Mechanisms of Action
The mechanism of action of hypericum is not fully understood. The extract from St. John's Wort contains polycyclic phenols, hypericin and pseudohypericin, which are among the presumed active components; other compounds include flavonoids (hyperoside, quercetin, isoquercitrin, rutin), kaempferol, luteolin, biapigenin, and hyperforin [8
]. Hypericin, believed to be one of the main active components in hypericum, decreases serotonin receptor density [11
]. Because hypericin does not cross the blood–brain barrier, one proposed mechanism of action for hypericin is the inhibition of monocyte cytokine production of interleukin 6 and 1β, resulting in a decrease in corticotropin releasing hormone and thus dampening production of cortisol [12
]. Hypericin also may inhibit reuptake of serotonin, norepinephrine, and dopamine [11
] and may thus result in reduced expression of beta adrenoreceptors and increased density of serotonin (5-HT2A and 5-HT1A) receptors [13
]. Hypericin also may have affinity for γ-aminobutyric acid receptors.
More recent investigations have implicated hyperforin as a possible active ingredient [14
]. Laakmann and colleagues [15
] performed a randomized, double-blind, placebo-controlled 6-week study of two different extracts of hypericum, on 147 patients. The two extracts contained 0.5% and 5% hyperforin, respectively. Patients who received the hypericum extract with 5% hyperforin showed greater improvement in mean Hamilton Depression Scale (HAM-D) scores than the group receiving the 0.5% hyperforin extract, and the latter group showed only slightly greater improvement than the placebo group.
Various mechanisms of antidepressant action for hyperforin have been proposed, including serotonin reuptake inhibition and norepinephrine and acetylcholine reuptake inhibition. Some studies suggest inhibition of serotonin, dopamine, norepinephrine, γ-aminobutyric acid , and l
], although serotonergic mechanisms probably are most important. Other mechanisms have been proposed also, including reduced expression of cortical beta-adrenoceptors and 5-HT2 receptors and synaptosomal release similar to that caused by reserpine [14
Other components of hypericum, including the flavonoids, are irreversible monoamine oxidase-A inhibitors, but the concentration of these compounds in the extract are so small that they are unlikely to be involved in the antidepressant mechanism [17
Most commercially available St. John's Wort preparations are standardized either to hypericin or hyperforin. Because there are several different preparations of the medication, the amount of other active ingredients may vary with different preparations, and there are no published head-to-head trials with different brands of Hypericum.
In general, hypericum has been reported to have efficacy greater than placebo and equal to active controls. There are approximately 35-40 published trials, including 26 placebo-controlled studies and 14 with a standard antidepressant as the active comparator [18
]. Most studies have been conducted in Europe, usually with patients already in clinical care in general practice settings [1
]. Results in such studies may be more predictive of effectiveness and acceptability in clinical practice but may differ widely from results in a controlled research setting. For example, the European studies generally report little about the methods of recruitment, whether consecutive patients were recruited, and what, if any, exclusion criteria were applied. Patient groups in many European studies of hypericum were not limited to major depression and included other diagnoses [1
In clinical trials hypericum has been compared with low doses of both imipramine and maprotiline [19
]. Doses of imipramine and maprotiline used in European clinical practice tend to be lower than those considered adequate by psychopharmacologists in the United States. In these clinical trials, the typical dose of imipramine or maprotiline is 75 mg/d . Despite the inadequate doses of active controls, the response rates in these trials seemed comparable to those in studies that use higher doses of tricyclic antidepressant agents (TCAs) (eg, imipramine >150 mg/d). The lack of a placebo control makes it difficult to interpret the results, but hypericum seemed to be at least as effective as low doses of imipramine and maprotiline. In these studies, response rates for hypericum ranged from 35.3% to 81.8%, and response for TCAs ranged from 41.2% to 77.8%.
A meta-analysis by Nierenberg [23
] examined four studies comprising a heterogeneous group of depressive conditions, in which hypericum, 300 mg three times per day, was judged to be effective in 79 of 120 subjects (65.8%), whereas placebo was considered effective in only 36 of 125 subjects (28.8%; chi square 32.24; P
< .0001). The placebo response rate seemed comparable to that observed in many outpatient studies of antidepressants conducted in the United States.
A meta-analysis by Linde and colleagues [24
] examined 15 trials comparing Hypericum with placebo and eight trials comparing Hypericum with TCAs in 1757 patients who had mild-to-moderate depression. In six trials that used single preparations of Hypericum (containing only St. John's Wort), hypericum yielded greater response rates than placebo (55.1% for Hypericum versus 22.3% for placebo) and comparable response rates to tricyclic antidepressants (63.9% for Hypericum versus 58.5% for tricyclic antidepressants). In two trials that used combination preparations of Hypericum (containing St. John's Wort and other herbal medications such as Kava), Hypericum was found to be more effective than TCAs (67.7% versus 50%). A meta-analysis by Voltz [25
] suggested that Hypericum may not be effective for acute treatment of severely depressed patients.
