Hypericum Extract Research Articles

St John's wort for depression--an overview and meta-analysis of randomised clinical trials

To investigate if extracts of Hypericum perforatum (St John's wort) are more effective than placebo in the treatment of depression, are as effective as standard antidepressive treatment, and have fewer side effects than standard antidepressant drugs. Systematic review and meta-analysis of trials revealed by searches. 23 randomised trials including a total of 1757 outpatients with mainly mild or moderately severe depressive disorders: 15 (14 testing single preparations and one a combination with other plant extracts) were placebo controlled, and eight (six testing single preparations and two combinations) compared hypericum with another drug treatment. A pooled estimate of the responder rate ratio (responder rate in treatment group/responder rate in control group), and numbers of patients reporting and dropping out for side effects. Hypericum extracts were significantly superior to placebo (ratio = 2.67; 95% confidence interval 1.78 to 4.01) and similarly effective as standard antidepressants (single preparations 1.10; 0.93 to 1.31, combinations 1.52; 0.78 to 2.94). There were two (0.8%) drop outs for side effects with hypericum and seven (3.0%) with standard antidepressant drugs. Side effects occurred in 50 (19.8%) patients on hypericum and 84 (52.8%) patients on standard antidepressants. There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders. Further studies comparing extracts with standard antidepressants in well defined groups of patients and comparing different extracts and doses are needed.

St John's wort as an antidepressant

Among the many remarkable differences between German and British medicine is the extensive use of herbal medicines in Germany. An example is the use of Hypericum perforatum (St John's wort) for psychological complaints. In 1994 German physicians prescribed almost 66 million daily doses of preparations containing hypericum alone, worth a total of DM61m (£26m).1 In this issue Linde et al (p 253) conclude from a meta-analysis that hypericum extracts are more effective than placebo for treating mild to moderately severe depressive disorders.2 How should this evidence be weighed? Diagnostically, depressive disorders form a heterogeneous group which includes major depression as well as depressive states not satisfying the criteria for the full syndrome. These diagnostic types are defined not by severity but by clusters of symptoms and by the length of time they last. Since the efficacy of antidepressants in major depression is well documented, this syndrome is useful when considering treatment with antidepressants. Antidepressant drugs are particularly recommended for moderate and more severe forms of major depression. …

Immunosuppressive effects of hypericin on stimulated human leukocytes: inhibition of the arachidonic acid release, leukotriene B4 and Interleukin-Iα production, and activation of nitric oxide formation

The present study describes the influence of hypericin of Hypericum perforatum on TPA- and LPS-induced arachidonic acid (AA) metabolism, as well as interleukin 1 α and nitric oxide (NO) production in human immunocompetent cells. The results show that hypericin inhibits the release of arachidonic acid (AA) from membrane phospholipids in calcium ionphore A23187-TPA stimulated human granulocytes in a dose-dependent manner (IC(50) 4 μM), but that calcium ionophore is not the only inducer. An inhibitory effect could be observed at concentrations of < 0.4 μM and in the presence of low concentrations of TPA (0.16 - 0.32 μM). As a result of this inhibition hypericin inhibits the release of LTB(4) but not of PGE(2). Hypericin also inhibits the production of IL-1α in LPS-stimulated human monocytes and activates NO production in isolated human leukocytes. This effect is comparable to the effect of LPS and is probably not associated with the IL 1 a or intermediates of the cycloxygenase pathway. The results as a whole let us assume that one important mechanism for the antiviral, antiinflammatory and antitumoral effects of hypericin and Hypericum extracts is the inhibition of the PKC-mediated signalling pathway which in turn influences the AA metabolism, and the interleukin-1 α production resulting in an immunosuppressive effect on the host immune system.

Treatment of mild/moderate depressions with Hypericum

105 out-patients with neurotic depressions or depressive irritations of short duration were treated in a double-blind study either with 3 × 300 mg Hypericum extract or placebo. The therapy phase was four weeks. The effectiveness was judged according to the Hamilton Depression Scale after two and four weeks. The values of the mean basic score fell in these periods in the active group from 15.81 to 9.64 and 7.17 and in the placebo group from 15.83 to 12.28 and 11.30. The difference between active and placebo groups were statistically significant with p < 0.05 and p < 0.01 achieved after 2 and 4 weeks respectively. In the active group 28 of 42 patients (67 %) and, in the placebo group, 13 of 47 patients (28 %) could be defined as responding to treatment. Notable side effects were not found.

