Hypericum perforatum

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References

American Herbal Pharmacopoeia: St John's Wort Monograph. Santa Cruz, CA.1997.

Bhattacharya SK, Chakrabarti A, Chatterjee SS. Activity profiles of two hyperforin-containing hypericum extracts in behavioral models. Pharmacopsychiatry 1998 Jun;31 Suppl 1:22-29.
Abstract: The behavioral activity profile of a therapeutically used alcoholic hypericum extract containing hyperforin (4.5%) in rodent models was compared with that of an experimental CO2 extract devoid of hypericines but highly enriched in hyperforin (38.8%). The antidepressant activities of 50, 150 and 300 mg/ kg/day of the alcoholic extract were similar to those of 5, 15 and 30 mg/kg/day respectively of the CO2 extract. The ethanol extract in the same dose range potentiated dopaminergic behavioral responses, whereas these effects were either absent or less pronounced in the CO2 extract treated groups. By contrast, serotoninergic effects of the CO2 extract were more pronounced than those of the alcoholic extract. These and various other observations made during the study confirm that although the antidepressant action of hypericum extracts depends on their hyperforin contents, their spectrums of central activity are due to other component(s). Our working hypothesis that hyperforin and serotoninergic mechanisms are involved in the therapeutically observed antidepressant activities of hypericum extracts is in agreement with these observations.

Biber A, Fischer H, Romer A, Chatterjee SS. Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers. Pharmacopsychiatry 1998 Jun;31 Suppl 1:36-43.
Abstract: Validated analytical methods suitable for determining hyperforin in plasma after administration of alcoholic Hypericum perforatum extracts containing hyperforin are described. After oral administration of 300 mg/kg Hypericum extract (WS 5572, containing 5% hyperforin) to rats maximum plasma levels of approximately 370 ng/ml (approx. 690 nM) were reached after 3 h, as quantified by a HPLC and UV detection method. Estimated half-life and clearance values were 6 h and 70 ml/min/kg respectively. Since therapeutic doses of Hypericum extracts are much lower than that used in rats, a more sensitive LC/MS/MS method was developed. The lower limit of quantification of this method was 1 ng/ml. Using this method, plasma levels of hyperforin could be followed for up to 24 h in healthy volunteers after administration of film coated tablets containing 300 mg hypericum extracts representing 14.8 mg hyperforin. The maximum plasma levels of approximately 150 ng/ml (approx. 280 nM) were reached 3.5 h after administration. Half-life and mean residence time were 9 and 12 h respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg of extract resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. Plasma concentration curves in volunteers fitted well in an open two-compartment model. In a repeated dose study, no accumulation of hyperforin in plasma was observed. Using the observed AUC values from the repeated dose study, the estimated steady state plasma concentrations of hyperforin after 3 x 300 mg/day of the extract, i.e., after normal therapeutic dose regimen, was approximately 100 ng/ml (approx. 180 nM).

Bisset NG (ed.), Wichtl M. Herbal Drugs and Phytopharmaceuticals, Boca Raton, FL. CRC Press, 1994

Bradley PR, ed. British Herbal Compendium, vol 1. Bournemouth, Dorset, UK: British Herbal Medicine Association, 1992.

Brinker F. Herb Contraindications and Drug Interactions. Second edition. Sandy, OR: Eclectic Institute Inc, 1998.

