saw palmetto is an herb well known for its ability to regulate prostate gland inflammation as a 5a-reductase inhibitor, affecting the conversion of testosterone to dihydrotestosterone. Its effects on androgen conversion and inhibition of the binding of sex hormones are suggested as a possible mechanism of action, but the Manual suggests that not enough evidence is available to prove claims of reversing prostate hypertrophy.10 There is no mention of its anti-inflammatory and antispasmodic properties that can contribute to improved urinary function in cases of hypertrophy. There is a mention of the herb's possible interaction with another sex hormone, estrogen, as it cautions pregnant women or those who may become pregnant not to take the herb.

The other herb receiving great attention due to its possible hormonal influences is black cohosh. The Manual notes that the rhizome portion of the plant does not contain phytoestrogen that can account for reported estrogenlike effects which are claimed to be the source of the herb's ability to relieve hot flashes, mood swings, and other menopausal symptoms. In fact, the only active ingredient mentioned in regard to this supplement is its small amount of salicylic acid providing an anti-inflammatory effect. This is surprising, considering the amount of research reported on the use of the herb throughout the world and positive review for treating menopausal symptoms by the German Commission E monograph.11 Aspirin sensitivity is listed as a contraindication in taking the herb.

The Notorious Herbs: Milk Thistle and St. John's Wort
The Merck Manual included two herbs that have been of great interest to the medical community for some time, mainly due to their potential for drug–herb interactions. Milk thistle and St. John's wort have been alleged to be able to affect liver enzyme function and alter liver metabolism of many medications that require the cytochrome P450 system. Milk thistle has little information written on it, but Merck does mention that its active ingredient, silymarin, has the ability to increase levels of intrahepatic glutathione. It has been suggested that this may be the key to protecting the liver, since glutathione is a necessary component in detoxification. St. John's wort is praised in the Merck as a well-researched herb with strong scientific evidence supporting its use in the treatment of mild to moderate depression. It is suggested that the mechanism of action, although unknown, may be related to its ability to increased levels of serotonin in the central nervous system. Dosage recommendations based on standardized extract preparations are listed, and caution is given to those taking other medications that affect serotonin levels and pregnant women.

Other Dietary Supplements
Two hormones – DHEA, mentioned as an adrenal hormone and proclaimed the "anti-aging" supplement, and melatonin, mentioned only for its unproven claim to help with jet lag and mild insomnia – are also listed in this chapter. Valerian root and kava, which have been widely used in Europe and are gaining popularity in the US, are referenced for their anxiolytic, sleep-enhancing effects. The Merck mentions that the FDA may have been prompted to mandate warning labels on kava products after over 20 people in Europe developed liver toxicity and/or failure after using the herb. Additional adverse effects such as neurologic damage, changes in blood chemistry, and possibility of the potentiating sedative-based medications are also listed with high dose usage. No information was listed as to short-term complications.

Additional supplements, such as green tea for its antioxidant effects, chamomile for its ability to soothe the digestive system, and feverfew for its anti-inflammatory and relaxant abilities, are also listed. Creatine and S-adenosyl-L-methionine (SAMe) are commonly seen supplements in nutrition and health-food stores used to enhance muscle development and in the treatment of depression and osteoarthritis pain. The hard-copy publication mentions SAMe's contraindications for patients with bipolar disorder, due to its ability to potentiate manic episodes.12 It has been known to affect neurotransmitters such as serotonin, making possible interaction with selective serotonin reuptake inhibitors (SSRIs) and MAOIs a reasonable concern.

In addition to the above dietary supplements, licorice and cranberry are in the online library. Information describing licorice's effects includes its claim to relieve sore throat and soothe coughs, while not enough clinical evidence is present to justify its claims of reversing stomach ulcers and gastric irritation. A majority of the information presented on licorice is on its main constituent, glycyrrhizic acid, and its effect on the kidney to potentiate the secretion of potassium, which may raise blood pressure. It is noted that the licorice flavoring in most candy products is not from natural sources. Cranberry's use has increased as its role in raising the acidity of urine to treat urinary tract infections, especially those caused by Escherichia coli, has become popular knowledge. The Merck does mention that there is strong evidence supporting this claim when cranberry juice used is the unsweetened type.

The Future of the Merck Manual – Edition 19
Therefore, any Physician who will propose improvements in the subject-matter... or in the arrangement, style, and form of this work, for future editions, will thus be rending valuable service, not only to its Publishers, but to the entire Profession as well!13
~A note to the readers of the First Edition of the Merck Manual, 1899

The Merck Manual has proved itself over the past century as a medical text and a document that is aware of changing medical thoughts and treatments. The inclusion of dietary supplements and recognition of different forms of alternative therapies is the first step toward identifying the need for change in medicine. These chapters serve as a link connecting Merck's first edition, when herbs and "poisons" were used and suppressive drugs were not an option, to the present. One can hope that, with the release of the 19th edition, increased use and updating of online medical resources, and the increased availability of electronic medical applications, there will be greater chances to provide the entire medical community and public with updated information about supplements and natural medicines. Other popular medical texts such as Harrison's Principles of Internal Medicine, published by McGraw-Hill, which is already including sections on alternative medicine starting with its 15th edition in 2001, will also help spread valuable information about potential natural treatments. Overall, our complementary and alternative medicine needs to be incorporated into mainstream medical information that gets out to other practitioners and the public in order for it to develop and grow. A book like the Merck Manual is and will be a staple in all forms of medical education for years to come; so for our medicine to be understood, it has to make its presence known in clinical settings and the written word.

1.  Beers M, Porter R, eds. Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:v–vii.
2.  Lane K, Berkow R. The Merck Manual: a century of medical publishing. CBE Views. 1999;22 (NR4):112–113.
3.  Berkow R. The book as mass commodity: the Merck Manual: "Firm and Faithful Help." Pub Res Q. 1987;3(1):56–59.
4.  Lane & Berkow, op. cit.
5.  Berkow, op. cit.
6.  Lane & Berkow, op. cit.
7.  Beers & Porter, op cit., 2728–2731.
8.  Ibid., 2728.
9.  Ibid., 2726–2731.
10.  Ibid., 2732.
11.  Mills S, Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine. London: Churchill Livingston;2000:303–310.
12.  Beers& Porter, op. cit. :2732.
13.  Berkow, op. cit.

Stephanie Pina is a licensed acupuncturist currently practicing at the Roselle
Center for Healing, an integrative medical office in Fairfax, Virginia, and a
licensed naturopath (Arizona). She completed her doctorate from Southwest College of Naturopathic Medicine and master's in Oriental Medicine from Phoenix Institute of Herbal Medicine and Acupuncture. She enjoys writing and lecturing on a variety of natural medicine topics. She has been previously published in To Your Health Magazine, Natural Awakenings, and the Townsend Letter. She can be reached at

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