Effect of St John's wort on the pharmacokinetics of fexofenadine The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum) Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Hyperforin content determines the magnitude of the St John's Wort–cyclosporine drug interaction The treatment of minor depression with St. John's Wort or citalopram: failure to show benefit over placebo. Coordinate induction of both cytochrome P4503A and MDR1 by St John's wort in healthy subjects Different effects of St John's Wort on the pharmacokinetics of simvastatin and pravastatin The interaction between St John's wort and an oral contraceptive Differential therapy of mild to moderate depressive episodes (ICD-10 F 32.0; F 32.1) with St. John's wort. Cytochrome P450 phenotypic ratios for predicting herb‐drug interactions in humans Effectiveness of St John's wort in major depression: a randomized controlled trial. Effects of Hypericum perforatum (St. John's wort) on hot flashes and quality of life in perimenopausal women: a randomized pilot trial Effects of St. John's wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy volunteers. Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea. Evaluating the safety of St. John's Wort in human pregnancy. P05.26. Systematic review of breastfeeding and herbs St. John's wort has no effect on pain in polyneuropathy Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial. Comparison of equivalence between the St. John's wort extract LoHyp-57 and fluoxetine. A Double-blind, Randomized Trial of St John's Wort, Fluoxetine, and Placebo in Major Depressive Disorder The effectiveness of St. John's Wort in major depressive disorder: a naturalistic phase 2 follow-up in which nonresponders were provided alternate medication. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.
St John 's wort is a popular over‐the‐counter dietary supplement and herbal remedy that has been implicated in drug interactions with several substrates of P‐glycoprotein . The effect of St John 's wort on P‐glycoprotein activity in vivo was examined with use of fexofenadine as selective probe drug St John 's wort(Hypericum perforatum ) is a popular over‐the‐counter dietary supplement and herbal remedy that has been implicated in drug interactions with substrates of several cytochrome P450 ( CYP ) isozymes . The effect of St John 's wort on CYP activity in vivo was examined with a probe drug cocktail Extracts of St John 's wort ( Hypericum perforatum ) are widely used in the treatment of depression , often as an over‐the‐counter drug . In contrast to its frequent use , knowledge about the pharmacokinetics of ingredients and drug interactions of St John 's wort is poor . We studied the interaction between hypericum extract LI160 and digoxin Concomitant administration of botanical supplements with drugs that are P-glycoprotein ( P-gp ) substrates may produce clinical ly significant herb-drug interactions . This study evaluated the effects of St. John 's wort and Echinacea on the pharmacokinetics of digoxin , a recognized P-gp substrate . Eighteen healthy volunteers were r and omly assigned to receive a st and ardized St. John 's wort ( 300 mg three times daily ) or Echinacea ( 267 mg three times daily ) supplement for 14 days , followed by a 30-day washout period . Subjects were also r and omized to receive rifampin ( 300 mg twice daily , 7 days ) and clarithromycin ( 500 mg twice daily , 7 days ) as positive controls for P-gp induction and inhibition , respectively . Digoxin ( Lanoxin 0.25 mg ) was administered orally before and after each supplementation and control period . Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay . Comparisons of area under the curve (AUC)((0 - 3 ) ) , AUC((0 - 24 ) ) , elimination half-life , and maximum serum concentration were used to assess the effects of St. John 's wort , Echinacea , rifampin , and clarithromycin on digoxin disposition . St. John 's wort and rifampin both produced significant reductions ( p < 0.05 ) in AUC((0 - 3 ) ) , AUC((0 - 24 ) ) , and C(max ) , while clarithromycin increased these parameters significantly ( p < 0.05 ) . Echinacea supplementation did not affect digoxin pharmacokinetics . Clinical ly significant P-gp-mediated herb-drug interactions are more likely to occur with St. John 's wort than with Echinacea Hyperforin ( HYF ) has been discussed as a potential cause of the reduction in the bioavailability of numerous drugs seen with St John 's wort ( SJW ) comedication . This study compared the effects of 2 SJW preparations with high and low HYF content on the pharmacokinetics of cyclosporine ( INN , ciclosporin ) ( CSA ) This paper presents new data addressing two important controversies in psychiatry : the construct of Minor Depression ( MinD ) and the efficacy of St. John 's Wort for milder forms of depressive disorders . Data are from a three-arm , 12 week , r and omized clinical trial of investigating the efficacy of St. John 's Wort ( 810 mg/day ) , citalopram ( 20 mg/day ) , or placebo for acute