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PubMed2006

Functional screening of traditional antidepressants with primary cortical neuronal networks grown on multielectrode neurochips.

We optimized the novel technique of multielectrode neurochip recordings for the rapid and efficient screening of neuroactivity. Changes in the spontaneous activity of cultured networks of primary cortical neurons were quantified to evaluate the action of drugs on the firing dynamics of complex network activity. The multiparametric assessment of electrical activity changes caused by psychoactive herbal extracts from Hypericum, Passiflora and Valeriana, and various combinations thereof revealed a receptor-specific and concentration-dependent inhibition of the firing patterns. The spike and burst rates showed significant substance-dependent effects and significant differences in potency. The effects of specific receptor blockades on the inhibitory responses provided evidence that the herbal extracts act on gamma-amino butyric acid (GABA) and serotonin (5-HT) receptors, which are recognized targets of pharmacological antidepressant treatment. A biphasic effect, serotonergic stimulation of activity at low concentrations that is overridden by GABAergic inhibition at higher concentrations, is apparent with Hypericum alone and the triple combination of the extracts. The more potent neuroactivity of the triple combination compared to Hypericum alone and the additive effect of Passiflora and Valeriana suggest a synergy between constituent herbal extracts. The extracts and their combinations affected the set of derived activity parameters in a concomitant manner suggesting that all three constituent extracts and their combinations have largely similar modes of action. This study also demonstrates the sensitivity, selectivity and robustness of neurochip recordings for high content screening of complex mixtures of neuroactive substances and for providing multiparametric information on neuronal activity changes to assess the therapeutic potential of psychoactive substances.

Action Potentials↗
PubMed2006

Superior efficacy of St John's wort extract WS 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo-controlled, multi-center trial [ISRCTN77277298].

BACKGROUND: The aim of the current study was to assess the antidepressant efficacy and safety of Hypericum perforatum (St. John's wort) extract WS 5570 at doses of 600 mg/day in a single dose and 1200 mg/day in two doses. METHODS: The participants in this double-blind, randomized, placebo-controlled, multi-center clinical trial were male and female adult out-patients with an episode of mild or moderate major depressive episode (single or recurrent episode, DSM-IV criteria). As specified by the relevant guideline, the study was preceded by a medication-free run-in phase. For the 6-week treatment, 332 patients were randomized: 123 to WS 5570 600 mg/day, 127 to WS 5570 1200 mg/day, and 82 to placebo. The primary outcome measure was the change in total score on the Hamilton Rating Scale for Depression (HAM-D, 17-item version) between baseline and endpoint. Additional measures included the number of responders, the number of patients in remission, and several other standard rating scales. Efficacy and safety were assessed after 2 and 6 weeks. The design included an interim analysis performed after randomization with the option of early termination. RESULTS: After 6 weeks of treatment, mean +/- standard deviation decreases in HAM-D total scores of 11.6 +/- 6.4, 10.8 +/- 7.3, and 6.0 +/- 8.1 points were observed for the WS 5570 600 mg/day, 1200 mg/day and placebo groups, respectively (endpoint analysis). Secondary measures of treatment efficacy also showed that both WS 5570 groups were statistically superior to placebo. Significantly more patients in the WS 5570 treatment groups than in the placebo group showed treatment response and remission. WS 5570 was consistently more effective than placebo in patients with either less severe or more severe baseline impairment. The number of patients who experienced remission was higher in the WS 5570 1200 mg/day group than the WS 5570 600 mg/day group. The incidence of adverse events was low in all groups. The adverse event profile was consistent with the known profile for Hypericum extract preparations. CONCLUSION: Hypericum perforatum extract WS 5570 at doses of 600 mg/day (once daily) and 1200 mg/day (600 mg twice daily) were found to be safe and more effective than placebo, with comparable efficacy of the WS 5570 groups for the treatment of mild to moderate major depression.

Adolescent↗
PubMed2002

Influence of GSTT1 and GSTM1 genotypes on sunburn sensitivity.

