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Herbal dietary supplements are the fastest growing product category in drug stores today, and fully three-fourths of the world's population rely on herbal medications to treat mental illness, according to panelists at an APA annual meeting symposium in Toronto in June.
That millions of people rely on herbs is no historical anomaly, but the recent resurgence of interest in herbs in Western medicine is striking, observed discussant Robert McCaleb, a doctoral candidate in botany and president of the Herb Research Foundation. The foundation maintains a database on herbal medicines, including recommended dosages and potential drug interactions, that may be accessed on the World Wide Web.
It is a nearly inviolable tenet of contemporary Western pharmacology that isolated, purified compounds are therapeutically superior to whole-plant preparations, and the isolation of such compounds is frequently portrayed as synonymous with progress in pharmacology. But the combination of technologically sophisticated receptor-binding studies and evaluations of efficacy of whole-plant extracts versus single compounds is causing some scientists to rethink this model. Although pure chemical compounds are often preferable, there is growing evidence that the therapeutic efficacy of certain herbs is optimized not through isolation of a single active compound, but rather through the synergy of the entire plant. For many pharmacologists, however, such thinking remains heresy.
One scientist who has researched the efficacy of whole-plant extracts versus single compounds is Jerry Cott, Ph.D., chief of the adult psychopharmacology research program at the National Institute of Mental Health (NIMH) in Bethesda, Md. His specialty is central nervous system drug development. Cott recently received approval from NIMH for a large, multicenter clinical trial to test the efficacy of St. John's Wort for major depression. The trial is slated to begin this October.
The history of pharmacology is "really the history of medicinal plants," and Western medicine owes a great debt to traditional, ethnic herbalists, who introduced many of the most important remedies to the world, often with little credit, said Cott. In North America, one-fourth of all prescriptions are for plant products or plant-based products, generally used in ways that "directly correlate to their traditional use."
Why would a contemporary pharmacologist focus on herbal medicine? It is "because of my dissatisfaction with the way we've been introducing new medications" in Western medicine, Cott commented. "I worked for drug companies for many years, and I worked at the Food and Drug Administration reviewing new drugs, and it's really true that most of our new drugs are incremental improvements on the ones that we already have. Most of those were discovered by accident or discovered because of their traditional use."
Even with the advent of molecular pharmacology, there is a need for "new medications that have unique mechanisms of action, and there's really not that many coming out, especially in psychopharmacology."
Despite the ballyhoo over selective serotonin reuptake inhibitors (SSRIs), for example, the drugs, while useful, are no more effective than the old tricyclics such as imipramine, despite a better side-effect profile.
"We're still churning out uptake inhibitors, and we haven't really advanced the field, in my estimation," said Cott.
The misguided notion that there must be one primary active ingredient in a medicinal herb has led Western pharmacologists to overlook the possibility that the most active compound in a plant may not reflect the totality of the plant's therapeutic potential. And for some reason, said Cott, it is often the most toxic compound in a plant that ends up being identified as the key to the plant's medical efficacy.
"If you look at the pharmacology and toxicology of these compounds, invariably the compound that's identified with the plant is the most toxic compound in the plant," he remarked. This may be because the more subtle actions of the various constituents as a whole are harder to quantify than those of a readily reproducible single compound.
A dramatic example involves the plant Rauwolfia serpentina, from which the compound reserpine has been extracted and identified as "the essence of Rauwolfia," said Cott. Although reserpine is a useful anti-psychotic and antihypertensive, it is the most toxic compound in Rauwolfia, and based on receptor-binding analysis of whole Rauwolfia extract versus reserpine, not the only potentially therapeutic compound in the plant, according to Cott. He found the crude extract had a high affinity for receptors to which pure reserpine does not bind.
On the basis of other pharmacological research, this binding profile suggests that the whole-plant extract of Rauwolfia may possess some properties of an atypical antipsychotic, that is, high antipsychotic efficacy with few side effects. It is possible that "we're actually throwing away some of the good stuff when we isolate reserpine," said Cott.
St. John's Wort preparations are currently standardized to the compound hypericin, which is the most toxic compound in the plant, but Cott is convinced that it is not the key or only active constituent. He also doubts the prevailing hypothesis that St. John's Wort works by inhibiting the reuptake of serotonin. Whole-plant extracts of the herb bind tightly to gamma aminobutyric acid (GABA) receptors, and Cott believes that this, not SSRI-like activity, is more likely responsible for the plant's therapeutic efficacy.
Herbals, while possibly safer than conventional prescription drugs, are not without risks, observed session chair Michael W. Smith, M.D., an assistant clinical professor of psychiatry at the Research Center on the Psychobiology of Ethnicity at Harbor-UCLA Medical Center. Many of the problems related to herbal medicine result not from the herbs themselves, but from contamination, adulteration, and mis-identification, he said. Some Chinese herbal preparations were found to be adulterated with drugs including ibuprofen and diazepam or, in a few cases, heavy metals such as lead. Such deliberate adulteration of herbs with chemical compounds has not been a problem with herbs grown in the United States for domestic use.
Even absent contamination, however, herbs occasionally cause difficulties. Some patients may use an herb instead of consulting a physician for an undiagnosed but serious medical condition that would respond better to conventional medicine. Overdosing and excessive chronic use of some herbs, particularly ephedra and yohimbine, have caused toxicity, Smith observed.
Another problem is herb-drug interactions. Reports of such difficulties are relatively rare, but one symposium participant reported such an interaction involving St. John's Wort and sertraline (Zoloft), which resolved when the patient discontinued the herb.
Conversely, said Smith, it is possible to use herb-drug interactions to increase therapeutic efficacy and cut the cost of therapy. He described a dramatic example from his own practice involving a patient with schizophrenia. In this case, the patient had proven resistant to virtually every major atypical antipsychotic drug. Smith had failed to produce adequate blood levels of olanzapine at normal therapeutic doses, but when he combined a normal dose of olanzapine with a normal dose of St. John's Wort, he saw a dramatic turnaround.
The patient, who hadn't spoken in full sentences for 18 years, returned to Smith's office speaking coherently after a short time on the St. John's Wort-olanzapine combination. A blood test revealed that the combination had produced a dramatic rise in olanzapine levels.
Used rationally, such combinations may enhance drug efficacy, said Smith, but when the physician or patient fails to factor in herb use, herbs may complicate other drug therapies.
Diet may also augment or interfere with drug therapies, raising or lowering blood levels, said Smith. Such common foods as corn, broccoli, carrots, and chili peppers have been shown to affect blood levels of some psychiatric drugs, he noted.
The Herb Research Foundation Web site is