treatment of MinD. Due to a high placebo response on all outcome measures , neither St. John 's Wort nor citalopram separated from placebo on change in depressive symptom severity , quality of life , or well-being . However , systematic assessment of potential adverse effects ( AEs ) led to three important observations : ( 1 ) prior to the administration of study compound , 60 % of subjects endorsed items that would be characterized as AEs once study compound was administered , ( 2 ) St. John 's Wort and citalopram were each associated with a significant number of new or worsening AEs during treatment , and ( 3 ) using a structured interview for identifying AEs at baseline and during treatment is informative . MinD was not responsive to either a conventional antidepressant or a nutraceutical , and both compounds were associated with a notable side effects burden . Other treatment approaches for MinD should be investigated Many drugs are cosubstrates of cytochrome P450 ( CYP ) 3A and MDR1 ; furthermore , their disposition is markedly affected by pretreatment with inducing agents , including St John 's wort . Such drug interactions reflect induction of both proteins through a common mechanism involving the steroid X receptor/pregnane X receptor . However , the relative contributions of enhanced metabolism and efflux transport to the overall induction process are unknown St John 's Wort , a widely used herbal product , is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates . The effects of St John 's Wort on the pharmacokinetics of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors simvastatin  ( an inactive lactone pro‐drug ) and pravastatin were determined in this study The popular herbal remedy St John 's wort is an inducer of cytochrome P450 ( CYP ) 3A enzymes and may reduce the efficacy of oral contraceptives . Therefore we evaluated the effect of St John 's wort on thedisposition and efficacy of Ortho‐Novum 1/35 ( Ortho‐McNeil Pharmaceutical , Inc , Raritan , NJ ) , a popular combination oral contraceptive pill containing ethinyl estradiol ( INN , ethinylestradiol ) and norethindrone ( INN , norethisterone ) The purpose of this report was to evaluate specific depressive symptoms that are most suitable for a therapy with the Ze 117 St. John 's wort extract . We examined the antidepressant efficacy and drug safety of Ze 117 and fluoxetine in a multicentric prospect i ve r and omized double-blind parallel group comparison according to generally accepted guidelines such as the Declaration of Helsinki and GCP . We treated out patients ( n = 240 ; Ze 117 : 126 ; fluoxetine : 114 ) with mild to moderate depressive episodes ( ICD-10 : F 32.0 , F 32.1 ; HAMD range : 16 - 24 ) with either two tablets St John 's wort ( Ze 117 ; 500 mg extract/day ) or fluoxetine ( 20 mg/day ) for 6 weeks . Antidepressant efficacy was evaluated with the vali date d HAMD psychometric method . A vali date d analysis of HAMD subscores was made to verify the efficacy for certain depressive symptoms . The main results were : * The HAMD responder rate was 60 % in the Ze 117 group compared to 40 % in the fluoxetine group ( p = 0.005 ) . * Particularly , there was a marked decrease of depressive agitation ( pre-post comparison : 46 % ) and anxiety symptoms ( 44 % ) during the therapy with St. John 's wort . Depressive obstruction ( 44 % ) and sleep disorders ( 43 % ) were reduced during the treatment , too . There were no statistically significant differences between the treatment groups . * Adverse events occurred in 28 patients ( 25 % ) in the fluoxetine group and in 18 ( 14 % ) of the St. John 's wort group ( p < 0.07 ) . St. John 's wort extract is a clinical ly effective equivalent to fluoxetine regarding overall depressive symptoms and main symptoms of depressive episodes . An especially interesting overall observation is that Ze 117 is particularly effective in depressive patients suffering from anxiety symptoms . St. John 's wort revealed better safety and tolerability data than fluoxetine Phytochemical‐mediated modulation of cytochrome P450 ( CYP ) activity may underlie many herb‐drug interactions . Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of St John 's wort , garlic oil , Panax ginseng , and Ginkgo biloba affected CYP1A2 , CYP2D6 , CYP2E1 , or CYP3A4 activity CONTEXT Extracts of St John 's wort are widely used to treat depression . Although more than 2 dozen clinical trials have been conducted with St John 's wort , most have significant flaws in design and do not enable meaningful interpretation . OBJECTIVE To compare the efficacy and safety of a st and ardized extract of St John 's wort with placebo in out patients with major depression . DESIGN AND SETTING R and omized , double-blind , placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States . PARTICIPANTS Two hundred adult out patients ( mean age , 42.4 years ; 67.0 % female ; 85.9 % white ) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression ( HAM-D ) score of at least 20 . INTERVENTION