The effects of St. John's wort extract and amitriptyline on autonomic responses of blood vessels and sweat glands in healthy volunteers

St. John's wort extract is widely used and advertised as a "natural antidepressant" lacking autonomic side effects. This randomized, double-blind, placebo-controlled study compared the effects of St. John's wort extract on autonomic responses of blood vessels and sweat glands with those of amitriptyline and placebo. A randomized, double-blind, crossover study was performed in healthy male volunteers aged 22 to 31 years (25 +/- 3 years; mean +/- SD) years. Subjects orally received capsules with 255 to 285 mg St. John's wort extract (900 microg hypericin content), 25 mg amitriptyline, and placebo 3 times daily for periods of 14 days each with at least 14 days between. Vasoconstrictory response of cutaneous blood flow (VR) and skin conductance response (SR) following a single deep inspiration were employed as parameters of autonomic function. St. John's wort extract had no effect on VR and SR. In contrast, SR was diminished and the dilation phase of VR was prolonged following multiple dosing with amitriptyline (P < 0.05). Decreased electrodermal reactivity observed with amitriptyline reflects inhibition of acetylcholine at peripheral m3-cholinoreceptors, whereas prolongation of VR induced by the tricyclic drug may be due to sustained activation of central and/or peripheral sympathetic neurons.     

A Double-blind, randomized trial of St John's wort, fluoxetine, and placebo in major depressive disorder

OBJECTIVE: This study looks to compare the antidepressant efficacy and safety of a standardized extract of St John's wort with both placebo and fluoxetine. METHOD: After a 1-week single-blind washout, patients with major depressive disorder diagnosed by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were randomized to 12 weeks of double-blind treatment with LI-160 St John's wort extract (900 mg/d), fluoxetine (20 mg/d), or placebo. The 17-item Hamilton Rating Scale for Depression (HAMD-17) was the primary efficacy measure, and analysis of covariance was used to compare differences in end point HAMD-17 scores across the 3 treatment groups, treating the baseline HAMD-17 as the covariate. RESULTS: One hundred thirty-five patients (57% women; mean age, 37.3 +/- 11.0; mean HAMD-17, 19.7 +/- 3.2) were randomized to double-blind treatment and were included in the intent-to-treat analyses. Analysis of covariance analyses showed lower mean HAMD-17 scores at end point in the St John's wort group (n = 45; mean +/- SD, 10.2 +/- 6.6) compared with the fluoxetine group (n = 47; 13.3 +/- 7.3; P < 0.03) and a trend toward a similar finding relative to the placebo group (n = 43; 12.6 +/- 6.4; P = 0.096). There was also a trend toward higher rates of remission (HAMD-17 <8) in the St John's wort group (38%) compared with the fluoxetine group (30%) and the placebo group (21%). Overall, St John's wort appeared to be safe and well tolerated. CONCLUSION: St John's wort was significantly more effective than fluoxetine and showed a trend toward superiority over placebo. A (25%) smaller than planned sample size is likely to account for the lack of statistical significance for the advantage (indicating a moderate effect size, d = 0.45) of St John's wort over placebo.     

The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system

RATIONALE: In therapeutic use, amitriptyline, reboxetine and citalopram have all been associated with apparent anticholinergic-like side effects (dry mouth, constipation, etc.), despite the very low antimuscarinic activity of reboxetine and citalopram in vitro. OBJECTIVES: We hypothesised that the spectral analysis of heart rate variability (HRV) might detect differences between amitriptyline, citalopram and reboxetine in their anticholinergic activities following a single peroral administration. METHODS: In this double-blind, cross-over study, amitriptyline (75 mg), citalopram (20 mg), reboxetine (4 mg) and placebo were randomly given at 1-week intervals to eight healthy male volunteers. Drug and catecholamine concentrations in plasma were determined repeatedly. The drug effect was assessed with periodic recordings of electrocardiogram (ECG) and blood pressure, and with measurements of salivary secretion. The ECG recordings were subjected to spectral analysis of HRV, in which the high frequency (HF) power of R-R interval (RRI) variability was supposed to reflect cardiac parasympathetic tone. RESULTS: Reboxetine increased heart rate and blood pressure and reduced the HF power of RRI and 3,4-dihydroxyphenylglycol (DHPG) plasma concentrations. Amitriptyline diminished salivary secretion and had a prominent sedative action. Measurements after citalopram did not differ significantly from placebo. CONCLUSIONS: Reboxetine, despite its low antimuscarinic activity in vitro, had distinct effects on the HF power of RRI, consistent with anticholinergic activity in vivo. Amitriptyline had a measurable anticholinergic effect in the salivary glands, but, surprisingly, not in the heart. We suggest that the sedative effect of amitriptyline could alter cardiac sympathovagal balance and, therefore, counteract the anticholinergic drug effect.     

Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort ( Hypericum perforatum ).

Extracts of St. John's wort ( Hypericum perforatum ) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with hypericum extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the possible interaction of hypericum extract LI160 with amitriptyline. Both antidepressants have a high probability of concomitant use. Twelve patients requiring amitriptyline treatment received a single dose of hypericum extract (900 mg) at day 1, continued by a 12-to 14-day treatment with retarded amitriptyline (75 mg twice daily). Then hypericum (900 mg/day) was added for another 14 to 16 days. Steady-state pharmacokinetics of amitriptyline were compared before and after multiple-dose treatment with hypericum extract. Furthermore, comparisons were made for single-dose kinetics of hypericum-extract ingredients hypericin, pseudohypericin, and hyperforin between the first day of concomitant treatment and LI160 alone. Multiple-dose comedication with LI160 led to a statistically significant decrease in the area under the plasma concentration-time curve within one dosing interval of amitriptyline by 22% ( p = 0.03) and nortriptyline by 41% ( p = 0.002), as well as of all hydroxylated metabolites, except for 10-E-hydroxynortriptyline. Plasma levels of amitriptyline and hydroxylated metabolites gradually decreased, whereas nortriptyline concentrations were already markedly decreased after 3 days of cotreatment with hypericum. Cumulative urinary amounts of amitriptyline and metabolites decreased to the same extent as plasma concentrations upon hypericum comedication. Induction of cytochrome P-450 enzymes or drug transporters (P-glycoprotein) by St. John's wort extract may explain this pharmacokinetic interaction. Physicians should be aware of this interaction when treating patients with amitriptyline.     

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.     

A systematic review and meta-analysis of Hypericum perforatum in depression: a comprehensive clinical review

The herbal remedy St John's wort is widely used as an antidepressant but its efficacy has not been systematically investigated. Meta-analyses and systematic reviews of published trials strongly suggest St John's wort is more effective than placebo although comparative efficacy to standard antidepressants is less clearly established. We updated and expanded previous meta-analyses of St John's wort, scrutinised the validity of published reports and examined possible mechanisms of action. Twenty-two randomised controlled trials were identified. Meta-analysis showed St John's wort to be significantly more effective than placebo (relative risk (RR) 1.98 (95% CI 1.49-2.62)) but not significantly different in efficacy from active antidepressants (RR 1.0 (0.90-1.11)). A sub-analysis of six placebo-controlled trials and four active comparator trials satisfying stricter methodological criteria also suggested that St John's wort was more effective than placebo (RR 1.77 (1.16-2.70)) and of similar effectiveness to standard antidepressants (RR 1.04 (0.94-1.15)). There was no evidence of publication bias. Adverse effects occurred more frequently with standard antidepressants than with St John's wort. The mechanism of action of St John's wort remains unknown. Future research should include large scale, appropriately powered comparisons of St John's wort and standard antidepressants.     

Comparison of German St. John's wort products according to hyperforin and total hypericin content

OBJECTIVES: To compare the hyperforin and hypericin content of currently available St. John's wort products and to determine their batch-to-batch reproducibility. DESIGN: Representative products were obtained either directly from the manufacturer or purchased from pharmacies in and around Frankfurt, Germany. For five batches from each of the eight manufacturers, 10 individual dosage forms (tablets or capsules) were analyzed for both hyperforin and hypericin content. SETTING: Laboratories of the Institute of Pharmaceutical Chemistry at Johann Wolfgang Goethe University, Frankfurt, Germany. PRODUCTS: Eight German St. John's wort products containing from 250 mg to 612 mg dry extract were studied. Three of these products are capsules, four are film-coated tablets, and one is a sugar-coated tablet. Two of the products (Jarsin 300 and Neuroplant 300) are also available in the United States. METHODS: Hyperforin concentrations were analyzed by high-performance liquid chromatography. Total hypericin concentrations were determined by polarography, an electrochemical method. Concentrations were compared among different batches of the same product and among products from different manufacturers. RESULTS: The products contained widely differing amounts of hypericin and hyperforin, even after correcting for differences in the amount of extract per dose. Some products demonstrated consistent concentrations of hyperforin and hypericin from batch to batch, others exhibited pronounced interbatch variability. CONCLUSION: The St. John's wort preparations studied exhibited large differences in hypericin and hyperforin content and are not interchangeable for the treatment of mild-to-moderate depression. Pharmacists should take this variability into account when counseling patients on the use of St. John's wort products.     

Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial

AIMS: Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St John's wort extract. The aim of the present study was to investigate the effects of St John's wort extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel. METHODS: Eighteen healthy females were treated with a low-dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg St John's wort extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel were assessed under steady-state conditions. RESULTS: During concomitant administration of low-dose oral contraceptive and St John's wort, there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 (77%), P < 0.015) and cycle B (15/17 (88%), P < 0.001) than with oral contraceptives alone (6/17 (35%)). The AUC(0,24 h) and Cmax of ethinyloestradiol remained unchanged during all study cycles, whereas the AUC(0,24 h) and Cmax of 3-ketodesogestrel decreased significantly from 31.2 ng ml-1 h to 17.7 ng x ml-1 h (43.9%; 95% confidence interval (CI) -49.3, -38.5, P = 0.001) and from 3.6 ng x ml -1 to 3.0 ng x ml -1(17.8%; CI -29.9, -5.7, P = 0.005), respectively, during cycle A and by 41.7% (CI -47.9, -35.6; P = 0.001) and by 22.8% (CI -31.2, -13.3; P < 0.001) during cycle B respectively, compared with the control cycle. CONCLUSIONS: There was no evidence of ovulation during low-dose oral contraceptive and St John's wort extract combination therapy, but intracyclic bleeding episodes increased. Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St John's wort-induced decreases in serum 3-ketodesogestrel concentrations, enhance the risk of unintended pregnancies.     

The influence of St. John's wort on the pharmacokinetics and protein binding of imatinib mesylate

STUDY OBJECTIVE: To determine the effect of St. John's wort on the pharmacokinetics of imatinib mesylate. DESIGN: Open-label, complete crossover, fixed-sequence, pharmacokinetic study. SETTING: Clinical research center. SUBJECTS: Ten healthy adult volunteers. INTERVENTION: Single 400-mg oral doses of imatinib were administered before and after 2 weeks of treatment with St. John's wort 300 mg 3 times/day. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of imatinib were significantly altered by St. John's wort, with reductions of 32% in the median area under the concentration-time curve from time zero to infinity (p=0.0001), 29% in maximum observed concentration (p=0.005), and 21% in half-life (p=0.0001). Protein binding ranged from 97.7-90.3% (mean 94.9%), was concentration independent, and was not altered by St. John's wort. Therapeutic outcomes of imatinib have been shown to correlate with both dose and drug concentrations. CONCLUSION: Coadministration of imatinib with St. John's wort may compromise imatinib's clinical efficacy.     

Effects of sertraline on autonomic and cognitive functions in healthy volunteers

Rationale Though sertraline, a selective serotonin reuptake inhibitor (SSRI), causes autonomic and cognitive adverse events such as dry mouth and somnolence, there is a paucity of appropriately designed studies on the cognitive and autonomic effects of the drug in the literature. Objective To compare the effects of sertraline on cognitive and autonomic functions with those of placebo in healthy humans. Method A randomized, double blind, cross over study of 12 healthy male volunteers aged 24 (21– 32; median; range) years. Subjects orally received 50 mg sertraline and placebo once daily for periods of 14 days each with at least 14 days in between. Heart rate variability (HRV), skin conductance level (SCL) and skin conductance response (SCR) following sudden deep respiration were employed as parameters for autonomic function. Quantitative EEG (qEEG) and psychometric tests served as parameters for cognitive function. Measurements were performed repeatedly before the start of drug administration and on the last treatment day. Results Sertraline caused a significant reduction of heart rate and SCL (P<0.05), whereas HRV and SCR were not changed. Cognitive functions such as flicker fusion frequency, memory, choice reaction time and psychomotor performance were not influenced by sertraline but slow and fast beta power density in the qEEG was increased. Conclusion Cognitive and psychomotor performance are not altered in healthy humans receiving multiple dosing with sertraline. The observed decreases in heart rate and SCL may be due to a sympatho-inhibitory effect of sertraline.     

