From the Spring 2002 issue of Nutrition Science News
Marilyn Sterling, R.D.
There was a lot of controversy raised regarding St. John's wort (Hypericum perforatum) last year following a study published in JAMA that discredited the herb's use in treating outpatients with major depression. 
Although the study drew concern, Jerry Cott, Ph.D., former chief of the Psychopharmacology Research Program at the National Institute of Mental Health in Bethesda, Md., responded by saying the study does not invalidate the use of the herb for mild-to-moderate depression. He called the study flawed because there was no active pharmaceutical drug used to compare with the herb and placebo.
Mark Blumenthal, founder and executive director of the American Botanical Council in Austin, Texas, stated that most clinical studies on St. John's wort, many of which were conducted in Europe, were targeted at cases of mild-to-moderate depressionnever at major or severe depression.
The study was conducted at Vanderbilt University and funded by Pfizer, the pharmaceutical manufacturer of Zoloft, a leading synthetic antidepressant medication.
Mechanisms Of Action
Although that study made headlines, other current studies on St. John's wort have concentrated on two areas: determining why it works and identifying potential side effects and drug interactions.
First, the good news: St. John's wort is as effective at relieving mild-to-moderate depression as the most commonly prescribed antidepressants, the selective serotonin reuptake inhibitors (SSRIs).
Researchers at St. John's Episcopal Hospital in Far Rockaway, N.Y., used a double-blind, randomized format to study 19 women and 11 men (average age 45) with mild-to-moderate depression. The subjects took either 900 mg/day St. John's wort or 75 mg/day SSRI sertraline for six weeks. Using the Hamilton Rating Scale for Depression, 47 percent of those taking St. John's wort improved compared with 40 percent of those taking the sertraline. 
In the past year, scientists have begun to explore how St. John's wort ameliorates depression. SSRIs prevent neurons from reabsorbing serotonin, leaving more of the neurotransmitter available to stimulate neuron firing, thereby improving mood.
In recent animal studies, researchers have documented that serotonin levels in the brain's hypothalamus and hippocampus are boosted by as little as 10 mg/kg body weight of St. John's wort.
In an animal study at the University of Bern in Switzerland, researchers concluded that St. John's wort contains active, but yet unknown, principles that are comparable to tricyclic antidepressants (TCAs) and SSRI-type antidepressants. 
When people take St. John's wort, tryptophan (the amino acid precursor to serotonin) levels in their blood drop, providing additional evidence that the herb boosts serotonin. The way St. John's wort increases serotonin levels is completely different from the mechanism of traditional antidepressant drugs, namely the older monoamine oxidase inhibitors and the current generation of SSRIs. 
SSRIs' effectiveness has made serotonin the focus of depression treatment. However, this may be too simplistic an approach. Researchers now understand that depression is a complex systemic illness involving multiple neurotransmitters, hormones, and the immune system. Depression alters levels of numerous neuropeptides, including norepinephrine and dopamine.
However, in an animal study at the Karolinska Institutet in Stockholm, Sweden, researchers concluded that St. John's wort taken in high doses can probably affect the neuronal 5-HT uptake mechanisms in a manner more reminiscent of TCAs than SSRIs. They believe hyperforin may play a major role in hypericum's (i.e., St. John's wort) action. Hypericum may enhance both 5-HT and noradrenaline transmission in the forebrain of the limbic brain circuits. Since this part of the brain controls mood, it could explain the antidepressant effects. 
There is increasing evidence that St. John's wort affects other neurotransmitters. The most neuro-active component of St. John's wort, hyperforin, inhibits the neuronal uptake of many neurotransmitters, therefore increasing their effective activity. Hyperforin increases the effectiveness of norepinephrine, dopamine, L-glutamate, and gamma-amino butyric acid (GABA), as well as serotonin. Researchers in the Department of Pharmacology at the University of Frankfurt in Germany concluded, "no other antidepressant compound exhibits a similar broad uptake-inhibiting profile."
As the number of St. John's wort users has grown, so has the concern about possible drug interactions and side effects. In a study of 43 people in Missouri who took 300 to 1,200 mg/day St. John's wort, 84 percent reported improvement. However, 47 percent reported side effects such as serotonin syndrome symptoms (which can include mental confusion, nausea, and cardiovascular and motor abnormalities), food-drug interactions, withdrawal symptoms, and a depressive relapse. Twelve percent of this group discontinued use, and one person reported a visit to the emergency room. After discontinuing use of the herb, 13 people reported withdrawal symptoms and two had a depressive relapse. 
In another study, researchers sent a questionnaire to all Australian and New Zealand psychiatrists regarding their clinical experiences with St. John's wort. Eighty percent responded that their patients used St. John's wort, often at their recommendation. However, 28 percent of those patients experienced side effects, some of which were described as serious, and eight percent experienced drug interactions. 
Some patients mix St. John's wort with SSRIs, which results in serotonin overload. In addition, there have been increasing reports of the herb's interaction with specific drugs. Deaths of transplant patients caused by tissue rejection have been attributed to the herb's interference with the immunosupressant cyclosporin.  Digoxin, used to stabilize heart rhythms; theophylline, used to treat asthma; and warfarin, used to prevent clotting, have reduced activity if combined with St. John's wort.
New research indicates that compounds found in St. John's wort activate one of the body's main detoxification and elimination systems, thereby affecting many more drugs than identified so far. The cytochrome P450 system is a set of enzymes used to break down many substances in the liver. Scientists have recently found that hyperforin, hypericin, and biapigenin activate five of the key cytochrome P450 enzymes. 
Of the P450 enzymes, CYP3A4 is one of the most importantinvolved in the breakdown of more than 50 percent of all pharmaceutical drugs currently used.  Treating human liver cells with hyperforin dramatically increases CYP3A4 activity. Thus, hypericum extracts are likely to interact with more drugs than expected. 
This does not mean that people taking St. John's wort with pharmaceuticals should suddenly discontinue use. Doing so could cause blood levels of the pharmaceuticals to become dangerously high. The dose of the medicine and the amount of St. John's wort may need to be an adjusted to accommodate use of both.
On another cautionary note, St. John's wort also interferes with the antiviral protease inhibitor Indinavir, used by AIDS patients, and with the effectiveness of oral contraceptives. [12, 13 ]
Other Safety Precautions
One serious side effect of St. John's wort is its potential to trigger mania in people with bipolar syndrome. Onset can be sudden and may be perceived initially as depression, with mania emerging later. In one case study, researchers in Amsterdam studied a 23-year-old woman with no psychiatric history who developed acute mania and psychosis while using St. John's wort. 
The safety of St. John's wort in pregnancy has not been established. In an experiment with mice, researchers found that a therapeutic dose of St. John's wort had no adverse effect on certain cognitive tasks in the offspring. 
St. John's wort is being taken more seriously by researchers and health care providers. Although its effectiveness in treating mild-to-moderate depression has been proven, it may have far-reaching side effects. To minimize the potential of mania or serious drug interactions, consumers should be encouraged to discuss St. John's wort use with a health care provider.
A Good Wort for Skin
Marilyn Sterling, R.D., M.P.H., is a consultant to the natural products industry, a freelance health writer, and a contributing editor to Nutrition Science News. She works part-time as a clinical nutritionist in Trinidad, Calif.
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