Buter B, Orlacchio C, Soldati A, Berger K. Significance of genetic and environmental aspects in the field cultivation of Hypericum perforatum. Planta Med 1998 Jun;64(5):431-437.
Abstract: Agronomical and biochemical parameters of seven Hypericum perforatum (St. John's wort) accessions grown at three experimental sites in Switzerland were followed over a two year period (1995-1996). Significant effects of environmental (= site) and genetic factors (= accession) on flowering dates, plant length, and plant dry matter production (= plant yield) were observed in both years; rankings of sites and accessions with regard to plant yield were similar in both years despite the fact that the first year crop contributed only a minor part to the overall yield of both years together. Maximum dry matter production per year reached 159 dt/ha for the total plant and 54 dt/ha for the flowering segment (i.e. the pharmaceutically relevant, upper segment of the plants comprising the majority of flowers). HPLC analysis of the constituents covered eight secondary metabolites (amentoflavone, biapigenin, hyperforin, hypericin, hyperosid, pseudohypericin, quercetin, rutin). Generally, secondary metabolite contents were significantly lower in the first year of cultivation ranging from 12% (hyperosid) to 83% (hyperforin) of the contents measured in the 1996-crop. Significant genetic effects on the production of all tested secondary metabolites (except biapigenin) were observed in 1996 whereas environmental effects appeared to be less distinct (except for amentoflavone and pseudohypericin). In conclusion, genetic factors strongly affected plant yield as well as secondary metabolite content in H. perforatum cultivation; the availability of genetically superior plant material next to improved agrotechnological methods therefore is supposed to become a key factor for successful future field production.

Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Muller WE. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci 1998; 63(6):499-510.
Abstract: We demonstrate that the phloroglucinol derivative hyperforin is not only the major lipophilic chemical constituent of the medicinal plant Hypericum perforatum (St. John's wort) but also a potent uptake inhibitor of serotonin (5-HT), dopamine (DA), noradrenaline (NA), GABA and L-Glutamate with IC50 values of about 0.05-0.10 microg/ml (5-HT, NA, DA, GABA) and about 0.5 microg/ml (L-glutamate) in synaptosomal preparations. Furthermore, potencies of two different hypericum extracts in two conventional pharmacological paradigms useful for the detection of antidepressants (behavioral despair, learned helplessness), closely correlate with their hyperforin contents. In addition, most till now known neuropharmacological properties of the clinically used hypericum extracts can also be demonstrated with pure hyperforin. It appears, therefore, that this non-nitrogenous constituent is a possible major active principle responsible for the observed clinical efficacies of the extract as an antidepressant and that it could also be a starting point for drug discovery projects engaged in the search of psychoactive drugs with novel mode of action.

Chatterjee SS, Noldner M, Koch E, Erdelmeier C. Antidepressant activity of hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry 1998 Jun;31 Suppl 1:7-15.
Abstract: Efforts leading to the identification of hyperforin as an antidepressive component of therapeutically used alcoholic hypericum extracts are described and discussed. Initially, the effects of this unique and major constituent of the herb were detected in peripheral organs using in vitro models and an extract was obtained by supercritical extraction of the herb by carbon dioxide. These extracts are highly enriched in hyperforin (38.8%) and are devoid of hypericines and numerous other components of alcoholic extracts. Studies with such an extract and with isolated hyperforin indicated that this acylphloroglucinol derivative can inhibit serotonin-induced responses and uptake of this neurotransmitter in peritoneal cells. Assuming that the effects of hyperforin were due to its actions on serotoninergic 5-HT3/5-HT4 receptors, further studies were conducted to investigate its effects on the CNS. These efforts revealed its antidepressant activity in the behavioral despair test and led to the working hypothesis that hyperforin and serotoninergic mechanisms are involved in the antidepressant activities of alcoholic hypericum extracts. The observations made during this study also indicate that hyperforin is the major, but not the only antidepressive component of alcoholic extracts.

Cott J, Misra R, Medicinal Plants: potential source for new psychotheraputic drugs In New Drug Developments from Herbal medicines in Neuropsychopharmacology, eds Kanba S, Richelson E, NY 1997.

Couldwell W, et al. Hypericin a potential antiglioma therapy.Neurosurgery 1994, 35:705-710.

D'Arcy PF. Adverse reactions and interactions with herbal medicines, part 1, adverse reactions. Adverse Drug Reactions and Toxicological Review 10 (Winter 1991) 189-208.

Demott K. St. John’s wort tied to serotonin syndrome. Clinical Psychiatry News 1998;26:28.

De Smet PAG, et al. (eds.) Adverse Effects of Herbal Drugs 2, Berlin: Springer-Verlag, 1993.

De Smet PAG, Nolen WA, St John's wort as an Antidepressant. BMJ, 1996 313:241-247.

Duran N, Song PS. Hypericin and its phytodynamic activity. Phytochemistry and Phytobiology. 1986.43: 677-680.