BACKGROUND: Exposure to sunlight may cause sunburn, skin cancer or phototoxic reactions to certain drugs such as Hypericum extract. All these are ultraviolet B (UVB)-mediated reactions which may be modulated by individual genetic susceptibility. UVB exposure results in oxidative stress. Many products of oxidative stress are detoxified by glutathione-S-transferases mu 1 (GSTM1) and theta 1 (GSTT1). Deletion polymorphisms (genotype *0/*0) of GSTM1 and GSTT1 occur in 50% and 20% of Caucasians, respectively. By affecting the individual ability to detoxify oxidative stress-related products, they may influence the severity of the cutaneous photoreaction. METHODS: Minimal erythema doses (MED) of UVB irradiation on the skin were determined in 110 subjects who were selected according to their GSTT1 genotype (28 GSTT1*0/*0, 54 GSTT1*A/*0, and 28 GSTT1*A/*A). Genotypes were detected with novel polymerase chain reaction (PCR) assays that allow the differentiation between homozygous and heterozygous GSTT1 and GSTM1 deletions. RESULTS: In the absence of GSTT1 enzyme, the susceptibility of individuals to UVB-induced inflammatory skin reactions increased significantly (p = 0.02, ANCOVA). 'Gene-equivalents' were calculated from the number of functional GSTM1 and GSTT1 alleles as a measure of the gene-dose. UVB sensitivity correlated with gene dose up to a threshold above which additional GSTT1 or GSTM1 alleles did not provide additional protection. Volunteers who were homozygously deficient in GSTT1 and GSTM1 were most sensitive to UVB. Interestingly, individuals with high GSTM1 gene-doses showed increased photosensitization after administration of Hypericum extract (St. John's wort). CONCLUSION: Individuals harboring the *0/*0 genotype of GSTT1 and/or GSTM1 showed enhanced UVB-induced cutaneous damage. Moreover, GST genotypes modulated Hypericum-induced photosensitization.

Adolescent↗
PubMed1999

[High dose St. John's wort extract as a phytogenic antidepressant].

In 1998 a special standardized high-dose hypericum extract has been approved in Austria and Germany for treatment of mild and moderate depression. The efficacy has been already recognized since 1984 from the German Health Authorities based on traditional knowledge. However, this has been substantiated in the subsequent years in controlled clinical trials. 20 of these studies including a total of 1,787 patients have been filed, among them 10 older studies in which hypericum was extracted with ethanol compared to newer studies in which the extract was methanol (LI 160). In the past 10 years several controlled clinical trials have been conducted compared with placebo as well as synthetic antidepressants. These studies have shown that the effective dosage is within a range of 600 to 900 mg extract. The side effects are substantially fewer than with synthetic antidepressants and range within 3%. The most important risk is photosensitization, which is however without clinical relevance in the recommended dosages. Recent pharmacological studies revealed that hypericum extracts have a similar mechanism of action like the selective serotonin reuptake inhibitors (SSRI), however, very likely to a smaller extent.

Antidepressive Agents↗
PubMed2000

[St. Johns wort extract as plant antidepressant].

In 1998 a standardized hypericum extract has been approved in Austria and Germany for treatment of mild and moderate depression. The efficacy has been already recognized since 1984 from the German Health Authorities based on traditional knowledge. However, this has been substantiated in the subsequent years in controlled clinical trials. Twenty of these studies including a total of 1787 patients have been filed, among them ten older studies in which hypericum was extracted with ethanol compared to newer studies in which the extract was methanol (LI 160). In the past ten years several controlled clinical trials have been conducted compared with placebo as well as synthetic antidepressants. These studies have shown that the effective dosage is within a range of 600-900 mg extract. The side effects are substantially fewer than with synthetic antidepressants and range within 3%. The most important risk is photosensitization, which is however without clinical relevance in the recommended dosages. Recent pharmacological studies revealed that hypericum extracts have a similar mechanism of action like the selective serotonin reuptake inhibitors (SSRI), however, very likely to a smaller extent.

Clinical Trials as Topic↗
PubMed1998

The scientific, quasi-scientific and popular literature on the use of St. John's Wort in the treatment of depression.