In the 2000s, approximately 10 notable studies by North American, European, and South American investigators have been published. Many of these studies are distinguished by their large-scale, randomized, double-blind design and/or by comparing St. John's Wort with newer antidepressants, particularly the selective serotonin reuptake inhibitors (SSRIs), as well as with placebo.
In a 6-week trial with 375 patients, Lecrubier and colleagues [26
] found that St. John's Wort, 900 mg/d, was significantly more effective than placebo, especially in patients who had higher baseline HAM-D scores. In an 8-week trial with 200 depressed subjects, Shelton and colleagues [27
] found that St. John's Wort, 900 to 1200 mg/d, was no more effective than placebo in the full intent-to-treat analysis, although among completers the remission rates were significantly higher with St. John's Wort than with placebo.
Brenner and colleagues [28
] compared St. John's Wort, 900 mg/d, versus sertraline 75, mg/d, in 30 depressed subjects for 6 weeks. St. John's Wort yielded a 47% response rate and sertraline a 40% response rate. The difference was not statistically significant. Gastpar and colleagues [29
] also compared St. John's Wort, 612 mg/d, against sertraline, 50 mg/d, in 241 depressed subjects for 12 weeks, with 161 subjects receiving an additional 12 weeks of treatment for a total treatment period of 6 months. By the first 12 weeks, Hypericum was found to yield a response rate comparable to sertraline, and this response was maintained in subjects who continued for the full 6 months. van Gurp and colleagues [30
] compared St. John's Wort, 900 to 1800 mg/d, with sertraline, 50 to 100 mg/d, in 12 community-based primary care offices. Eighty-seven depressed subjects were treated for 12 weeks. No significant differences in mean HAM-D scores were found, and St. John's Wort resulted in significantly fewer adverse events.
] compared St. John's Wort, 500 mg/d, with fluoxetine, 20 mg/d, for 6 weeks in 240 depressed subjects. St. John's Wort yielded a 60% response rate and fluoxetine a 40% response rate. Results barely reached significance in favor of St. John's Wort. The authors noted that St. John's Wort had a more favorable adverse-effects profile. Only 8% of subjects receiving St. John's Wort reported adverse events compared with 23% receiving fluoxetine. Behnke and colleagues [32
] compared St. John's Wort with fluoxetine in 70 mildly to moderately depressed subjects for 6 weeks. They found HAM-D score decreases of 50% for St. John's Wort and 58% for fluoxetine, with the efficacy of St. John's Wort approximately 80% of that of fluoxetine on the HAM-D and the von Zerssen Depression scales.
The Hypericum Depression Study Group [33
] compared St. John's Wort at doses of 900 to 1500 mg/d versus sertraline, 50 to 100 mg/d, or placebo for 8 weeks in 340 depressed subjects. St. John's Wort and sertraline both yielded a response rate of approximately 24%; the response rate for placebo was 32%. This report, along with that of Shelton and colleagues [27
], resulted in a great deal of media attention during 2002, and St. John's Wort sales worldwide dropped temporarily in the immediate aftermath [5
Fava and colleagues [34
] at the Massachusetts General Hospital (MGH) conducted a study similar to the Hypericum Group's, comparing St. John's Wort, 900 mg/d, with fluoxetine, 20 mg/d, versus placebo for 12 weeks. The study was powered for 180 subjects, but the sponsor closed the study prematurely because of the media hysteria over the previously mentioned negative studies, which were published while the MGH study was in progress. Consequently, only 135 subjects were recruited. The results showed a trend toward significance for St. John's Wort against placebo with regard to decrease in HAM-D scores and a significant advantage for St. John's Wort against fluoxetine. Remission rates were 38% for St. John's Wort, 30% for fluoxetine, and 21% for placebo, but these differences did not reach significance. In view of the placebo response rate, which was consistent with the literature, the authors concluded that the observed results were “real” and suggested that if the full complement of 180 subjects had been recruited, both St. John's Wort and fluoxetine would have beaten placebo by a statistically significant margin.
Moreno and colleagues [35
] compared hypericum, 900 mg/d, with fluoxetine, 20 mg/d, or placebo in 72 depressed subjects. After 8 weeks, the authors found that hypericum yielded a remission rate of 12%, significantly lower than that of fluoxetine (34.6%) and placebo (45%).