Erdelmeier CA. Hyperforin, possibly the major non-nitrogenous secondary metabolite of Hypericum perforatum L. Pharmacopsychiatry 1998 Jun;31 Suppl 1:2-6.
Abstract: An overview of the constituents of Hypericum perforatum is given, with special emphasis on the acylphloroglucinol hyperforin. Previous work on the chemistry of hyperforin and on other components derived from hyperforin in H. perforatum is reviewed. A new optimized method of isolating hyperforin on a large scale is presented, including full spectroscopic characterization of the isolate.

Ernst E. Second thoughts about safety of St. John's Wort. Lancet. Dec 11th.1999;354, 9195.

Fox F, et al. Photoactivated hypericin is an anti-proliferative agent that induces a high rate of apoptotic death of normal, transformed, and malignant T lymphocytes: implications for the treatment of cutaneous lymphoproliferative and inflammatory disorders.J Invest Dermatol, 1998;111, 2:327-332.
Abstract: Hypericin is a photodynamic compound activated by either visible (400- 700 nm) or UVA (320-400 nm) light, and has been shown to inhibit the growth of a variety of neoplastic cell types. In this study, hypericin was found to inhibit proliferative responses of malignant T cells derived from the blood of patients with cutaneous T cell lymphoma. Control cells included peripheral blood mononuclear cells (PBMC) from normal volunteers or Epstein-Barr virus-transformed lymphocytes. Cells from each of these populations were incubated with serial dilutions of hypericin or 8-methoxypsoralen and then stimulated with the mitogen ConA (10 microg per ml). Cultures were prepared in the dark to minimize photoactivation of the hypericin. Proliferation was measured by [3H]thymidine labeling after 72 h. Hypericin, photoactivated with 1.1- 3.3 J white light per cm2, inhibited cellular proliferation of malignant T cells with IC50 values from 0.34 to 0.53 microM, normal PBMC with IC50 values of 0.11-0.76 microM, and Epstein-Barr virus- transformed cells with IC50 values of 0.75-3.2 microM. UVA- photoactivated hypericin (0.5-2.0 J per cm2) could also inhibit proliferation with IC50 values of 0.57-1.8 microM, 0.7-4.6 microM, and 2.0-3.7 microM for malignant, normal, or Epstein-Barr virus-transformed cells, respectively. Hypericin, photoactivated with either UVA or white light, could induce near complete apoptosis (94%) in malignant cutaneous T cell lymphoma T cells, whereas lower levels of apoptosis (37-88%) were induced in normal PBMC. These data indicate that hypericin inhibits mitogen-induced proliferation of malignant T cells from patients with cutaneous T cell lymphoma, PBMC from normal individuals, as well as Epstein-Barr virus-transformed lymphocytes, and that inhibition of cell proliferation is dependent on the concentration of hypericin used and the dose of light required to photoactivate the compound. Induction of apoptosis is, in part, one mechanism by which photoactivated hypericin inhibits malignant T cell proliferation.

Golsch S, Vocks E, Rakoski J, Brockow K, Ring J [Reversible increase in photosensitivity to UV-B caused by St. John's wort extract].[Article in German] Hautarzt 1997 Apr;48(4):249-252

Holzl J, Demisch L, Gollnik B. Investigations about Antidepressive and Mood Changing Effects of Hypericum perforatum. Planta Med. 1989.55:643.

Kaehler ST, Sinner C, Chatterjee SS, Philippu A. Hyperforin enhances the extracellular concentrations of catecholamines, serotonin and glutamate in the rat locus coeruleus. Neurosci Lett. 1999 Mar 12;262(3):199-202.
Abstract: Hyperforin is the main antidepressant component of hypericum perforatum (St. John's Wort). Using the push-pull superfusion technique we tested whether hyperforin influences extracellular concentrations of neurotransmitters in the rat locus coeruleus. Hyperforin (10 mg/kg, i.p.) not only enhanced the extracellular levels of the monoamines dopamine, noradrenaline and serotonin, but also that of the excitatory amino acid glutamate. The levels of the main serotonin metabolite 5-hydroxyindolacetic acid, as well as those of the amino acids GABA, taurine, aspartate, serine and arginine, were not influenced. Together with in vitro studies, our findings suggest that the antidepressant property of hyperforin is due to enhanced concentrations of monoamines and glutamate in the synaptic cleft, probably as a consequence of uptake inhibition.

