There are many active chemical constituents in St. John's Wort. These chemicals, called hypericin, pseudohypericin, and hyperforin, have all been investigated for their anti-depressant properties. However, the reason why St. John's Wort successfully treats depression is not entirely clear. The first studies found that St. John's Wort was a weak inhibitor of monoamine oxidase (MAO). One group of antidepressants (so-called monoamine oxidase inhibitors such as Marplan, Nardil, and Parnate) work by this same mechanism. MAO is a substance that breaks down various neurotransmitters (chemical messengers in the brain and nervous system). Inhibiting MAO, or keeping it from breaking down the neurotransmitters which control mood (such as dopamine, serotonin and noradrenaline), allows these chemicals to stay working in the brain for longer periods of time and thus subsequently improving mood.
More recent studies showed that St. John's Wort may activate adenosine, gamma-aminobutyric acid (GABA), and glutamate receptors (receptors are chemical channels designed to receive certain brain chemicals). Activation of adenosine receptors is thought to produce a feeling of calm and contentment. Malfunctioning GABA receptors can cause depression and anxiety; therefore, activation of these receptors regulates mood. Disturbances in glutamate activity at receptors can lead to depression and suicidality; activating these receptors can decrease these feelings.
Still other studies have investigated the effects of St. John's Wort on additional neurotransmitter receptors. The herb seems to downregulate (reduce the number of) beta-adrenergic receptors and upregulate (increase the number of) serotonin receptors. Beta-adrenergic receptors are designed to receive a nerve stimulating hormone called epinephrine (also called adrenaline), which has the effect of increasing heart beat and blood pressure, and preparing skeletal muscles to work. Downregulating these beta-adrenergic receptors has a calming effect. Epinephrine has less opportunity to stimulate the receptors (because there are fewer chemical channels to receive it) which activate those muscles.
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Why does St. John's ability to upregulate serotonin matter? Both depression and anxiety have been linked to a lack of serotonin. Upregulating or increasing the number of serotonin receptors can allow the serotonin that is already present to have more opportunity to stimulate the related neurons (nerve cells). The net effect is a decrease in depression or anxiety.
Like so many other herbs, it is difficult to uncover the exact mechanism by which St. John's Wort works. Most herbs are a complex mixture of chemicals, each with their own properties. The effect of St. John's Wort is probably related to the combination of chemicals rather than just one chemical acting in one part of the brain.
St. John's Wort has been the subject of multiple treatment studies. The first human studies using St. John's Wort to treat mild depression demonstrated that this herb was as effective as prescription antidepressants. Later studies showed that St. John's Wort was also effective in treating major depression. Recent studies, that were perhaps better designed, revealed mixed results for the effectiveness of St. John's Wort. Since standards vary for the production of herbal supplements (many of these studies have used different formulations of St. John's Wort), the results are difficult to interpret.
On the whole, it appears that a good quality St. John's Wort supplement is a good substitute for many prescription antidepressant medications. However, the use of St. John's Wort in high doses (what one would find in a typical supplement), is not without its cautions. While there are very few actual side effects to taking the herb, it does have the potential to interact with other medications (see below).
Safety and Dosing
A typical dose of St. John's Wort is between 500 and 1,100 mg a day of a standardized herbal extract containing at least 0.3% hypericin.
St. John's Wort is relatively safe. In a review of over 20 trials, St. John's Wort had only mild side effects (see box), which are often less less noticeable than side effects caused by traditional antidepressant medications. The most common side effect for St. John's Wort is an increased sensitivity to sunlight. People who experience this photosensitizing effect should use extra sunscreen and limit sun exposure while taking St. John's Wort.
Side Effects of St. John's Wort:
- Stomach upset
- Sleep problems
- Skin rash
St. John's Wort can interfere with many prescription and non-prescription drugs. This herb can change how quickly the liver processes drugs, which can cause another prescription medication to leave the body more quickly than it should. It can also directly interfere with the action of another drug (adding or subtracting from its effects).
For example, St. John's Wort has the ability to reduce the effectiveness of many drugs including cyclosporin (an immune-suppressing drug), warfarin (used to prevent or treat blood clots), digoxin (heart medicine), theophylline (used to treat asthma and other respiratory diseases), HIV protease inhibitors (used to treat HIV/AIDS), anticonvulsants (used to prevent seizures), oral contraceptives (birth control pills) and more. It also has the potential to increase the effects of antidepressant medications such as monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs). The herb also increases the risk of a rare condition called serotonin syndrome (or serotonin toxicity) that produces mental confusion, agitation, headache, shivering, sweating, hypertension (high blood pressure), tachycardia (fast heart rate), and other symptoms.
The list of drugs that St. John's Wort can interfere with is long, and future research may discover other medications that should not be mixed with this herb. Therefore, it is best to check with your health care provider before trying St John's Wort, especially if you are taking any prescription medications.
WARNING: The use of St. John's Wort has been linked to manic episodes in people with bipolar disorder (manic depression). As mentioned previously, a manic episode, the high energy component of bipolar disorder, is characterized by a euphoric (joyful, energetic) mood, hyperactivity, a positive, expansive outlook on life, a hyper-inflated inflated sense of self-esteem, impulsive/risk-taking behavior, and a reduced need for sleep. While the number of these cases is low, it is best to avoid St. John's wort if you suffer from bipolar disorder or if you aren't sure if you have bipolar disorder vs. conventional unipolar depression. If you use St John's wort, begin treatment only under the supervision of a licensed professional health care provider.