Determination of total hypericins in St. John's wort and herbal medicinal products

The work aimed to determine the levels of hypericins expressed as hypericin in the herbal substance of St. John's wort, in capsules and tablets containing the extract of St. John's wort, tablets containing powdered herb and in tincture and juice from fresh St. John's wort, by HPLC method with spectrophotometric detection. In addition, the amount of hypericins in the infusion prepared from St. John's wort was determined by HPLC and spectrophotometry methods. According to traditional indications aqueous infusions from St. John's wort containing mainly hydrophilic components are used in gastrointestinal diseases. On the other hand, ethanolic extracts containing hypericin and hyperforin affect the CNS and are indicated for the treatment of episodes of mild depressive disorders. The results obtained in the work indicate that the daily dose of hypericins taken by a patient as infusions is 0.328 mg on average for herbs in sachets and in bulk form. It can be compared to the daily dose of hypericins contained in tablets and capsules based on the alkoholic extract of St. John's wort and tablets containing powdered St. John's wort herb. For solid dosage forms, this dose ranges from 0.288 mg to 0.636 mg. The assays were performed using consistent analytical methods for all tested pharmaceutical products and consequently it was possible to compare doses taken by patients and their strength of action.     

St John's wort: a potential therapy for elderly depressed patients?

St John's wort (Hypericum perforatum) has a 2000-year history of use as a medicinal herb. Its modern application as a plant extract for treating depression has undergone scientific investigation over the last decade, and its effectiveness has been shown in studies comparing it with placebo and reference antidepressants. Our own work supports the contention that LI 160, the best-documented St John's wort medication, is effective at a high dosage even in patients with severe depression. Since the new Berlin Aging Study revealed significant treatment deficiencies among elderly depressive patients, St John's wort extracts may be a useful alternative to benzodiazepines to avoid nontreatment of early depression. Because St John's wort preparations have better tolerability than tricyclic antidepressants, elderly people in particular, can benefit from their use.     

Differential effects of Saint John's Wort (hypericum perforatum) on the urinary excretion of D-glucaric acid and 6beta-hydroxycortisol in healthy volunteers

OBJECTIVE: We investigated the effects of treatment with Saint John's wort (hypericum perforatum) extract on the urinary excretion of D-glucaric acid, 6beta-hydroxycortisol, and free cortisol in order to assess the effect of this extract on the activity of hepatic xenobiotic metabolizing enzymes. METHODS: Forty-eight healthy volunteers (25 male and 23 female) received a daily dose of 1800 mg hypericum extract for 14 days. Urinary excretion of D-glucaric acid, 6beta-hydroxycortisol, and free cortisol was measured in 24-h urine samples on the day preceding the initiation of hypericum treatment and after 14 days of treatment. D-Glucaric acid was measured enzymatically. Cortisol and 6beta-hydroxycortisol were quantified using high-performance liquid chromatography with ultraviolet detection. RESULTS: Urinary excretion of D-glucaric acid was unaffected after a 14-day treatment with Saint John's wort extract (26.7 micromol/day vs 27.7 micromol/day; 95% confidence interval of the difference: -1.9 to 3.8). The urinary excretion of 6beta-hydroxycortisol increased from a mean baseline value of 254 microg/day to 369 microg/day (P<0.0001) indicating induction of CYP3A. While the excretion of free cortisol was unaltered, the ratio of 6beta-hydroxycortisol to free cortisol changed significantly from 9.9 at baseline to 14.3 (95% confidence interval of the difference: 2.3-6.5) after Saint John's wort treatment. CONCLUSIONS: High-dose treatment with Saint John's wort extract induced CYP3A activity in healthy volunteers as evidenced by increased 6beta-hydroxycortisol excretion. This enzyme induction most likely contributes to the decreased bioavailability observed upon co-administration of various drugs with Saint John's wort extract. The D-glucuronic acid pathway appeared unaffected by Saint John's wort.     

Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with conventional drugs without clear evidence of safety or the risk of herb-drug interactions. The aim of this study was to assess potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between St John's wort and gliclazide in healthy subjects with different cytochrome P450 2C9 (CYP2C9) genotypes. EXPERIMENTAL APPROACH: A crossover controlled study was conducted in 21 healthy subjects. Each received gliclazide (80 mg) either alone or during 15 days treatment with St John's wort. The area under the plasma concentration-time curve (AUC(0-infinity)), apparent clearance (CL/F) and elimination half-life (t 1/2) of gliclazide and incremental changes in glucose and insulin AUC(0-4) were compared. CYP2C9*2 and CYP2C9*3 alleles were identified using PCR followed by restriction enzyme digestion analysis. KEY RESULTS: St John's wort significantly altered gliclazide pharmacokinetics in all except for four healthy subjects. The mean ratio and 90% confidence interval (CI) of gliclazide AUC(0-infinity) and CL/F were 0.67 (0.55-0.81) and 1.50 (1.24-1.81), respectively, after St John's wort treatment. St John's wort decreased gliclazide t (1/2), with mean ratio and 90% CI of 0.85 (0.74-0.93). There were no significant changes in glucose or insulin AUC(0-4) after St John's wort treatment and no significant differences according to CYP2C9 genotype. CONCLUSIONS AND IMPLICATIONS: Treatment with St John's wort significantly increases the apparent clearance of gliclazide which is independent of CYP2C9 genotype. People with diabetes receiving this combination should be closely monitored to evaluate possible signs of reduced efficacy.     

Effects of oral administration of extracts of Hypericum perforatum (St John's wort) on brain serotonin transporter, serotonin uptake and behaviour in mice

The pharmacological effects of extracts of Hypericum perforatum (St John's wort) were characterized in-vitro and ex-vivo, in relation to its behavioural effects. In in-vitro experiments, St John's wort inhibited brain synaptosomal [(3)H]serotonin uptake in mice with little effect on specific [(3)H]paroxetine binding. For selective serotonin-reuptake inhibitors (SSRIs), the IC50 value for [(3)H]serotonin uptake (molar concentration of unlabelled drug necessary to displace 50% of specific uptake) correlated well with the inhibition constant K(i) value for [(3)H]paroxetine binding in mouse brain. Oral administration of St John's wort (900 mg kg(-1)), paroxetine (1 mg kg(-1)) and sertraline (10 mg kg(-1)) brought about significant increases in the K(m) value for [(3)H]serotonin uptake into brain synaptosomes 4 h later, and only SSRIs suppressed specific [(3)H]paroxetine binding in mouse brain. St John's wort and SSRIs significantly inhibited marble-burying behaviour in mice and the time-course of attenuation of this behaviour by St John's wort was similar to that of [(3)H]serotonin uptake inhibition. In the forced swimming test, St John's wort, but not SSRIs, suppressed the immobility time of mice after oral administration. These results provide the first in-vivo evidence to suggest that the mode of antidepressant action of St John's wort differs from that of SSRIs. Thus, this study may have a significant impact on phytotherapy with St John's wort.     

Effects of standardized extracts of St. John's wort on the single-unit activity of serotonergic dorsal Raphe neurons in awake cats: comparisons with fluoxetine and sertraline.

St. John's wort is widely used as an herbal remedy for depression. Although its mechanism of action remains unknown, some evidence suggests that St. John's wort might act via brain serotonin (e.g., as a serotonin reuptake inhibitor). To determine whether St. John's wort affects the central serotonergic system, we monitored the discharge rate of serotonin-containing neurons in the dorsal raphe nucleus of awake cats following systemic administration of two clinical preparations of St. John's wort, Jarsin 300 (15-600 mg/kg, p.o.) and Hyperforat (0.5-4.0 ml, i.v.). Both preparations were found to have no effect on neuronal activity. This contrasts sharply with the action of fluoxetine and sertraline (2 mg/kg, p.o.), two selective serotonin reuptake inhibitors (SSRIs), which markedly depressed neuronal activity by increasing the synaptic availability of serotonin at inhibitory somatodendritic 5-HT(1A) autoreceptors. The failure of St. John's wort to depress neuronal activity cannot be attributed to an impairment of the 5-HT(1A) autoreceptor mechanism, since pretreatment with Jarsin 300 (300 mg/kg, p.o.) did not alter the responsiveness of serotonergic neurons to the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (10 microg/kg, i.v.). Overall, these findings indicate that the mode of action of St. John's wort is different from that of conventional antidepressant drugs, which elevate brain serotonin and evoke negative feedback control of serotonergic neurons.     