Keeler RF, Tu AT. Handbook of Natural Toxins. New York: Marcel Dekker, Inc. 1983.

Kasper, S.Treatment of seasonal affective disorder (SAD) with hypericum extract. Pharmacopsychiatry 1997, 30 Suppl 2:89-93.
Abstract:Seasonal affective disorder (SAD) is a subgroup of major depression and characterized by a regular occurrence of symptoms in autumn/winter and full remission or hypomania in spring/summer. Light therapy (LT) and recently pharmacotherapy with specific antidepressants have been shown to be beneficial. Within the array of pharmacotherapy hypericum extract has also been found to be effective in a single-blind study (Martinez et al., 1994). In this 4 weeks treatment study 900 mg of hypericum was associated with a significant reduction in the total score of the Hamilton Depression Rating Scale. There was no significant difference when bright light therapy was combined with hypericum, compared to the situation without bright light therapy. Overall, hypericum was well tolerated and therefore the data suggest that pharmacological treatment with hypericum may be an efficient therapy in patients with SAD, which needs to be substantiated in further controlled studies.

Laakmann G, Schule C, Baghai T, Kieser M. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry 1998 Jun;31 Suppl 1:54-59.
Abstract: In a randomized, double-blind, placebo-controlled, multicenter study, the clinical efficacy and safety of two different extracts of St. John's wort were investigated in 147 male and female outpatients suffering from mild or moderate depression according to DSM-IV criteria. Following a placebo run-in period of three to seven days, the patients were randomized to one of three treatment groups: During the 42-day treatment period, they received 3 x 1 tablets of either placebo, Hypericum extract WS 5573 (300 mg, with a content of 0.5% hyperforin), or Hypericum extract WS 5572 (300 mg, with a content of 5% hyperforin). The manufacturing process for the two Hypericum preparations was identical, so that they differed only in their hyperforin content. Efficacy regarding depressive symptoms was assessed on days 0, 7, 14, 28, and 42, using the Hamilton Rating Scale for Depression (HAMD, 17-item version) and the Depression Self-Rating Scale (D-S) according to von Zerssen. In addition, the severity of illness was also rated by the investigators on days 0 and 42 using the Clinical Global Impression (CGI) scale. The last observation of patients withdrawn from the trial prematurely was carried forward. At the end of the treatment period (day 42), the patients receiving WS 5572 (5% hyperforin) exhibited the largest HAMD reduction versus day 0 (10.3 +/- 4.6 points; mean +/- SD), followed by the WS 5573 group (0.5% hyperforin; HAMD reduction 8.5 +/- 6.1 points) and the placebo group (7.9 +/- 5.2 points). As regards the change in the HAMD total score between day 0 and treatment end and its relationship to the hyperforin dose, a significant monotonic trend was demonstrated in the Jonckheere-Terpstra test (p = 0.017). In pairwise comparisons, WS 5572 (5% hyperforin) was superior to placebo in alleviating depressive symptoms according to HAMD reduction (Mann-Whitney U-test: p = 0.004), whereas the clinical effects of WS 5573 (0.5% hyperforin) and placebo were descriptively comparable. These results show that the therapeutic effect of St. John's Wort in mild to moderate depression depends on its hyperforin content.

Lantz MS, Buchalter E, Giambanco V . St. John's wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999 Spring;12(1):7-10.
There is increasing interest in and use of the herbal preparation St. John's wort. Hypericin, the major active ingredient, has many psychoactive properties. The agent is sold in the US as a nutritional supplement and is recommended for numerous conditions, including depression, anxiety, insomnia, and inflammation. We report a series of five cases of clinically diagnosed central serotonergic syndrome among elderly patients who combined prescription antidepressants with St. John's wort. Older adults are large consumers of both over-the-counter and prescription medications. They are particularly vulnerable to interactions between medications and products sold as nutritional or herbal supplements. St. John's wort requires further evaluation due to potential for drug interactions with central nervous system agents and for more definitive therapeutic indications.