Participants completed a 1-week , single-blind run-in of placebo , then were r and omly assigned to receive either St John 's wort extract ( n = 98 ; 900 mg/d for 4 weeks , increased to 1200 mg/d in the absence of an adequate response thereafter ) or placebo ( n = 102 ) for 8 weeks . MAIN OUTCOME MEASURES The primary outcome measure was rate of change on the HAM-D over the treatment period . Secondary measures included the Beck Depression Inventory ( BDI ) , Hamilton Rating Scale for Anxiety ( HAM-A ) , the Global Assessment of Function ( GAF ) scale , and the Clinical Global Impression-Severity and -Improvement scales ( CGI-S and CGI-I ) . RESULTS The r and om coefficient analyses for the HAM-D , HAM-A , CGI-S , and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction ( for HAM-D scores , P<.001 , P = .16 , and P = .58 , respectively ) . Analysis of covariance showed nonsignificant effects for BDI and GAF scores . The proportion of participants achieving an a priori definition of response did not differ between groups . The number reaching remission of illness was significantly higher with St John 's wort than with placebo ( P = .02 ) , but the rates were very low in the full intention-to-treat analysis ( 14/98 [ 14.3 % ] vs 5/102 [ 4.9 % ] , respectively ) . St John 's wort was safe and well tolerated . Headache was the only adverse event that occurred with greater frequency with St John 's wort than placebo ( 39/95 [ 41 % ] vs 25/100 [ 25 % ] , respectively ) . CONCLUSION In this study , St John 's wort was not effective for treatment of major depression Objective : The aim of this pilot double-blind , r and omized clinical trial , which initially targeted breast cancer survivors , was to obtain preliminary evidence of the effect of Hypericum perforatum extract ( St. John 's wort extract ) compared with placebo on symptoms and quality of life of symptomatic perimenopausal women . We also assessed practical difficulties in recruiting women to such a trial . Methods : Symptomatic perimenopausal women aged 40 to 65 years who experience hot flashes ( three or more per day , Heart and Estrogen/Progestin Replacement Study scale ) were r and omly assigned to receive ethanolic St. John 's wort extract ( 900 mg TID ) or placebo . The women were asked to keep a daily diary during the week before r and omization and during the week before the 3-month follow-up ( primary outcome ) to record hot flash frequency and intensity . A hot flash score ( frequency × severity ) was calculated . The Menopause-Specific Quality of Life question naire was used to assess menopause-specific quality of life . Results : Forty-seven women were r and omized . After 12 weeks of treatment , a nonsignificant difference favoring the St. John 's wort group was observed in the daily hot flash frequency ( St. John 's wort , −2.3 ± 3.6 ; placebo , −1.0 ± 2.2 ; P = 0.11 ) and the hot flash score ( −3.8 ± 8.3 and −1.8 ± 6.5 , respectively ; P = 0.10 ) . After 3 months of treatment , compared with the placebo group , women in the St. John 's wort group reported significantly better menopause-specific quality of life ( P = 0.01 ) and significantly fewer sleep problems ( P = 0.05 ) . Conclusions : Hypericum perforatum may improve quality of life in ways that are important to symptomatic perimenopausal women , but these results need to be confirmed by a larger clinical trial Tacrolimus is an immunosuppressant approved for the prevention of rejection following transplantation and is a substrate for CYP3A and P-glycoprotein . A pharmacokinetic interaction between St. John 's wort ( antidepressant herbal product and inducer of CYP3A and P-glycoprotein ) and tacrolimus was evaluated in 10 healthy volunteers . The pharmacokinetics of tacrolimus were obtained from serial blood sample s collected following single oral doses ( 0.1 mg/kg ) prior to and during an 18-day concomitant St. John 's wort dosing phase ( 300 mg orally three times daily ) . Coadministration of St. John 's wort significantly decreased  tacrolimus AUC ( 306.9 microg.h/L + /- 175.8 microg.h/L vs. 198.7 microg.h/L + /- 139.6 microg.h/L ; p=0.004 ) and increased apparent oral clearance ( 349.0 mL/h/kg + /- 126.0 mL/h/kg vs. 586.4 mL/h/kg + /- 274.9 mL/h/kg ; p=0.01 ) and apparent oral volume of distribution at steady state ( 11.5 L/kg + /- 4.3 L/kg vs. 17.6 L/kg + /- 9.6 L/kg ; p=0.04 ) . St. John 's wort appears to induce  tacrolimus metabolism , most likely through induction of CYP3A and P-glycoprotein Cytochrome P450 2D6 ( CYP2D6 ) , an important CYP isoform with regard to drug-drug interactions , accounts for the metabolism of approximately 30 % of all medications . To date , few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo . Six botanical extracts were evaluated in three separate studies ( two extracts per study ) , each incorporating 16 healthy volunteers ( eight females ) . Subjects were r and omized to receive a st and ardized botanical extract for 14 days on separate occasions . A 30-day washout period was interposed between each supplementation phase . In study 1 , subjects received milk thistle ( Silybum marianum ) and black cohosh ( Cimicifuga racemosa ) . In study 2 , kava kava ( Piper methysticum ) and goldenseal ( Hydrastis canadensis ) extracts were administered , and in study 3 subjects received St. John 's wort ( Hypericum perforatum ) and Echinacea ( Echinacea purpurea ) . The CYP2D6 substrate , debrisoquine ( 5 mg ) , was administered before and at the end of supplementation . Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios ( DURR ) . Comparisons of pre- and post-supplementation DURR revealed significant inhibition ( approximately 50 % ) of CYP2D6 activity for goldenseal , but not for the other extracts . Accordingly , adverse herb-drug interactions may result with concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 substrates St. John 's Wort is a herbal therapy , shown to be effective in treating mild to moderate depression ; a disease common in women in their childbearing years . With a significant proportion of unplanned pregnancies , exposure to St. John 's Wort into pregnancy is expected to occur . The purpose of this study was to determine whether exposure to this agent in pregnancy is associated with major malformations . We prospect ively collected and followed subjects taking St. John 's Wort and compared them to a matched group of pregnant women taking other pharmacologic therapy for depression and a third group of healthy women , not exposed to any known teratogens . We obtained follow-up information on 54 St. John 's Wort exposed pregnancies and 108 pregnancies in the two comparator groups . Our results indicated that the rates of major malformations were similar across the three groups , with 5 % , 4 % and 0 % in the St. John 's Wort , disease comparator , and health group , respectively ( p=0.26 ) , This was not different that the 3 - 5 % risk expected in the general population . The live birth and prematurity rates were also not different among the three groups . Though further large scale studies are still needed , this first study on the effects of St. John 's Wort in human pregnancy does provide some evidence of fetal safety Results Thirty-two studies met the inclusion criteria . Clinical studies were divided into three categories : survey studies ( n=11 ) , safety studies ( n= 8) , and efficacy studies ( n= 13 ) . Six studies were r and omized controlled trials . The most common herbs studied were St. John ’s wort ( Hypericum perforatum L. ) ( n=3 ) , garlic ( Allium sativum L. ) extract ( n=2 ) , and senna ( Cassia senna L. ) ( n=2 ) . Studies were very heterogeneous with regards to study design , herbal intervention , and outcome measures . Overall , poor method ological quality predominated among the studies & NA ; Tricyclic antidepressants are the mainstay of treatment of painful polyneuropathy but can not be used in a substantial number of patients . St. John 's wort is a herbal antidepressant , which may act via mechanisms similar to the tricyclics . The aim of this study was to test if St. John 's wort would relieve  painful polyneuropathy . The study design was r and omized , double‐blind , placebo‐controlled and cross‐over . Fifty‐four patients were assigned to one of the two treatment sequences . The daily dose of St. John 's wort was three tablets each containing 900 & mgr;g totalhypericin . During the two treatment periods of 5 weeks duration , patients rated constant pain , lancinating pain paroxysms , touch‐evoked pain and pain on pressure by use of 0–10 point numeric rating scales . Forty‐seven patients – 18 diabetics and 29 non‐diabetics – completed the study . There was a trend of lower total pain score ( sum of the individual pain scores ) on St. John 's wort than on placebo ( median 14 vs. 15 , P=0.05 ) . None of the individual pain ratings were significantly changed by St. John 's wort as compared to placebo ( P=0.09–0.33 ) . Complete , good or moderate pain relief was experienced by nine patients with St. John 's wort and two with placebo ( P=0.07 ) . In conclusion , St. John 's wort has no significant effect on pain in polyneuropathy 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 In a r and omised double-blind comparative trial , the antidepressant efficacy of a daily dose of 800 mg of the St. John 's wort extract LoHyp-57 ( dry extract of St. John 's wort , drug extrakt ratio 5 - 7:1 , solvent , ethanol 60 % [ w/w ] ) was shown to be equivalent to that of 20 mg fluoxetine ( CAS 54910 - 89 - 3 ) in elderly patients with mild or moderate depressive episodes according to ICD 10 ( International Statistical Classification of Diseases and Related Health Problems ) . Treatment was given for six weeks . 149 out- patients ( 129 females and 20 males ) were included in the intention-to-treat analysis . 