Botanicals are dietary supplements derived from plant sources that have purported health benefits. Echinacea for the common cold, St. John’s Wort for depression, ginkgo biloba for memory improvement and ginseng for energy enhancement are typical examples. Generally such products are assumed to be safe because they are “natural.” Of course whether a substance is natural or not has nothing to do with its efficacy or toxicity. The only way to determine these is by experimentation. But when it comes to botanicals, such experimentation is not easy.
 Contrary to prescription drugs which tend to be single chemical entities and are quite amenable to testing at different doses, botanicals are complex mixtures. Panax ginseng, for example, has been found to contain over five hundred different compounds! Different varieties of ginseng will have different chemical profiles and even for one specific variety the composition will depend on when it is harvested, how much sun exposure it has seen and how it is processed. Attempts are sometimes made at standardization, but that also presents problems. Take the case of St. Johns Wort. Dozens of compounds have been identified in this plantt with one, hypericin, usually being the subject of standardization because it is readily tested for. Hypericin does not have any anti-depressant activity but the thinking is that if a supplement contains a given dose of this compound, all the other compounds will be present in a fixed ratio. Actually, this is not the case.
 The best candidate for the antidepressant effect of St. John’s Worth is hyperforin, a compound that boosts the activity of serotonin, norepinephrine and dopamine, all neurotransmitters that are associated with mood elevation. It turns out, however, that the amount of hyperforin in an extract of St. John’s Wort is unrelated to the amount of hypericin, so that different supplements may have significantly different activity even if they are standardized to 0.3% hypericin, which is commonly done. Obviously, standardization should be in terms of hyperforin.
 But this is not the biggest problem with St. John’s Wort. The major concern is that it can cross react with other medications, enhancing or detracting from their effect. Since St. John’s Wort increases serotonin levels, it can result in “serotonin syndrome” if taken concurrently with drugs that have a similar effect, such as the serotonin reuptake inhibitors (SSRIs). Symptoms can range from tremor and diarrhea to very dangerous confusion, muscle stiffness, drop in body temperature, and possibly even death.
Another issue is that hyperforin can activate genes that code for the production of Cytochrome P450 3A4, an enzyme found mainly in the liver and in the small intestine that oxidizes small foreign organic molecules, such as toxins or drugs, so that they can be removed from the body. Digoxin, used to treat congestive heart failure, is an example of a drug that is eliminated from the body via reaction with this enzyme. If the enzyme levels are unusually high because of ingested hyperforin, the drug will be more quickly eliminated, reducing its efficacy. Dozens of prescription drugs are metabolized by the cytochrome P-450 enzymes, meaning that people taking them should stay away from St. John’s Wort. A number of “miracle babies” have been born to women who took St. John’s Wort while they were also taking the birth control pill.
