Herbal Medicines Pose Potential Drug Interaction Hazard

A standing room only symposium audience at the annual meeting of the American Psychiatric Association considered the hazards and benefits of herbal medicines, and, perhaps for the first time since the 1960s era of psychedelic experimentation, reconsidered the therapeutic and research potential of hallucinogenic substances. The symposium, "Herbal Medicine: Ancient Roots to Modern Use," presented June 3 at the 151st annual meeting of the APA in Toronto, featured speakers from the National Institute of Mental Health (NIMH), the UCLA Department of Psychiatry and the Heffter Research Institute, a nonprofit institution in Santa Fe, N.M., devoted to furthering scientific investigation of hallucinogens.

The psychiatrists' apparent interest in natural medicinals may be driven by the rising popularity and widespread use of the products among the public. In one new research presentation at the APA meeting, investigators at the Medical University of South Carolina reported finding that 22% of 623 subjects recruited for a psychiatric medication clinical trial had used natural health substances within a month of participating in the trial (Emmanuel, 1998). A survey published in the Journal of the American Medical Association in May indicated that two in five Americans utilized some form of alternative medicine (Astin, 1998). In his editorial in the May 1 issue of Psychiatric News, APA president Herbert Sacks, M.D., advised that psychiatrists obtain complete medical histories by "closely query[ing] patients who may also be seeing an alternative medicine practitioner or self-medicating [Psychiatric News, 1998]."

It was partly a concern that many of his own psychiatric patients use an array of herbal substances that prompted Michael Smith, M.D., assistant professor of psychiatry at Harbor-UCLA Medical Center, Torrance, Calif., to broaden his investigation of disparate pharmacologic responses between ethnic groups, to include consideration of how these responses might be influenced by the herbal substances used for dietary and medicinal purposes. As an investigator in one of three research centers funded by the NIMH to study ethnicity, Smith found that his work in pharmacogenetics differentiating ethnic phenotypes of hepatic cytochrome P450 isoenzymes-was readily applicable to ascertaining the effects of herbal substances on CYP450 drug metabolism.

In his presentation, "Herbal Medicine and Psychiatry: Potential for Toxicity," Smith indicated that the CYP450 system can be as sensitive to dietary and medicinal herbs as to synthesized pharmaceuticals, and that there is significant potential for herb-drug interaction (see Table). In one example, CYP 3A3/4, 1A2 and 2A6 are inhibited by naringenin, a human metabolite of the bioflavonoid naringen, found in grapefruit as well as in plums and corn. Such flavones are also found in many herbal preparations, Smith indicated, often in higher concentrations than occur in the whole plant. The substrates of 3A3/4 that are potentially affected include nifedipine (Procardia), terfe-nadine (Seldane), alprazolam (Xanax), quetiapine (Seroquel), the investigational antipsychotic ziprasidone (Zeldox), and the anticonvulsants being investigated for bipolar affective disorder, lamotrigine (Lamictal) and gabapentin (Neurontin).

Quercitin, a bioflavonoid which inhibits 1A2, not only occurs in grapefruit, but in a range of herbal products, such as St. John's wort (Hypericum perforatum), kava (Piper methysticum), Ginkgo biloba, and valerian (Valeriana officinalis), used to affect mood or cognition. This substance in each of these plants could potentially, depending on the composition and potency of the herbal product, reduce metabolism of 1A2 substrates such as caffeine, theophylline and several psychiatric medications including haloperidol (Haldol), clozapine (Clozaril), olanzapine (Zyprexa) and the tertiary amine tricyclic antidepressants (e.g., amitriptyline [Elavil] and imipramine [Tofranil]).

Smith remarked on the irony that coffee breaks at the meeting were sponsored by the manufacturer of the antidepressant Luvox (fluvoxamine), another 1A2 inhibitor capable of heightening the plasma concentration of these substrates, including the caffeine being served.

Increasing drug plasma concentration by inhibiting metabolism of the drug is not always an adverse interaction, Smith pointed out, but may be a way to achieve or enhance therapeutic response. He described one patient who had not responded to olanzapine at recommended dosages, but who became more responsive as the olanzapine plasma concentration was initially increased with the addition of fluvoxamine, and then significantly elevated with the addition by the patient's father, unbeknownst to Smith of St. John's wort.

Smith recounted this case to Psychiatric Times, commenting, "We tripled the [olanzapine] concentration with the St. John's wort; meaning that there's a possibility that...assuming for the sake of argument that there's a direct dose to concentration relationship...it would take an approximate daily dose of 90 mg to produce that same result with just olanzapine by itself. "The addition of the St. John's wort by the father," Smith indicated, "produced the same result with a dramatic savings in olanzapine drug cost.

Questioned about the emergence of extrapyramidal symptoms (EPS) or other toxicity, Smith reported that the patient had not had EPS at the significantly elevated olanzapine serum levels produced with the St. John's wort, but had manifested this adverse reaction with a previous attempt at raising olanzapine levels by increasing the daily dosage to 30 mg. Smith opined that the absence of EPS with the addition of St. John's wort, despite markedly elevated olanzapine plasma levels, may be a function of the herb increasing dopamine in the nigrostriatal tract, which has been suggested in very preliminary research in animals (Müller, 1997). Such an effect could, Smith speculated, afford protection from EPS emerging from high-dose drug blockade of striatal dopamine receptors.

In addition to the well-characterized inhibition of 2D6 by fluoxetine (Prozac), paroxetine (Paxil) and other drugs affecting such substrates as tricyclic antidepressants and 1C-antiarrythmics Smith related that 2D6 inhibition has also been found to occur with a chili pepper (Piper longum) and black pepper (Piper nigrans).

"It turns out that [East] Indian 'Ayurveda' medicine used to use this combination with other herbal treatments, and we couldn't figure out why," Smith related. "People have speculated that it may have been to augment the effects of the main treatment," he said.

With an accurate history of diet, herbal and drug intake, and phenotype characteristics, one can understand, Smith said, "why it is that certain people based upon what they eat and their genetics may potentially do better on a lower dose."

A recent example of the potential for selective, therapeutic inhibition of CYP450 metabolism is the encouraging finding reported in Nature that individuals with a genetic deficit in 2A6 capacity to metabolize nicotine are less likely to begin smoking, and will tend to smoke fewer cigarettes if they do begin (Pianezza et al., 1998). Smith indicated that researchers are now pursuing a selective inhibitor of 2A6 which could be, in his words, an "Antabuse for nicotine."

These factors, with additional well-controlled interaction studies in humans, can also become the basis for the physician to modify dose response, Smith indicated, by selectively manipulating CYP hepatic drug metabolism.

References:

References

1.

Astin JA (1998), Why patients use alternative medicine: results of a national study. JAMA 279(19):1548-1553

2.

Emmanuel NP, Cosby C, Crawford M et al. (1998), Herb use in subjects assessed for clinical trials. New Research 302. Presented at the American Psychiatric Association 1998 Annual Meeting. June 2; Toronto.

3.

Müller WE, Rolli M, Schafer C, Hagner U (1997), Effects of

Hypericum

extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry 30(suppl2):102-107.

4.

Pianezza ML, Sellers EM, Tyndale RFG (1998), Nicotine metabolism defect reduces smoking. Nature 393(6687):750.

5.

Sacks HS (1998), Our medicated society: Fresh challenges posed by alternative medicine and marketing of psychopharmacologicals. Psychiatric News. May 1: 3, 43.