Lieberman S. Nutriceutical review of St. John's wort (Hypericum perforatum) for the treatment of depression. J Womens Health. 1998 Mar;7(2):177-182. (Review)

Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St John's wort for depression--an overview and meta-analysis of randomised clinical trials. BMJ, 313:253, 1996.

Lopez-Bazocchi I, et al. Antiviral activity of the photoactive plant pigment hypericin. Photochem. Photobiol. 1991,54:95-98.

McLeskey CH, Meyer TA, Baisden CE, Gloyna DF, Roberson CR. The incidence of herbal and selected nutraceutical use in surgical patients. Annual Meeting of American Society of Anesthesiologists (ASA) October 1999.
Abstract: An estimated 60 million American adults are reported to use herbal products. Consumers assume, because these products are natural, they are harmless. However, reports of allergic reactions, adverse effects and drug-herb interactions are surfacing. Following IRB approval, a questionnaire was given to 979 presurgical patients. Subjects were asked to indicate the amount and duration of products taken. Age and surgical procedure were noted. 170 surgical patients (17.4%) reported taking such products. Median age of herb users and non-users was 62 years. Of the patients taking these agents, 55% took only one product, 45% took multiple products. In decreasing order, the most commonly utilized herbs among this group were: gingko biloba (32.4%), garlic (26.5%), ginger (26.5%), ginseng and St. John's Wort (14%). Nutraceuticals most widely used were glucosamine (17%), chromium picolinate (17%) and chondroitin (12%). Over 40 herbs were listed as occasionally taken. Females represented 63% of herbal users and 54% of non-users (p=0.05). 19.3% of female patients took one or more of these products vs. 14.5% of male patients. Neurosurgical, gynecologic and orthopedic surgical patients' use of herbals was slightly higher than other surgical groups at 21%, 21% and 20%. Recently one-third of the American public has been identified as users of herbal products. Our lower incidence may result from reluctance of patients to admit taking such products or lack of understanding among patients regarding drug intake and contents of these products. Anesthesia providers, surgeons, and patients should be aware that these medications may not be harmless and are in increasing use. Adverse effects and drug-herbal interactions may suggest alterations in an anesthetic plan.

Miccoli L. Light-induced photoactivation of hypericin affects the energy metabolism of human glioma cells by inhibiting hexokinase bound to mitochondria. Cancer Res. 1998 58, 24:5777-5786.
Abstract: Glucose-dependent energy required for glioma metabolism depends on hexokinase, which is mainly bound to mitochondria. A decrease in intracellular pH leads to a release of hexokinase-binding, which in turn decreases glucose phosphorylation, ATP content, and cell proliferation. Thus, intracellular pH might be a target for therapy of gliomas, and a search for agents able to modulate intracellular pH was initiated. Hypericin, a natural photosensitizer, displays numerous biological activities when exposed to light. Its mechanism and site of action at the cellular level remain unclear, but it probably acts by a type II oxygen-dependent photosensitization mechanism producing singlet oxygen. Hypericin is also able to induce a photogenerated intracellular pH drop, which could constitute an alternative mechanism of hypericin action. In human glioma cells treated for 1 h with 2.5 microg/ml hypericin, light exposure induced a fall in intracellular pH. In these conditions, mitochondria-bound hexokinase was inhibited in a light- and dose-dependent manner, associated with a decreased ATP content, a decrease of mitochondrial transmembrane potential, and a depletion of intracellular glutathione. Hexokinase protein was effectively released from mitochondria, as measured by an ELISA using a specific anti- hexokinase antibody. In addition to decreased glutathione, a response to oxidative stress was confirmed by the concomitant increase in mRNA expression of gamma-glutamyl cysteine synthetase, which catalyzes the rate-limiting step in overall glutathione biosynthesis, and is subject to feedback regulation by glutathione. Hypericin also induced a dose- and light-dependent inhibition of [3H]thymidine uptake and induced apoptosis, as demonstrated by annexin V-FITC binding and cell morphology. This study confirmed the mitochondria as a primary target of photodynamic action. The multifaceted action of hypericin involves the alteration of mitochondria-bound hexokinase, initiating a cascade of events that converge to alter the energy metabolism of glioma cells and their survival. In view of the complex mechanism of action of hypericin, further exploration is warranted in a perspective of its clinical application as a potential phototoxic agent in the treatment of glioma tumors.

