Herbal Supplements and the Brain: Understanding Their Health Benefits and Hazards by S.J. Enna and Stata Norton. Upper Saddle River, NJ: FT Press; 2012. Hardcover, 272 pages. ISBN: 978-0132824972. $34.99.

Herbal Supplements and the Brain is a rather unique book. While the subject matter is common to readers of HerbalGram, the fact that it’s written by two leading mainstream pharmacologists is, I believe, a first. S.J. Enna, PhD, is a particularly well-known neuropharmacologist who has been the editor of several pharmacology journals and is a past president of the American Society for Pharmacology and Experimental Therapeutics. the late Stata Norton, PhD, was a professor emeritus in the University of Kansas Medical Center’s Department of Pharmacology, Toxicology, and Therapeutics. As a pharmacologist myself, I was looking forward to the pharmacological perspective on these herbs.

The authors begin by reviewing the history of plants used as medicine, offering critiques along the way. Some inconsistencies nagged me from early on. In the history section, the authors claim that few botanical medicines were used by early humans for purposes similar to modern-day uses. Yet on the next page they acknowledge that a 30,000-year-old Neanderthal grave in Iraq revealed a medicine bag with flowers from six plants that are all used today for purposes that would have been very relevant to the cave man. They additionally assert that, in many cases, the active constituents of the plants are unknown, and that this makes it impossible to determine their effects in humans. This was a disappointing beginning and gave me the feeling that this viewpoint might carry on throughout the book. In a section on Hippocrates, there was discussion of how his humoral theory of disease held back the progress of medicine for hundreds of years. There was no mention of his statement that we should “let food be thy medicine and medicine be thy food.” There was also no mention of his famous contributions on the ethics of medicine including the physician’s oath “to abstain from doing harm.”

Chapter 3 is about “thinking like a pharmacologist.” While I have used this phrase myself, I must say that it felt uncomfortable to see the hubris present, and to read some of the tenants that I no longer hold to be “self-evident.” In reference to modern drug development and regulation, for example, the authors state that “… it is not necessary for consumers to be concerned about the safety and effectiveness of prescription or over-the-counter medications.” Wow... I’m not sure I ever believed that. I certainly don’t believe it now, after 15 years of experience reviewing the safety and efficacy of prescription drugs. While there is much reductionist thinking in this chapter, there is useful information about how to approach the study of identifying useful chemicals in a plant. A particularly useful strategy that persists throughout the book is the importance of determining whether bioactive molecules in a plant actually are absorbed into the body after oral administration. This simple exercise often can eliminate many of the potential candidates for active constituents of a plant that were identified previously by in vitro test results. The authors go on to say that one must demonstrate the presence of the molecule in the brain as well. This seems a bit of a stretch since this is not required of synthetic compounds. The authors appear to suggest that a good scientist should deny evidence (e.g., for sedation by a plant) that (1) has been used for this purpose for hundreds of years, and (2) that shows sedative effects in animals, unless and until we have positively identified a single component that reaches the brain in sufficient quantities and binds to a known brain receptor that could account for the pharmacologic property.

The next chapter drives this point home by discussing the brain as a “target” for medication. In covering the topic of neurotransmission, they suggest that a psychoactive drug must be shown to produce a measurable effect on a neurotransmitter receptor. My concern with this strategy is that it will produce only more drugs like the ones we already have. In a discussion of clinical trials, the authors propose that the crossover study is clearly the best design. In actuality, this is not the case, because crossover designs suffer from carryover effects and other problems of interpretation that limit their usefulness. Drs. Enna and Norton fail to mention the importance of an active control comparison in drug studies. If there is only placebo and test drug, the results cannot be interpreted unless there is a significant difference between the two groups. If neither treatment works, it is just as likely that the study design was poor as it is that the drug actually didn’t work. A positive control that works and a negative control that doesn’t (placebo) suggests you have a good study design that is capable of measuring the endpoint of interest. This is especially true for drugs that work on the central nervous system, where placebo rates as high as 50 percent are not uncommon.

Subsequent chapters deal with selected herbal medicines by reviewing their history, known chemistry, pharmacodynamics (drug action), and pharmacokinetics (drug absorption, distribution, metabolism, etc.). The chapters include the herbs Ginkgo biloba (Ginkgoaceae), St. John’s wort (Hypericum perforatum, Hypericaceae), valerian (Valeriana officinalis, Valerianaceae), lemon balm (Melissa officinalis, Lamiaceae), kava (Piper methysticum, Piperaceae), lavender (Lavandula angustifolia, Lamiaceae), kudzu (Pueraria montana, Fabaceae), daffodil (Narcissus pseudonarcissus, Amaryllidaceae), passion flower (Passiflora incarnata, Passifloraceae), and tea (Camellia sinensis, Theaceae), as well as selected caffeinated beverages. I found the coverage of these to be very uneven. This was especially the case for phytomedicines that are the subject of thousands of publications such as ginkgo and St. John’s wort. The vast literature was not evenly reviewed, and there were many missing references (that is, relevant statements were made without literature citations). Entire areas of relevant research and well-known research papers were unmentioned for these two herbs. While this is not surprising for authors who are not deeply experienced in this subject area, it was still disappointing as conclusions were being drawn without a basis in the available literature. On the other hand, the chapters dealing with lesser-researched plants (for which available literature could much more easily be grasped as a whole) seemed more comprehensive and thus more useful.

The title suggests that the purpose of the book is to understand the health benefits and hazards of plants acting on the central nervous system. I don’t know of any book that has been able to accomplish this. It’s a very tall order. For this purpose, there are other references that better review the literature, especially for ginkgo and St. John’s wort. I do think the book has a niche, however. Readers with an advanced degree in the life sciences will be much happier with this book and will be able to relate to it. In my opinion, the pharmacologic detail will be out of reach for most laypeople and consumers.

Those looking for a general reference guide or introduction to herbs will want to look elsewhere. And the sometimes condescending language that has found its way onto most pages may put off serious students of natural medicine. I absolutely agree that one must seek truth (if such a thing really exists in medicine) in an unbiased manner. But the scientist must realize that just because one explores truth on the molecular level, it does not mean that one is inherently free of bias, or that another’s truth on a different level of organization is somehow less useful. Learning what questions to ask and in what order to ask them is a useful skill and can be practiced while reading this book. But again, it leads to a pre-specified end, i.e., a single compound binding to a known receptor.

Mechanism of action is a highly interesting and useful tool. But I think we can expect that the pharmacologic effects (and mechanisms of action) of dietary supplements are going to be much more subtle than the ever more potent and selective world of synthetic pharmaceutics. If we are patient and keep an open mind, exploring these fascinating natural compounds will surely lead us to undreamed of systems, substrates, homeostatic processes, and epigenetic effects. The latter may begin to tell us what the things we eat are doing to us or for us.

—Jerry Cott, PhD
Pharmacologist, toxicologist
Silver Spring, MD