Herbal hazards: Which psychotropics interact with four common supplements

Recommendation. Limited data show a slight benefit in treating dementia by slowing cognitive and behavioral decline, but ginkgo biloba cannot be recommended as a first-line treatment until further controlled trials are available.

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ST. JOHN’S WORT FOR DEPRESSION

St. John’s wort (Hypericum perforatum), used to treat mild-to-moderate depression and anxiety,¹³ is one of the most-recognized herbal remedies. It accounted for 12% of the natural products used in the NCCAM survey. Several clinical trials assessing St. John’s wort are in progress and include placebo-controlled evaluations in obsessive-compulsive disorder and social phobia.¹⁴

As with ginkgo, St. John’s wort has many proposed active constituents; most preparations are standardized based on a hypericin content of 0.3%. Its mechanism of action in depression is unclear but laboratory models hint that it may be related to very mild inhibition of:

• monoamine oxidase (MAO)
• catechol-O-methyltransferase(COMT)
• selective serotonin reuptake
• interleukin-6 release (thereby increasing corticotropin-releasing hormone levels)
• norepinephrine uptake.¹⁵

Efficacy. St. John’s wort has been studied in mild, moderate, and major depression and compared with placebo and prescription therapies. In treating mild and moderate depression, St. John’s wort has been more effective than placebo and equivalent to tricyclic antidepressants.^16,17 Criticisms of these trials include lack of product standardization, lack of comparison with standard antidepressants at appropriate dosages, and small sample sizes. Larger trials comparing St. John’s wort with placebo and sertraline in treating major depression showed no difference in effect among the three.^18,19

Adverse effects are generally infrequent and include insomnia, anxiety, GI upset, and photosensitivity reactions.²⁰ St. John’s wort can induce hypomania and mania in patients with bipolar disorder and cause psychosis in schizophrenic patients.¹³

Drug-herb interactions. Of greatest concern with St. John’s wort use is the remarkable number of drug-herb interactions that have been identified (Table 2 and Table 3).^13,21 The primary mechanisms appear to be substantial induction of CYP 3A4, induction of P-glycoprotein mediated drug elimination, and—to a lesser extent—induction of other CYP isoenzymes.²² Interactions resulting in serotonin syndrome have been documented, with restlessness, sweating, and agitation.²³

The 3A4 isoenzyme metabolizes most drugs processed via the CYP system.¹² Severe interactions seen with St. John’s wort include:

• reduced cyclosporine levels, resulting in heart transplant rejection in two patients
• reduced antiretroviral levels in HIV patients
• pregnancy in women taking oral contraceptives.

Enzyme induction may persist for as long as 14 days after patients stop taking St. John’s wort.

Dosage. The recommended St. John’s wort dosage (using standardized 0.3% hypericin content) is 300 mg 2 or 3 times daily. Dosages of 1,200 to 1,800 mg/d have been used.^13,18 Benefits may not be seen for 2 to 3 weeks, and experience with use beyond 8 weeks in mild-to-moderate depression is very limited.

Recommendation. Advise patients to taper off St. John’s wort when stopping therapy to decrease the risk of withdrawal symptoms such as confusion, headache, nausea, insomnia, and fatigue.²¹ Given the high risk for drug interactions associated with St. John’s wort, we do not recommend its use in patients receiving any other medications.

KAVA KAVA AND LIVER TOXICITY

Kava kava (Piper methysticum) is used by some patients to treat anxiety and insomnia. Compared with other nutritional supplements, kava is less commonly used—by only 6.6% of adults using nutritional supplements,¹—and it is not being evaluated in NIH-sponsored trials.

The active-ingredient content varies considerably in kava root, so extracts are standardized to contain 70% kava-lactones (WS 1490). Although its exact mechanism is unclear, kava appears to:

• alter the limbic system
• inhibit monoamine oxidase type B (MAO-B)
• increase the number of gamma-aminobutyric acid (GABA) binding sites
• relax skeletal muscle
• produce anesthesia.²⁴

Table 2

Documented interactions with St. John’s wort