St. John's Wort, also known as Hypericum, is an herbal product that is available in health food stores as an allegedly 'safe' alternative to antidepressants developed by the pharmaceutical industry. Recently it has received extensive coverage through the media, especially in the United States. To the best of our knowledge, Germany is the only country where it has been formally approved for clinical use. We reviewed both the vulgar and the scientific literature on this product. Although the few controlled studies that have been conducted pertain to adjustment disorder with depressed mood, several books and the media advocate its use for clinical and/or chronic depression. The high placebo rate in these studies, often in the 50% range, does indeed suggest that the controlled trials have been conducted on mild transient depressions; extrapolation to more serious or chronic depressions would therefore be unwarranted. We could not find any published literature comparing the efficacy of Hypericum to a standard antidepressant versus placebo. Furthermore, the studies claiming safety and freedom from potentially serious side effects appear flawed methodologically. Actually, little is known about the putative mechanism of action of Hypericum in depression; if indeed it does involve serotonergic mechanisms or monoamine-oxidase inhibition, it invites caution with concurrent use with an SSRI and, of course, with a MAOI. A skeptic might conclude that St. John's Wort should not be used until more definitive data are available. A less conservative view would be that, while its current widespread use is not warranted, the product may still have some merit for mild nonchronic depressive states below the clinical threshold. If this were conclusively proven, it would indeed constitute an important development in the field of antidepressants.

Antidepressive Agents↗
PubMed2005

Herb-drug interactions: a literature review.

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations. Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine). In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Animals↗
PubMed1998

Treatment of depression--newer pharmacotherapies.

OBJECTIVES: Depressive disorders are persistent, recurring illnesses that impose enormous personal suffering on individuals and their families. Major depression alone is estimated as the fourth most important cause of worldwide loss in disability-adjusted life years and is likely to become the second most important within 20 years. A continued quest for more effective treatments has spawned newer antidepressants and herbal treatments, which have contributed to explosive growth in antidepressant prescribing, increasing pharmacy costs, and wider but sometimes confusing choices for clinicians and patients. This evidence report provides a comprehensive evaluation of the benefits and adverse effects of newer pharmacotherapies and herbal treatments for depressive disorders in adults and children. SEARCH STRATEGY: Pertinent literature from 1980 to January 1998 was identified from a specialized registry of controlled trials, meta-analyses, and experts. The registry contained trials addressing depression that had been identified from multiple electronic bibliographic databases, hand searches of journals, and pharmaceutical companies. The search, which yielded 1,277 records, combined terms "depression," "depressive disorder," or "dysthymic disorder" with a list of 32 specific "newer" antidepressant and herbal treatments. SELECTION CRITERIA: Randomized controlled trials were reviewed if they (1) were at least 6 weeks in duration; (2) compared a "newer" antidepressant with another antidepressant (newer or older), placebo, or psychosocial intervention; (3) involved participants with depressive disorders; and (4) had a clinical outcome. Two or more independent reviewers identified 315 trials that met these criteria. DATA COLLECTION AND ANALYSIS: Two persons independently abstracted data from each trial. Data were synthesized descriptively, paying attention to participant and diagnostic descriptors, intervention characteristics, study designs and clinical outcomes. Some data were analyzed quantitatively using an empirical Bayes random-effects estimator method. Primary outcomes were response rate, total discontinuation rates (dropouts), and discontinuation rates due to adverse events. Response rates were defined as a 50 percent or greater improvement in symptoms as assessed by a depression symptoms rating scale or a rating of much or very much improved as assessed by a global assessment method. MAIN RESULTS: There were 264 trials that evaluated antidepressants in patients (adults and children) with major depression. Of these, 81 compared newer agents with placebo, 150 newer with older agents, 32 newer agents with newer agents, and 1 newer agent with psychotherapy. There were 14 trials evaluating hypericum (St. John's wort), 27 trials each in primary care patients and older adults, 10 trials limited to patients with specific concomitant illnesses, 9 trials in patients with dysthymia, 3 trials each in patients with mixed anxiety depression and subsyndromal depression, 2 trials in adolescents, and 1 in the postpartum setting. Most trials were conducted in outpatients and examined only acute phase treatment of less than 12 weeks' duration. Newer antidepressants were more effective than placebo in treating major depression (risk ratio 1.6, 95% CI 1.5 to 1.7) and dysthymia (risk ratio 1.7, 95% CI 1.3 to 2.3). They were effective among older adults and in primary care patients. In general, there were no significant differences in efficacy among individual newer agents or between newer and older agents. Hypericum (St. John's wort) was more effective than placebo in treating mild to moderately severe depressive disorders (risk ratio 1.9, 95% CI 1.2 to 2.8). Whether hypericum (St. John's wort) is as effective as standard antidepressant agents given in adequate doses was not established. No significant differences were found between newer and older antidepressants in overall discontinuation rates. Selective serotonin reuptake inhibitors (SSRIs), reversi

Adult↗
PubMedDate not supplied

Hydroalcoholic plant extracts with anti-inflammatory activity.