How should these recent studies be interpreted in the context of the previous literature? A recent Cochrane review declared similar response rates overall for St. John's Wort, SSRIs, and TCAs but cautioned about the “inconsistent and confusing” nature of the data [18
]. In comparisons between St. John's Wort and placebo, the results tended to favor St. John's Wort but more so in cases where there was not a strict diagnosis of major depressive disorder. Trials with strictly diagnosed depression according to Diagnostic and Statistic Manual of Mental Disorders, 4th edition (DSM) criteria showed less robust results [18
]. More studies are necessary to clarify some of the questions about efficacy that the aforementioned studies have raised.
Safety and Tolerability
In the past few years, increasing numbers of adverse drug–drug interactions between St. John's Wort and other medications have been reported in the literature. These interactions are thought to occur largely through the liver enzyme CYP-450-3A4 and have resulted in decreased activity of several drugs, including warfarin, cyclosporin, oral contraceptives, theophylline, phenprocoumon, digoxin, indinavir, and irinotecan [36
]. Extreme caution, therefore, is required with HIV-positive patients who take protease inhibitors, cancer patients receiving chemotherapy, and transplant recipients who take immunosuppressive drugs. It also is recommended that St. John's Wort not be combined with SSRIs, because anecdotes of “serotonin syndrome” have been reported, presumably related to St. John's Wort's monoamine oxidase inhibitor activity [41
When St. John's Wort is used as monotherapy, adverse events are relatively uncommon and mild [42
]. Patients have complained of dry mouth, dizziness, constipation, other gastrointestinal symptoms, and confusion [1
]. Woelk and colleagues [43
] followed 3250 patients treated with hypericum by 633 physicians in routine clinical practice and found that only 2.4% of patients mentioned side effects of gastrointestinal symptoms and allergic reactions. Only 1.5% of patients stopped taking the drug because of these side effects. So far, there seem to be no published reports assessing the effects of an hypericum overdose.
Phototoxicity has long been associated with hypericum in grazing animals and has been reported, albeit rarely, in humans [44
]. Brockmoller and colleagues [45
] found that doses of hypericum as high as 1800 mg caused minor increases in sensitivity to UV light in humans but no phototoxicity. Siegers and colleagues [46
] have recommended that patients who take an overdose of hypericum should be isolated from UV radiation for 7 days, but this caution may not necessarily apply to patients receiving regular doses. As a general precaution, the author and colleagues recommend that patients who take St. John's Wort use sunscreen and other protection when spending large amounts of time in the sun.
At least 17 cases of psychosis resulting from St. John's Wort have been reported, of which 12 comprised mania or hypomania [47
]. Bipolar patients therefore should be advised to use St. John's Wort only with a concurrent mood stabilizer.
Recommendations and Special Considerations for Women who are Pregnant or Breastfeeding
Hypericum has been shown to be more effective than placebo and equal to low-dose TCAs in most controlled trials but has had less impressive results against the SSRIs and placebo in the more recent studies, perhaps in part because of the recruitment of more severely and/or chronically depressed patient samples [14
Recommended doses of St. John's Wort based on the literature fall between 900 mg and 1800 mg/d, usually divided on a twice- or thrice-daily basis. St. John's Wort seems to have a relatively benign side-effect profile, although, given the risk of interactions, care needs to be taken with patients taking multiple medications. Likewise, in view of the risk of cycling, caution should be exercised in patients who have bipolar disorder.
The literature as a whole suggests that St. John's Wort may be less effective in cases of more severe and/or more chronic depression, and people who have milder forms of depression therefore may be the best candidates for St. John's Wort. A collaborative study of St. John's Wort for minor depression at MGH and Cedars-Sinai Medical Center has recently been completed, and data analysis is currently underway. Hypericum needs to be studied further in depressed subjects who have rigorously diagnosed DSM-IV major depression, using placebo and active controls for acute treatment periods of at least 8 to 12 weeks. Longer-term continuation treatment also merits investigation, and systematic tracking of side effects needs to be further developed.
Little is known about toxic effects that hypericum may have during pregnancy and breastfeeding. A systematic literature review [48
] found that in-utero exposure to SJW in animals may be associated with low birth weight but no advers effects on cognitive development; breastfeeding while on SJW was associated with colic and drowsiness or lethargy [48
]. Given SJW's CYT-P 450 induction, concerns were raised over its potential interference with other medications administered during pregnancy or lactation [48
]. One small prospective study found no significant differences in fetal malformations in women exposed to SJW during pregnancy, compared to pregnant women on other antidepressants and pregnant women with no teratogen exposure [49
]. Studies examining hyperforin and hypericin levels in breast milk have suggested safety for children and mothers [50
] and one small prospective study suggests no increase in adverse events in children exposed to SJW in mother's milk, though cases of lethargy and drowsiness were reported [52
]. The data, however, are scanty and long-term studies of safety are required [53
]. In the absence of safety data, it is recommended that women who are pregnant or intend to become pregnant avoid St. John's wort.