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essay by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon

Since the initial reports of HIV infection in the U.S. in the early 1980s, a large number of people with this disease have pursued herbal remedies. Prior to the development of highly effective anti-HIV drug combinations, thousands of HIV infected people tried a variety of herbal therapies to boost their immune systems, inhibit opportunistic infections, alleviate symptoms, and inhibit HIV itself. Due to the deadliness of the disease, preliminary studies, many of them in vitro only, were grasped at as hope for a cure or effective limitation of the disease, and a variety of natural substances were tried, including roots of leguminous plants, such as licorice and astragalus, Oriental medicinal mushrooms, and ordinary garlic. From about 1983, when the viral nature of the disease was established, until 1995, when the drug cocktails became available, a culture of using herbs for people with HIV had developed. This occurred especially in large cities, and with an emphasis on Chinese herbs, since the main licensed health profession in the U.S. involving herb prescribing is acupuncture (licensing in a few states has been granted for naturopaths, who also prescribe herbs). During that time, none of the herbs had been shown to be substantially effective for inhibiting HIV, but many people were convinced that they helped, some to the point that they considered herbal supplements to be life-saving.

It is not surprising, then, that even after highly active drug therapies were developed many of those with HIV infection continued to use herbs. The drug therapies did not cure the disease, so herbs were sought to provide additional protection from the virus and to restore the damaged immune functions. Herbs were also considered a possible means to minimize drug side effects. The situation surrounding HIV infection appeared brighter in the late 1990s, with the virus better controlled and with herbs apparently able to help alleviate a variety of symptoms as well as reducing the anxiety that accompanies taking drugs that are, in the view of many, toxic substances.

What did come as a surprise was news-emerging first in 1999 and formally published in 2000-that a very popular herb, St. John's Wort, appeared to lower indinavir blood levels significantly. This herb, Hypericum perforatum, had been used primarily for its anti-depressant actions, but it also had been shown in laboratory tests to possess HIV-inhibiting action, which attracted HIV-infected patients to the herb even more. The reports of indinavir interaction were soon accompanied by other reports suggesting that this herb interacted with a very wide range of drugs, from birth control pills to warfarin, with the same potential adverse consequence: lowering the drug dosage to an ineffective level.

The growth in popularity of St. John's Wort had been driven by a number of published controlled clinical studies of its effectiveness as an antidepressant beginning in 1993, and it rapidly became one of the top selling herbs. From 1997-2000, for example, it was the 5th largest selling herb in the U.S., with retail sales of about $48 million dollars. The news about herb-drug interactions triggered a retreat from reliance on this herb, a change that was intensified when some new clinical reports, beginning with one published in JAMA in 2001, questioned its efficacy for depression. Then the drop-off began: by 2002, the sales of St. John's Wort were cut in half compared to their peak levels, and by 2003 they had declined by another 40%. The herb in no longer extensively used, although it is still available and some consumers remain unaware of its effects on drug levels.

The mechanism of herb-drug interaction with St. John's Wort has been elucidated, and the greatest concern is focused on medications that are substrates on CYP3A4; this enzyme degrades many drugs. St. John's Wort induces production of the enzyme, hence the drugs are degraded faster. This is the same enzyme that is inhibited by grapefruit juice, which has the opposite effect of increasing drug levels in the blood. Both St. John's Wort and grapefruit juice are among the strongest of the known natural substances that affect drug levels when consumed at ordinary doses. In addition to CYP3A4, St. John's Wort affects phosphorylated glycoprotein (P-glycoprotein or Pgp), which also metabolizes drugs. Aside from indinavir, the metabolism of other protease inhibitor anti-HIV drugs are also affected by St. John's Wort.

The question then arises: how many other herbs might have this effect on the drugs of concern for people with HIV? Fortunately, it appears that few other commonly used herb materials have such a dramatic effect. Just as fruits other than grapefruit have minimal impact on drug metabolism, so too, herbs other than St. John's Wort appear to have limited effect. St. John's Wort has an unusual ingredient, hypericin (pictured below), that confers the high level of activity.

Chemical structure of hypericin
Chemical structure of hypericin

As mentioned, many people with HIV use herbs routinely; they usually have their viral load tests done at intervals (typically six months to a year) to monitor continuing efficacy of their drug treatment. Thus far, St. John's Wort is the only herb that has been demonstrated to actually affect blood levels of HIV drugs in people. However, induction of CYP3A4 does occur to some extent with several herbs and components isolated from herbs, such as kaempherol and quercetin (which are also found in ordinary foods, such as fruits, vegetables, and tea) and allicin (in garlic). High doses of quercetin may be given as an antioxidant and even higher doses are recommended to inhibit allergies. The antioxidant levels of quercetin (typically less than 1 gram) have been used by thousands of HIV infected individuals while utilizing the drug cocktails, seemingly without adverse consequence; the higher doses (up to 2 grams per day) are used less frequently and the effects may remain unknown.

A difficulty with detecting actual herb-drug interactions is the complexity of individual cases where the interaction may occur, as well as the problem of poor reporting. One can easily get the sense from reading medical literature that herb-drug interactions are a rampant problem. However, a review of that literature, based on an intensive search for and evaluation of herb-drug interaction reports, yielded the following: "108 cases of suspected interactions were found: 68.5% were classified as 'unable to be evaluated,' 13% as 'well-documented' and 18.5% as 'possible' interactions. Warfarin was the most common drug (18 cases) and St. John's Wort the most common herb (54 cases) involved." In another evaluation of the literature published two years later, it was observed that there were very few well-supported interactions detected: namely 22 that involved more than an individual report, or a simple pharmacology study, or a mere suggestion of potential interaction. The main drug of concern again was Warfarin and the primary herb was St. John's Wort. In all, it appeared that the rate of well-documented herb-drug interactions has been about 4 per year. No doubt, many more instances occurred and were not reported, perhaps due to their minor nature or uncertainty in attributing the cause. Even so, the numbers should be kept in perspective: the nutriceutical industry estimated (for 1999) that 21 million adults are regular users of herbal remedies, so the rate of serious herb-drug interactions appears to be quite small given the high level of prescription and OTC drug use in this country.

There are a number of steps to take in order to avoid herb-drug interactions, of which avoiding St. John's Wort is the most important. Caution should be taken when consuming herbs in large doses, since the higher dose provides an opportunity for affecting drug metabolizing enzymes. Before embarking on use of any herb at high dosage, it is important to check the current literature, which is done quite effectively by using the free PubMed website ( For example, if one types into the search box "Indinavir, herb-drug interactions," several article abstracts will be made available (14 of them as of January 2005). The articles mostly focus on St. John's Wort, but some abstracts mention numerous other herbs that show some effect on the same enzyme systems in laboratory experiments. Those who wish to be maximally cautious about the interactions may wish to avoid the mentioned herbs altogether, while others might simply avoid high dosage preparations that include them.

Since 1992, The Institute for Traditional Medicine has operated a clinic in Portland, Oregon that has provided Chinese medicine to patients with HIV and has provided support to similar clinics in San Francisco and elsewhere. Patients at these facilities take their prescribed drug cocktails and also utilize high-dosage protocols involving herbs (St. John's Wort is not among them) and have not reported increases in viral load or suspicion of herb-drug interactions. While such informal monitoring does not provide clear evidence for the absence of such interactions, the apparent lack of adverse effects is entirely consistent with the findings mentioned above for formal medical reports: that herb-drug interaction incidents are infrequent.

February 2005