The aim of the present study was to investigate if standardized hydroalcoholic plant extracts such as Calendula officinalis, Hypericum perforatum, Plantago lanceolata and Glycyrrhiza glabra can suppress in cell-free systems the activities of 5-lipoxygenase (5-LO) and cyclooxygenase-2 (COX-2), key enzymes in the formation of proinflammatory eicosanoids from arachidonic acid (AA). Studies were undertaken to compare the above mentioned plant extracts to a known NSAID (nimesulide) in their ability to inhibit both cyclooxygenase (COX-2) and lipoxygenase (5-LO) activities in cell-free systems. We report on 2 vegetal extracts (Hypericum perforatum and Glycyrrhiza glabra) that inhibit 5-LO activity and 2 vegetal extracts (Plantago lanceolata and Glycyrrhiza glabra) that inhibit COX-2 activity. In this study, we demonstrate for the first time that Glycyrrhiza glabra extract efficiently suppresses both eicosanoids and leukotrienes formation in cell-free systems, implying that this extract directly acts as a dual inhibitor of 5-LO and COX-2 activities. With regard to the properties of dual COX-2/5-LO inhibitors, Glycyrrhiza glabra extract might be a potential drug possessing anti-inflammatory activity devoid of the most troublesome (gastric) side effects seen for drugs used as COX-2 and 5-LO inhibitors. Hypericum perforatum, Plantago lanceolata and Glycyrrhiza glabra extracts can be added to an already impressive list of these species that have anti-inflammatory activity.

Anti-Inflammatory Agents↗
PubMed2002

St John's wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial.

RATIONALE AND OBJECTIVE: Preliminary data have shown that St John's wort might possess some specific efficacy in patients with somatoform complaints. Therefore, the efficacy of the Hypericum extract LI 160 in patients with somatoform disorders should be studied in a double-blind placebo-controlled fashion. METHODS: This was a multicentre, randomised, placebo controlled, 6-week trial comparing the efficacy of LI 160 (600 mg/day) and placebo in 151 out-patients suffering from somatization disorder (ICD-10: F45.0), undifferentiated somatoform disorder (F45.1), or somatoform autonomic dysfunctions (F45.3). The primary outcome measure was the decrease of the Hamilton Anxiety Scale, subfactor somatic anxiety (HAMA-SOM), during the trial period. RESULTS: LI 160 was superior effective concerning the primary outcome criterion HAMA-SOM [decrease from 15.39 (SD 2.68) to 6.64 (4.32) in the Hypericum group and from 15.55 (2.94) to 11.97 (5.58) in the placebo group (statistically significant difference, P=0.001)]. This was corroborated by the result of a statistically significant superior efficacy in the outcome criteria additionally used such as Clinical Global Impression, HAMA-total score, HAMA, subscore psychic anxiety, Hamilton Depression Scale, Self-Report Symptom Inventory 90 items - revised (SCL-90-R), and SCL-90-R, subscore somatic anxiety. The efficacy of LI 160 was preserved after splitting the population in those with and those without mild depressive symptoms [corrected]. Tolerability of LI 160 was excellent. CONCLUSION: The data from this trial show excellent efficacy and tolerability for LI 160 in somatoform disorders. The efficacy is independent of an existing depressive mood. This is the first study showing the efficacy of a drug in patients with somatisation disorder independent of depressive symptomatology.

Adolescent↗
PubMed2006

Determination of St. John's wort flavonoid-metabolites in rat brain through high performance liquid chromatography coupled with fluorescence detection.