Effects of Hypericum Extract on the Expression of Serotonin Receptors

The influence of hypericum extract LI 160 on the expression of serotonin receptors was investigated using a neuroblastoma cell line to establish a model for the regulation of neurotransmitters by immunologically active compounds such as cytokines. The cells were incubated with hypericum extract LI 160 in kinetic form for 2, 4, 6, 8, and 10 hours, then washed. The serotonin receptor expression analysis was compared to that of a placebo control solution. The neuroblastoma cells showed a clearly reduced expression of the serotonin receptors under treatment with hypericum extract. First stimulation experiments with interleukin-1 (IL-1) and hypericum extract suggest that a further reduction of the serotonin receptors is possible when IL-1 is added.

Effects of hypericum extract on the expression of serotonin receptors.

The influence of hypericum extract LI 160 on the expression of serotonin receptors was investigated using a neuroblastoma cell line to establish a model for the regulation of neurotransmitters by immunologically active compounds such as cytokines. The cells were incubated with hypericum extract LI 160 in kinetic form for 2, 4, 6, 8, and 10 hours, then washed. The serotonin receptor expression analysis was compared to that of a placebo control solution. The neuroblastoma cells showed a clearly reduced expression of the serotonin receptors under treatment with hypericum extract. First stimulation experiments with interleukin-1 (IL-1) and hypericum extract suggest that a further reduction of the serotonin receptors is possible when IL-1 is added.

Modulation of cytokine expression by hypericum extract.

The effect of hypericum extract LI 160 on the stimulated cytokine expression was investigated in vitro in a whole blood culture system. Blood samples were taken from five healthy volunteers and four depressive patients. The release of interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) was measured quantitatively after an incubation time of 24 hours on microtiter plates. A massive suppression of the interleukin-6 release was found for PHA-stimulated hypericum extract. Possible relations to the antidepressive effects of hypericum extract are discussed.

Modulation of Cytokine Expression by Hypericum Extract

The effect of hypericum extract LI 160 on the stimulated cytokine expression was investigated in vitro in a whole blood culture system. Blood samples were taken from five healthy volunteers and four depressive patients. The release of interleukin-6 (IL-6), interleukin-lβ (IL-lβ) and tumor necrosis factor-α (TNF-α) was measured quantitatively after an incubation time of 24 hours on microtiter plates. A massive suppression of the interleukin-6 release was found for PHA-stimulated hypericum extract. Possible relations to the antidepressive effects of hypericum extract are discussed.

Inhibition of MAO by fractions and constituents of hypericum extract.

The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition.

Placebo-Controlled Double-Blind Study Examining the Effectiveness of an Hypericum Preparation in 105 Mildly Depressed Patients

One hundred and five outpatients with mild depressions of short duration were treated in a double-blind study with either 3 x 300 mg hypericum extract or placebo. The therapy phase was 4 weeks. The effectiveness was judged according to the Hamilton Depression Scale after 2 and 4 weeks. The values of the mean basic score in these periods fell from 15.8 to 9.6 or 7.2 in the active group, and in the placebo group, from 15.8 to 12.3 and 11.3. The difference between active and placebo groups were statistically significant with P &lt; .05 and P &lt; .01 achieved after 2 and 4 weeks, respectively. In the active group, 28 of 42 patients (67%) and, in the placebo group, 13 of 47 Patients (28%) responded to treatment. Notable side effects were not found.

Inhibition of MAO by Fractions and Constituents of Hypericum Extract

The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10-3 mol/L. At 10-4 mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition.

Clinical investigation of the antidepressant effectiveness of hypericum.

To date, 25 controlled therapy studies have investigated the antidepressive effectiveness of hypericum extracts. A total of 1592 treatment cases have been included. The dosage was typically 300 to 900 mg total extract daily; the therapy duration was 2 to 6 weeks. Fifteen studies were performed comparing hypericum extracts with placebo, 10 studies as comparative studies. This paper presents an overview of their results.

Pharmaceutical quality of hypericum extracts.

Hypericum extracts contain at least ten constituents or groups of components that may contribute to the pharmacological effects. It is not yet possible to correlate the antidepressive mode of action with specific constituents; therefore, the pharmaceutical quality of the extracts was characterized on the basis of typical leading substances and especially the hypericins. For the analysis and improvement of the production procedure, the content of hypericin and pseudohypericin was measured experimentally. The drug material was extracted with different solvents and the yield was analyzed for each kind of solvent, its concentration and extraction temperature. Optimal yields were obtained with 80% methanol at temperatures of 80 degrees C.

Pharmaceutical Quality of Hypericum Extracts

Hypericum extracts contain at least ten constituents or groups of components that may contribute to the pharmacological effects. It is not yet possible to correlate the antidepressive mode of action with specific constituents; therefore, the pharmaceutical quality of the extracts was characterized on the basis of typical leading substances and especially the hypericins. For the analysis and improvement of the production procedure, the content of hypericin and pseudohypericin was measured experimentally. The drug material was extracted with different solvents and the yield was analyzed for each kind of solvent, its concentration and extraction temperature. Optimal yields were obtained with 80% methanol at temperatures of 80°C.

