A Guggul Prescription for Drug Interactions

Google the term guggul and you’ll uncover a host of Web sites touting the virtues of fat-soluble extracts from India’s myrrh tree (Commiphora mukul). Most of the Internet buzz promotes the cholesterol-lowering attributes of guggulipids, although many Web sites also claim that these herbal products can also fight atherosclerosis, osteoarthritis, obesity, inflammation, diabetes, stroke—even acne and canker sores.

The herbal supplements are staples of Ayurvedic medicine, a 4,000-year-old set of Indian practices. Most of the Web sites selling the products seek to reassure would-be buyers that there’s science to support the power of guggulipids, especially in lowering cholesterol, by citing decades-old articles from journals in India.

Few of the promotional blurbs make any mention of an Aug. 13, 2003, report in the Journal of the American Medical Association. In it, Philippe O. Szapary of the University of Pennsylvania and his colleagues reported no advantage of guggulipids over a placebo during an 8-week trial in Philadelphia-area adults with elevated cholesterol. Indeed, that study reported, for this population of men and women, there were indications that guggulipids might actually raise blood concentrations of low-density lipoprotein (LDL) cholesterol, the type that has been linked to heart disease.

However, because the Food and Drug Administration doesn’t regulate herbal supplements in terms of their purported function—only their safety—manufacturers and suppliers are free to market such preparations even if they do absolutely nothing in the human body. However, a couple of recent studies have reported disquieting evidence indicating that guggulipids are anything but inert.

These studies show that the products’ active ingredients—a pair of mirror-image molecules known as guggulsterones—activate a molecule on many human-cell surfaces that serves as the master regulator of how the body processes most prescription drugs.

These findings suggest that taking guggulipids would reduce how long some medicines circulate in blood and therefore their efficacy. The drugs affected are all normally broken down, or metabolized, by an enzyme system known as CYP 3A4, notes David Moore of the Baylor College of Medicine in Houston.

St. John’s wort, a popular herbal antidepressant, is already known to lessen drugs’ action by tampering with the CYP 3A4 system. That became clear after transplant patients who had been surreptitiously taking St. John’s wort began rejecting their new organs despite taking drugs to prevent that complication (see We’re Very Supplemented).

Last year, in the Sept. 17, 2003, Journal of the American Medical Association, John S. Markowitz of the Medical University of South Carolina and his colleagues reported that St. John’s wort diminished the therapeutic efficacy of CYP 3A4-processed medicine by reducing the blood concentrations of those prescription drugs.

“Roughly 60 percent of all clinically prescribed medications are metabolized by CYP 3A4,” says Jeff Staudinger of the University of Kansas, who coauthored the most recent study on guggulsterones. How big a dose of these drugs a doctor will prescribe and how often they should be taken is usually based on data collected in people and animals with normally functioning CYP 3A4 systems.

If the CYP 3A4 system speeds up—which is what guggulsterones do to it—bigger, more frequent doses of a medicine are needed, Staudinger says. Affected drugs include commonly prescribed blood thinners, birth control pills, AIDS medicines, anticancer drugs, and a host of heart medicines, including cholesterol-lowering statins.

Moore says that when patients ask him for advice on a guggulipid supplement, he tells them to “give it a try” unless they’re taking a prescription medicine. Then he recommends steering clear of guggul remedies.

Herb’s a ‘dirty’ drug

Moore says he was prompted to investigate guggulipids because of a growing body of reports that the guggulsterones in them can lower cholesterol. Two years ago, his team reported that the herbal agents can cut cholesterol, at least in mice.

The scientists attributed the effect to guggulsterones’ inhibition of a cell-surface molecule known as FXR, which is essentially a receptor of bile acids. The connection made sense, because the body uses cholesterol to make bile acids, which help digest fat.

Moore took a guggul supplement himself and found that it lowered his cholesterol by 10 percent. However, he abruptly stopped taking the herbal preparation when further research by his team showed that the myrrh compounds in it also activate another cell receptor. This one is the pregnane X receptor—or PXR—the master controller of CYP 3A4.

The finding that “guggulsterones activate PXR strongly suggests that guggulipids should have effects on drug metabolism [in people].” Indeed, he adds, a decade-old report in an Indian medical journal showed that a single oral dose of a guggulipid diminished the blood concentration of two heart drugs in healthy volunteers.

This past August, Staudinger’s group decided to probe the PXR link further. In test-tube studies, the researchers measured how much guggulsterone was needed to turn on PXR and showed that the active amount was well within the range of concentrations that could occur in people taking guggul supplements at doses suggested by their manufacturers. His team’s data appear in the August Journal of Pharmacology and Experimental Therapeutics.

PXR is a receptor that is alert to foreign compounds, such as drugs. When it recognizes them, it signals the body to turn on its CYP 3A4-enzyme system and break down these materials. The more PXR receptors that are triggered, the more the CYP 3A4 system is stimulated to detoxify certain drugs.

The problem, Staudinger says, is that drug manufacturers don’t expect other CYP 3A4 triggers to be present in a patient’s body. The unexpected addition of a guggulsterone, he says, “will just accelerate the rate at which [the enzyme system] essentially chews up medications.”

He argues that all powerful drugs are “very dirty—they hit multiple systems.” Guggulipids qualify as such dirty drugs, despite their all-natural, herbal lineage. Not only do they inhibit the FXR receptor and turn on the PXR receptor, but they also can turn on receptors that normally respond to progesterone and estrogen, two sex hormones. In fact, Staudinger’s recent experiments show that guggulipids are effective hormone mimics.

Pharmaceutical companies usually try to tailor their products to have narrowly focused activity—for instance, synthetic hormones that dampen cell growth in the breast but not other organs. The value and risks associated with natural products such as guggulsterones, Staudinger argues, is their relative versatility when it comes to triggering processes within the body.

Caution urged

No rigorously controlled study has confirmed the impacts of gugguls’ CYP-activation on the efficacy of drugs in people. On the other hand, both Moore and Staudinger say that there’s no reason to think guggulipids wouldn’t affect the metabolism of prescribed drugs much differently from the destructive way that St. John’s wort does. Still, studies of that issue are needed, the researchers say.

In the absence of data from such trials, most Web sites pushing guggulipids merely point out that there have been few published side effects and no known reports of serious drug interactions.

In fact, Staudinger cautions, “any herb has the potential to act like a drug.” Indeed, most of today’s prescription drugs were derived from medicinal plants. What consumers must understand, both he and Moore argue, is that, like conventional pharmaceuticals, herbal products have the potential to both offer benefits and trigger side effects.