Flavonoids with the quercetin structure are widely distributed throughout the plant kingdom. Some effects such as their anti-oxidative and radical scavenging capacities are broadly discussed in literature. Furthermore, some Hypericum flavonoids show activity in depression-relevant animal model assays. So far, only one study concerning the pharmacokinetic profile of Hypericum perforatum (St. John's wort, SJW) flavonoids has been reported, but no data concerning their bioavailability in the CNS is on-hand. Thus, we developed a method for the quantification of quercetin, tamarixetin and isorhamnetin, both metabolites of quercetin, in very low concentrations in the rat brain in order to investigate the ability of flavonoids to cross the blood-brain barrier. The brain samples for analysis were taken 4h after feeding an oral dose of an alcoholic SJW extract or pure isoquercitrin. We found the presence of quercetin and isorhamnetin/tamarixetin after feeding a SJW extract at 7 ng/g brain and 35 ng/g brain, respectively. In addition, we examined blood plasma taken from the same rats to correlate plasma and brain levels. The plasma levels were 350 ng/mL for quercetin and 1006 ng/mL for isorhamnetin/tamarixetin after intake of SJW extract.

Animals↗
PubMed2005

The first prenylation step in hyperforin biosynthesis.

Prenylation reactions contribute considerably to the diversity of natural products. Polyprenylated secondary metabolites include hyperforin which is both quantitatively and pharmacologically a major constituent of the medicinal plant Hypericum perforatum (St. John's wort). Cell cultures of the related species Hypericum calycinum were found to contain a prenyltransferase activity which is likely to catalyze the first prenylation step in hyperforin biosynthesis. The enzyme was soluble and dependent on a divalent cation, with Fe2+ leading to maximum activity (Km=3.8 mM). The preferred prenyl donor was DMAPP (Km=0.46 mM) and the preferred prenyl acceptor was phlorisobutyrophenone (Km=0.52 mM). A broad pH optimum from 6.5 to 8.5 and a temperature optimum from 35 to 40 degrees C were observed. The formation of hyperforins in H. calycinum cell cultures was preceded by an increase in dimethylallyltransferase activity, with the maximum specific activity being 3.6 microkat/kg protein.

Bridged Bicyclo Compounds↗
PubMed2005

Photogenotoxicity of hypericin in HaCaT keratinocytes: implications for St. John's Wort supplements and high dose UVA-1 therapy.

Extract of St. John's Wort (Hypericum perforatum) is commonly used as natural remedy for treatment of mild to moderate depression. However, it contains a powerful photoactive component, hypericin, which can cause a severe photodermatitis when eaten by grazing animals (hypericism). In humans, there is evidence that supplementation with St. John's Wort can reduce the minimal erythemal dose (MED) in patients undergoing high dose UVA-1 phototherapy. This is a recent development in phototherapy where the most erythemogenic parts of the UVA spectrum are filtered out, allowing delivery of higher doses of the longer wavelengths of UVA. Although current published evidence suggests that the plasma levels of hypericin are unlikely to cause clinical phototoxicity, it has been established that photoactive compounds can cause DNA damage at sub-toxic and sub-erythemal doses, the effects of which might not be apparent for many years after the event. The present study used HaCaT keratinocytes to investigate the photoclastogenic ability of hypericin on irradiation with UVA. The results show that although the combination of hypericin and UVA light increased the genotoxic burden, when all factors are taken into account, the risk of significant photogenotoxic damage incurred by the combination of Hypericum extracts and UVA phototherapy may be low in the majority of individuals.

Anthracenes↗
PubMed1999

Mania associated with St. John's wort.

BACKGROUND: St. John's wort, the popular herbal remedy touted as an antidepressant, is generally thought to be benign, with few reported side effects. Given its possible efficacy as an antidepressant, evaluation of its propensity to cause affective switching should be evaluated. METHODS: This report presents two cases of mania temporally associated with the use of St. John's wort (hypericum). RESULTS: As with other antidepressant agents, St. John's wort may precipitate hypomania, mania, or an increased cycling of mood states, particularly in patients with occult bipolar disorder. CONCLUSIONS: Because the majority of people who take this popular over-the-counter preparation do so without formal psychiatric evaluations, risk of hypericum-induced mania may be significant. Physicians should screen patients for a history of hypomania or mania before recommending use of St. John's wort for depression.

Adult↗
PubMed1999

In vitro transport and uptake of protohypericin and hypericin in the Caco-2 model.