72 of these patients were assigned to the ICD 10 diagnostic criterion F32.0 ( mild depressive episode ) , while 77 patients were suffering from moderate depressive episodes , corresponding to F32.1 . The principal target criterion was the patient 's global score on the HAMILTON Depression Scale ( items 1 - 17 ) . During the six-week course of treatment with LoHyp-57 , the HAMILTON global score fell from 16.60 points at entry to 7.91 points , and in the fluoxetine sample it fell from 17.18 to 8.11 points . In the group of patients with mild depressive episodes , the score showed a mean fall from 14.21 to 6.21 points on LoHyp-57 , and from 15.21 to 7.46 points on fluoxetine . In patients with moderate depressive episodes , the score showed a mean fall from 18.73 to 9.43 points on LoHyp-57 and from 19.10 to 8.75 points on fluoxetine . The efficacy of both medications was found to be equivalent both in mild and moderate depressive episodes . Both treatment groups showed adverse drug reactions ( ADRs ) . Twelve ADRs with a possible relationship to the study medication were reported during treatment with LoHyp-57 . Six patients were prematurely withdrawn from treatment with the study medication for this reason . On fluoxetine 17 ADRs occurred with a possible relationship to the study medication . These led to ab and onment of treatment and therefore premature withdrawal from the study in 8 cases Objective : This study looks to compare the antidepressant efficacy and safety of a st and ardized 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 r and omized 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 r and omized 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 BACKGROUND A continuation study of an extract of St. John 's wort ( Hypericum perforatum ) for depression was performed in follow-up to an acute study that found no significant difference between St. John 's wort extract and placebo . METHOD Seventeen subjects with DSM-IV-defined major depressive disorder who responded to St. John 's wort extract in the acute-phase study ( phase 1 ) were continued on double-blind treatment with the same preparation for 24 weeks . Ninety-five subjects who did not respond to either St. John 's wort or placebo  were treated with an antidepressant for 24 weeks . RESULTS During antidepressant treatment , mean scores on the Hamilton Rating Scale for Depression for phase 1 nonresponders decreased significantly ( p < .0001 ) , with no significant difference between St. John 's wort nonresponders and placebo nonresponders . Of the 17 subjects continued on treatment with St. John 's wort extract , 5 ( 29.4 % ) relapsed . CONCLUSIONS The subjects who did not respond to St. John 's wort extract or placebo in phase 1 were , by and large , not resistant to antidepressant treatment . This suggests that the lack of efficacy found by Shelton et al. in the acute-phase study was unlikely to be the result of a high proportion of treatment-resistant subjects UNLABELLED M : The aim of this study was to investigate the effect of St John 's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin  . METHODS This was an open-label , three-way crossover r and omized study in 12 healthy male subjects , who received a single 25-mg dose of warfarin alone or after 14 days ' pretreatment with St John 's wort , or 7 days ' pretreatment with ginseng .  Dosing with St John 's wort or ginseng was continued for 7 days after administration of the warfarin dose . Platelet aggregation , international normalized ratio ( INR ) of prothrombin time , warfarin enantiomer protein binding , warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured . Statistical comparisons were made using anova and 90 % confidence intervals are reported . RESULTS INR and platelet aggregation were not affected by treatment with St John 's wort or ginseng . The apparent clearances of S-warfarin after warfarin alone or with St John 's wort or ginseng were , respectively , 198 + /- 38 ml h(-1 ) , 270 + /- 44 ml h(-1 ) and 220 + /- 29 ml h(-1 ) . The respective apparent clearances of R-warfarin were 110 + /- 25 ml h(-1 ) , 142 + /- 29 ml h(-1 ) and 119 + /- 20 ml h(-1 ) [ corrected ] . The mean ratio and 90 % confidence interval ( CI ) of apparent clearance for S-warfarin was 1.29 ( 1.16 , 1.46 ) and for R-warfarin it was 1.23 ( 1.11 , 1.37 ) when St John 's wort was coadministered . The mean ratio and 90 % CI of AUC(0 - 168 ) of INR was 0.79 ( 0.70 , 0.95 ) when St John 's wort was coadministered . St John 's wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers . CONCLUSIONS St John 's wort significantly induced the apparent clearance of both S-warfarin and R-warfarin , which in turn result ed in a significant reduction in the pharmacological effect of rac-warfarin . Coadministration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin
Clinicians and patients should beware of possible decreases in the systemic bioavailability of conventional drugs when taken concomitantly with St John 's wort
OBJECTIVE To determine the method ological quality of clinical trials that examined possible interactions of St John 's wort with conventional drugs , and to examine the results of these trials .