St John's wort and depression: slight efficacy at best, many drug interactions

(1) St John's wort has been widely used for centuries as a herbal remedy. Dozens of trials, of variable quality, have examined the therapeutic value of St John's wort. Published meta-analyses show that St John's wort extracts are more effective than placebo in patients with mild and moderate depression. (2) Trials show that St John's wort is about as effective as tricyclic and serotonin reuptake inhibitor antidepressants. (3) There is insufficient evidence to determine the efficacy of St John's wort in patients with more severe depression. (4) Few, mostly minor adverse effects have been reported, but there may be a small risk of serotonin syndrome and cutaneous photosensitisation. (5) Some components of St John's wort interfere with CYP3A4, one of the main cytochrome P450 isoenzymes. CYP3A4 is involved in the metabolism of many commonly used drugs. St John's wort reduces the efficacy of several drug groups including: immunosuppressants (risk of graft rejection), oral contraceptives (risk of pregnancy), oral anticoagulants (risk of thrombosis), and HIV protease inhibitors. It can also reduce the bioavailability of digoxin. (6) In practice, St John's wort is an inappropriate treatment for severe depression. It is, however, an acceptable option for short-term management of transient depressed mood when there is no risk of drug interactions and when the patient is properly informed of this risk. (7) In short, the risk-benefit balance of St John's wort is no better than that of standard antidepressants, mainly because of the risk of drug interactions.     

Mechanism of action of St John's wort in depression : what is known?

Extracts of Hypericum perforatum L. (St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature.     

Effects of antidepressants on the brain/plasma distribution of corticosterone.

It is well established that hypothalamic-pituitary-adrenal (HPA) axis dysregulation, characterized by elevated circulating cortisol concentrations and impaired negative feedback inhibition, is associated with affective disorders. As normalization of the HPA axis function and mood-stabilizing effects occur simultaneously during antidepressant treatment, it is likely that these effects are either directly or indirectly dependent. Although data concerning the outward transport of glucocorticoids from the brain by P-glycoprotein (Pgp) are inconsistent, it has been hypothesized that antidepressants exert their clinical activity in parts by inhibiting Pgp, subsequently leading to enhanced brain glucocorticoid levels and the normalization of the HPA axis function. Here, we report on the effects of different antidepressants (amitriptyline, fluoxetine, mirtazapine, St John's wort extract) on the brain/plasma distribution of corticosterone in mice after acute and subchronic treatment. The four antidepressants exerted different effects on the corticosterone concentration in brain and plasma. Changes in corticosterone levels were highly correlated, suggesting passive diffusion between both tissues. St John's wort extract and fluoxetine elevated brain and plasma corticosterone concentrations after subchronic treatment. Mirtazapine and amitriptyline had no effect on corticosterone concentration after subchronic treatment, possibly because both are also potent antagonists at the 5-HT2 receptor, which mediates HPA axis stimulation by serotonergic stimuli. In addition, St John's wort is the only antidepressant tested which slightly elevated Pgp protein level in the brain.     

Current St John's wort research from mode of action to clinical efficacy.

Preparations from St. John's wort extracts are used in the treatment of depression in many countries and represent an accepted alternative to synthetic antidepressants or behavioural therapy. St. John's wort extracts are therefore used in a therapeutic area which extends well beyond the traditional field of herbal medicine. The current status of preclinical and clinical research is summarised. St. John's wort extract has a clear inhibitory effect on the neuronal uptake not only of serotonin, noradrenaline, and dopamine but also of gamma-aminobutyric acid (GABA) and L-glutamate. No other antidepressant shows an approximately equally broad inhibitory profile. In good agreement with the effects in various biochemical models of antidepressant action, many effects in a number of behavioural pharmacology models of antidepressant efficacy could also be demonstrated for St. John's wort extract. Similar doses of John's wort also cause changes in the above-mentioned neurotransmitter systems in the brain. Out of all individual substances of St. John's wort only hyperforin and its structural analogue adhyperforin inhibit the re-uptake of the investigated neurotransmitters. However, hyperforin does not act as a competitive inhibitor at the transmitter binding sites of the transporter proteins but it affects the sodium gradient which then leads to an inhibition of uptake. The broad spectrum of action which characterises St. John's wort extracts has only been described for the pure substance hyperforin. Over the past year a number of good clinical studies have been carried out which confirm the efficacy and tolerability of St. John's wort extracts in mild depressive disorders, even if the therapeutic efficacy has recently been questioned by an American study. All studies have confirmed the good tolerability of St. John's wort extract and the very low frequency of adverse events. However, some drug interactions have been found to occur with St. John's wort extract, a number of which are of clinical relevance. In summary, pharmacological activity and therapeutic efficacy of St. John's wort extract as an antidepressant are supported by a large number of scientific publications. Within the wide range of components in St. John's wort extract, hyperforin plays an important, if not an outstanding role.