The intestinal absorption characteristics of protohypericin, a protonaphthodianthrone present in Hypericum extract, were studied and compared with those of hypericin. The Caco-2 model was used as a model of the intestinal mucosa to assess transepithelial transport and cell uptake. The experimental work was performed in specific light conditions that prevented both the photoconversion of protohypericin into hypericin and the photosensitization of the cells. Following application of the individual compounds (80-200 microM) to the apical side of the monolayers, the appearance in the basolateral compartment was found to be very low (<0.5%/5 h), but was comparable for both compounds. A lag-time of 2-3 h was observed, suggesting gradual saturation of binding sites on the membrane or inside the cells. Uptake experiments of protohypericin and hypericin by Caco-2 cells revealed a very significant cellular accumulation (4-8%); uptake was characterised by saturation after 3 h. The findings of this study suggest that protohypericin has comparable absorption characteristics as hypericin and may contribute to the beneficial effect of Hypericum extract after oral dosing.

Anthracenes↗
PubMed2003

St John's wort, conventional medication, and placebo: an egregious double standard.

The efficacy of antidepressant medication is generally thought to be well established, whereas that of hypericum (St John's wort) is considered doubtful. The data fail to support these discrepant conclusions. Instead they show that hypericum and conventional antidepressants are equally effective (or ineffective). This suggests that different standards are being used to evaluate the two types of treatment.

Antidepressive Agents↗
PubMed2003

Hyperforin-containing extracts of St John's wort fail to alter gene transcription in brain areas involved in HPA axis control in a long-term treatment regimen in rats.

We previously showed that a methanolic extract of St John's wort (SJW) (Hypericum) and hypericin, one of its active constituents, both have delayed regulation of genes that are involved in the control of the hypothalamic-pituitary-adrenal (HPA) axis. Hyperforin, another constituent of SJW, is active in vitro and has been proposed to be the active constituent for therapeutic efficacy in depression. We therefore examined if hyperforin has delayed effects on HPA axis control centers similar to those of Hypericum and hypericin. We used in situ hybridization histochemistry to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) oral administration of two hyperforin preparations, fluoxetine (positive control), and haloperidol (negative control) on the expression of genes involved in the regulation of the HPA axis. Fluoxetine (10 mg/kg) given daily for 8 weeks, but not 2 weeks, significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 22% in the paraventricular nucleus (PVN) of the hypothalamus and tyrosine hydroxylase (TH) mRNA by 23% in the locus coeruleus. Fluoxetine increased levels of mineralocorticoid (MR) (17%), glucocorticoid (GR) (18%), and 5-HT(1A) receptor (21%) mRNAs in the hippocampus at 8, but not 2, weeks. Comparable to haloperidol (1 mg/kg), neither the hyperforin-rich CO(2) extract (27 mg/kg) nor hyperforin-trimethoxybenzoate (8 mg/kg) altered mRNA levels in brain structures relevant for HPA axis control at either time point. These data suggest that hyperforin and hyperforin derivatives are not involved in the regulation of genes that control HPA axis function.

Adrenal Glands↗
PubMed2005

St John's wort versus placebo in obsessive-compulsive disorder: results from a double-blind study.

Although St John's wort (Hypericum perforatum) is one of the most widely used and studied herbal medicines for depression, less is known about its efficacy in anxiety disorders, in spite of the fact that patients with anxiety disorders are among the most likely to self-medicate using alternative treatments. Pharmacokinetic evidence for the serotonergic, domaminergic and GABAminergic activity of hypericum, and a recent successful open-label study, suggests that it may be effective for obsessive-compulsive disorder (OCD). Sixty subjects were randomized to 12 weeks of treatment with St John's wort (LI 160) or matching placebo. Subjects with Hamilton Depression Scale scores of 16 or above were excluded. A flexible-dose schedule was utilized (600-1800 mg/day). The mean change on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) with St John's wort (3.43) was not significantly different than the mean change found with placebo (3.60) (P=899). No significant differences were found on any of the Y-BOCS subscales. The percentage of patients rated as 'much' or 'very much' improved at endpoint was not significantly different between St John's wort (17.9%) and placebo (16.7%) (P=0.905). Only one patient from each group discontinued due to adverse events [sinus infection (St John's wort); confusion (placebo)]. The results fail to support the efficacy of St John's wort for OCD.

Administration, Oral↗