Effectiveness and Tolerance of the Hypericum Extract LI 160 Compared to Maprotiline: A Multicenter Double-Blind Study

A randomized, double-blind study examining the effectiveness and tolerance of a standardized hypericum preparation when compared to maprotiline was performed in a group of 102 patients with depression, in accordance with ICD-10, F 32.1. The study was conducted in the offices of neurology and psychiatry specialists. The patients received, over a period of 4 weeks, either 3 x 300 mg of the hypericum extract or 3 x 25 mg maprotiline pills of identical appearance. Effectiveness was determined using the Hamilton Depression Scale (HAMD), the Depression Scale according to von Zerssen (D-S), and the Clinical Global Impression Scale (CGI). The total score of the HAMD scale dropped during the 4 weeks of therapy in both treatment groups by about 50%. The mean values of the D-S scale and the CGI scale showed similar results, and after 4 weeks of therapy, no significant differences in either treatment group were noticed. The onset of the effects occurred up to the second week of treatment, but were observed earlier with maprotiline than with the hypericum extract. On the other hand, maprotiline treatment resulted in more cases of tiredness, mouth dryness, and heart complaints.

Inhibition of MAO and COMT by Hypericum Extracts and Hypericin

The influence of hypericin, hypericum total extract, and hypericum fractions on the activity of MAO and COMT, prepared in vitro from pork liver, were investigated in several concentration steps. An inhibition of MAO could be shown in the following concentrations (extract correlated to a mean molecular value of 500): hypericin to 10-3 mol/ L, hypericum total extract to 10-4 mol/L, one extract fraction up to 10-5. A COMT inhibition could not be shown for hypericin, with hypericum extract to 10-4 mol/L and with two extract fractions also up to 10-4 mol/L. The MAO inhibiting fraction contained hypericins as well as flavonols, the COMT-inhibition fraction being mainly flavonols and xanthones. The concentrations of inhibition shown might not be sufficient to explain the clinically proven antidepressive effect of hypericum particularly with regard to the inhibition of MAO activity.

Clinical Investigation of the Antidepressant Effectiveness of Hypericum

To date, 25 controlled therapy studies have investigated the antidepressive effectiveness of hypericum extracts. A total of 1592 treatment cases have been included. The dosage was typically 300 to 900 mg total extract daily; therapy duration was 2 to 6 weeks. Fifteen studies were performed comparing hypericum extracts with placebo, 10 studies as comparative studies. This paper presents an overview of their results.

Inhibition of MAO and COMT by hypericum extracts and hypericin.

The influence of hypericin, hypericum total extract, and hypericum fractions on the activity of MAO and COMT, prepared in vitro from pork liver, were investigated in several concentration steps. An inhibition of MAO could be shown in the following concentrations (extract correlated to a mean molecular value of 500): hypericin to 10(-3) mol/L, hypericum total extract to 10(-4) mol/L, one extract fraction up to 10(-5). A COMT inhibition could not be shown for hypericin, with hypericum extract to 10(-4) mol/L and with two extract fractions also up to 10(-4) mol/L. The MAO inhibiting fraction contained hypericins as well as flavonols, the COMT-inhibition fraction being mainly flavonols and xanthones. The concentrations of inhibition shown might not be sufficient to explain the clinically proven antidepressive effect of hypericum particularly with regard to the inhibition of MAO activity.

Effects of Hypericum Extract LI 160 Compared with Maprotiline on Resting EEG and Evoked Potentials in 24 Volunteers

In a randomized double-blind study, the effect of hypericum extract was compared to that of maprotiline in 24 healthy volunteers. The investigations included measurements of resting EEG as well as visual and acoustic evoked potentials. In resting EEGs, both medications revealed oppositely directed changes in the theta frequencies, and mainly similarly directed changes in alpha and beta frequencies. Measurements of evoked potentials in the theta and beta frequencies supported these results. The results indicate improved cognitive functions mainly with the treatment of hypericum extract.

Benefits and Risks of the Hypericum Extract LI 160: Drug Monitoring Study with 3250 Patients

Effectiveness and acceptance of a 4-week treatment with hypericum extract LI 160 were investigated by 663 Private practitioners. The results of the 3250 patients (76% women and 24% men), were recorded using data sheets. The age of the patients ranged from 20 to 90 years (mean 51 years). Of the patients, 49% were mildly depressed, 46% intermediate, and 3% severely depressed. In about 30% of the patients, the situation normalized or improved during the therapy. Undesired drug effects were reported in 79 (2.4%) patients and 48 (1.5%) discontinued the therapy. Most frequently noted side effects were gastrointestinal irritations (0.6%), allergic reactions (0.5%), tiredness (0.4%), and restlessness (0.3%).