Muenscher WC. Poisonous Plants of the United States. New York: The MacMillan Company.1951.

Muller WE, Rossol R, Effects of Hypericum Extract on the supression of serotonin receptors. J. Geriatric Psychiatry Neurology, 1994 7S63-64.
Abstract: 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.

Muller WE, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry 1998 Jun;31 Suppl 1:16-21.
Abstract: Hydroalcoholic hypericum extract inhibits the synaptosomal uptake of serotonin, norepinephrine, and dopamine with about similar affinities and leads to a significant down-regulation of cortical beta-adrenoceptors and 5-HT2-receptors after subchronic treatment of rats. While neither hypericine nor kaempferol did show any reuptake inhibiting properties, hyperforin was identified as the unspecific reuptake inhibitor of hypericum extracts with half-maximal inhibitory concentrations for the three synaptosomal uptake systems mentioned above between 80 and 200 nmol/l. Moreover, a hyperforin-enriched (38%) CO2 extract also leads to a significant beta-receptor down-regulation after subchronic treatment. The data suggest hyperforin as the active principle of hypericum extracts in biochemical models of antidepressant activity.

Murphy JM. Preoperative considerations with herbal medicines. AORN J.1999 Jan;69(1):173-5, 177-178, 180-183.

Okpanyi SN, Weischer ML. Experimental Animal Studies of the Psychotropic Activity of a Hypericum Extract. Arzneim.-Forsch., 1987.37:10-13.

Rao S G, et al. Calendula and Hypericum: two homeopathic drugs promoting wound healing in rats. Fitoterapia. 1991;6:508-510.

Ramussen P. St. John's Wort: A review of its use in depression. Aust J Med Herbalism .1998; 10(1):8-13.

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Roots I, et al. Evaluation of the photosensitisation of the skin upon single and multiple dose intake of Hypericum extract: 2nd Intnl Congress on Phytomedicine, Munich 1996

Schellenberg R, Sauer S, Dimpfel W. Pharmacodynamic effects of two different hypericum extracts in healthy volunteers measured by quantitative EEG. Pharmacopsychiatry 1998 Jun;31 Suppl 1:44-53.
Abstract: A double-blind, randomized, placebo-controlled parallel-group trial (phase I) was performed to evaluate the central pharmacodynamic effects of two hypericum extracts with different contents of hyperforin (0.5% and 5.0%) but identical hypericin content. Three groups of 18 volunteers between 18 and 35 years of age participated in the trial. The volunteers receiving verum took 900 mg of the extract once a day for 8 consecutive days. The primary aim of this study was to observe the frequency bands, i.e., delta (1.25-4.5 Hz), theta (4.75-6.75 Hz), alpha-1 (7.0-9.5 Hz), alpha-2 (9.75-12.5 Hz), beta-1 (12.75-18.5 Hz), and beta-2 (18.75-35 Hz). This was the first study of its kind testing hypericum controlled on the basis of its hyperforin contents. A quantitative topographic EEG (qEEG) was performed on days 1 and 8 as an indicator of drug-induced pharmacological action. The volunteers' electrophysiological data were obtained prior to application and 2, 4, 6, 8, and 10 hours post administration. Plasma samples for evaluation of the pharmacokinetics of hyperforin were also obtained. The qEEG results of the placebo group on days 1 and 8 showed no significant changes with regard to their physiological daily rhythm. In both verum groups (0.5% and 5.0% hyperforin content), reproducible central pharmacodynamic effects were apparent in comparison to placebo, in particular with the extract containing 5.0% of hyperforin. A peak pharmacodynamic efficacy was observed between 4 and 8 hours post administration. These results were confirmed on day 8 of the trial. The extract containing 5.0% hyperforin showed a marked tendency to produce higher increases in qEEG baseline power performances than the one containing 0.5% hyperforin. These higher baseline outputs on day 8 were seen at the delta, theta, and alpha-1 frequency values. Compared to placebo there was a significant increase in qEEG power performance in the delta and beta-1 frequency values exclusively for the extract containing 5.0% hyperforin. The theta and alpha-1 frequency values showed a noticeable tendency more emphasized on day 8 than on day 1. Preclinical trials in rats have been observed with similar changes in the frequency bands mentioned above, especially in the cholinergic (delta), noradrenergic (theta) and serotonergic (alpha) neurotransmitter systems. These experimental findings suggest that hypericum extracts with a high hyperforin content have a shielding effect on the central nervous system.

Shakirova KK, et al. Antimicrobial properties of some species of St John's Wort cultivated in Uzbekistan. Mikrobiol.Zh. 1970; 32:494-497.

Sparenberg B, Demisch L, Hoelzl J. Antidepressive constituents of St. Johnswort.. PZ Wiss., 1993.6:50-4, (Chem Abstr. 1 19:85914z).

Staffeldt B, Kerb R, Brockmoller J, Ploch M, Roots I. Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S47-S53.

Voelker R. Herbs and Anesthesia. JAMA, May 26, 1999;281(20),1882.

Weber N, et al. The antiviral agent hypericin has in vitro activity against HSV-1 through non specific association with viral and cellular membranes. Antiviral Chemistry and Chemotherapy. 1994 5:83-90.

Weller M.. Hypericin-induced apoptosis of human malignant glioma cells is light- dependent, independent of bcl-2 expression, and does not require wild- type p53. Neurol Res. 1997. 19,5:459-470.
Abstract:Hypericin and tamoxifen are experimental agents for the adjuvant chemotherapy of malignant glioma. We report that hypericin and tamoxifen induce apoptosis of 7 human malignant glioma cell lines in a concentration- and time-dependent manner. Illumination is essential for the cytotoxicity of hypericin but not tamoxifen. Apoptosis is unaffected by inhibitors of RNA and protein synthesis or free radical scavengers, does not require wild-type p53 activity, and occurs in glioma cells expressing high levels of bcl-2. There is no correlation between hypericin and tamoxifen-induced cytotoxicity and inhibition of protein kinase C (PKC). Ectopic expression of a murine bcl-2 transgene provides modest protection from tamoxifen but does not affect hypericin toxicity. Hypericin and tamoxifen do not modulate glioma cell killing induced by tumor necrosis factor-alpha (TNF-alpha) or CD95 ligand. Both drugs augment the acute cytotoxicity of various cancer chemotherapy drugs but fail to shift their EC50 values in modified colony formation assays. These data do not provide further supportive evidence how to enhance the limited efficacy of tamoxifen treatment for human malignant glioma. However, hypericin is a promising agent for the treatment of malignant glioma if local photodynamic activation of hypericin in the glioma tissue can be achieved.

Westbrooks RG, Preacher J W. Poisonous Plants of North America. Los Angeles: University of Southern California Press.1986.

Wheatley D, Hypericum in seasonal affective disorder (SAD).Curr Med Res Opin. 1999.151:33-37.
Abstract: Volunteers from the membership of the SAD Association took part in a postal survey, before and after eight weeks' treatment with Hypericum (Kira), using an 11-item rating scale. The maximum score is 44 and the mean score in 168 patients using Kira alone was 21.3. This fell to 13 at endpoint (p 0.001). The corresponding figures for 133 patients using Kira + light therapy were 20.6 and 11.8, respectively (p 0.001). In both groups, there was significant improvement in anxiety, loss of libido and insomnia. There were no significant between-group differences on any measure except that improvement in sleep was greater in the Kira + light group (p 0.01). On the results of this survey, Hypericum would appear to be an effective treatment for SAD.

Wölk H, Burkhard G, Grünwald J. et al. Benefits and Risks of the Hypericum extract IL60: drug monitoring study with 3250 patients. J. Geriatric Psychiatry Neurology, 1994; 7 S34-38.