St. John's Wort is a very popular treatment for depression in Germany and is widely prescribed by German physicians.  However, despite extensive research showing benefit for mild, moderate, and severe depression, it has not found much favor among American psychiatrists.  It is the only herbal treatment with any good evidence of benefit.  It causes very few side-effects, but it can seriously interfere with the breakdown of some important medications used in transplants, in heart disease, and in AIDS patients.  Thus, it probably should not be used in these particular situations.  Of course, prescription anti-depressants have their own drug interference problems.

In view of its very low level of side-effects and low cost, it seems reasonable to try St. John's Wort before trying standard anti-depressants.  There is no research looking at taking St. John's Wort and other anti-depressants at the same time.  It's always better to use just one anti-depressant at a time, unless two are partially helpful and none are better. Hypericum or hyperfolin is the active ingredient in St. John's Wort.  It appears to work for blocking serotonin reuptake, similar to the mechanism of action of many standard anti-depressants.

St. John's Wort as Good as SSRI Citalopram: In a 6-week DB PC study of 388 outpatients with moderate depression, St. John's wort hypericum extract STW3-VI (900 mg) did just as well as the SSRI citalopram (20 mg) and both did better than placebo (p < 0.0001). At the end of treatment 54.2 % (hypericum extract), 55.9 % (citalopram) and 39.2 % (placebo) of the patients had at least a 50% decrease in depression. Significantly more adverse events with "certain", "probable" or "possible" relation to study medication were documented in the citalopram group (hypericum: 17.2 %, citalopram: 53.2 %, placebo: 30 %). Comparative Efficacy and Safety of a Once-Daily Dosage of Hypericum Extract STW3-VI and Citalopram in Patients with Moderate Depression: A Double-Blind, Randomised, Multicentre, Placebo-Controlled Study. Gastpar M, et al. University of Essen, Germany. Pharmaco Psychiatry 2006 Mar;39(2):66-75.

St. John's Wort Found Effective Once Again: Non-Significantly Bette than Prozac: In a 12-week DB PC study of St John's wort extract (900 mg/d), fluoxetine (20 mg/d), or placebo with 135 adults with major depression, the HAMD-17 depression scores dropped the most in the St John's wort group ( 10.2 vs. 12.6 placebo and 13.3 fluoxetine). 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%). A Double-blind, Randomized Trial of St John's Wort, Fluoxetine, and Placebo in Major Depressive Disorder. Fava M, et al. MGH-Harvard. J Clin Psychopharmacol. 2005 Oct;25(5):441-447.  

St. John's Wort Did as Well as Paroxetine (Paxil) for Moderate to Severe Depression: In a 6-week DB PC study of 251 adults with acute Major Depression, half severely depressed by HAMD depression scores, comparing hypericum 300 mg three times a day to paroxetine 20 mg once a day with a doubling of the doses after two weeks if necessary, the HAMD depression scores decreased by 57% with hypericum and 45% with paroxetine. Patients were not excluded due to suicide risk. Side-effects were twice as high with paroxetine. This is the second study to show hypericum as good as a standard anti-depressant for severe depression. Significantly more showed remission with hypericum (50% vs. 35%). Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. A Szegedi et al. Karlsruhe. BMJ 3/5/2005;330:503

St. John's Wort Did as Well as Sertraline (Zoloft) for Depression: In a 24-week DB PC study of 241 adults with moderate depressive disorder, 50 mg sertraline or 612 mg hypericum extract were equally effective with HAMD depression scores decreasing 22.0 points for hypericum and 22.1 points for sertraline to 8.3 (hypericum) and 8.1 points (sertraline). Side-effects were less with hypericum. Efficacy and Tolerability of Hypericum Extract STW3 in Long-term Treatment with a Once-daily Dosage in Comparison with Sertraline. Gastpar M, Singer A, Zeller K. University of Essen, Germany. Pharmacopsychiatry. 2005 Mar;38(2):78-86.  

St. John's Wort Superior for Mild to Moderate Depression: A German meta-analysis of the 30 best studies using St. John wort found  a significant advantage for St. John's Wort compared to placebo (2129 patients, RR = 0.66, p < 0.00001, NNT = 4.2, mean response: 53.3 vs. 32.7 %). Compared to standard antidepressants, St. John's Wort demonstrated similar effectiveness (2231 patients, RR = 0.96, mean response: 53.2 % vs. 51.3 %). In the sub-group of mild to moderate depression, corresponding with the indication for St. John's Wort assigned by the German health authority, the herbal antidepressant showed better results against the standard antidepressants (1166 patients, RR = 0.85, p = 0.01, NNT = 14.3, mean response 59.5 vs. 52.9 %). This result viewed together with St. John's Wort's favourable side-effects profile, leading to a lower rate of drop-outs, suggests treatment with St. John's Wort should be attempted for milder forms of depression. Meta-Analysis of Effectiveness and Tolerability of Treatment of Mild to Moderate Depression with St. John's Wort. Roder C, Schaefer M, Leucht S. Berlin, Fortschr Neurol Psychiatr. 2004 Jun;72(6):330-43.  

34 Double Blind Studies: By the spring of 2002, results from 34 controlled, double-blind trials of Hypericum extracts in some 3,000 patients, predominantly with mild to moderate forms of depression, had been published. In ten studies, the dosages ranged from 300 mg to 1050 mg of extract per day. Five of the ten studies were placebo-controlled and in all five cases, the Hypericum extract was shown to be significantly superior. Results with Hypericum were as good or even better than with imipramine or fluoxetine. In the period since 1990, a total of twelve controlled trials have been published with one particular extract prepared with 80% methanol in water (V/V), of which six were placebo-controlled, two compared Hypericum with imipramine and one each with maprotiline, amitriptyline, sertraline or light therapy. Dosages ranged from 450-1200 mg extract per day. Statistical analysis of the total Hamilton scores showed significant differences between Hypericum extract and placebo in four of the six placebo-controlled studies and a trend in favor of the active treatment in the other two. Of the five comparative trials against four different synthetic antidepressants, amitriptyline was significantly superior to Hypericum after six weeks of therapy, whilst there were no significant differences in treatment outcome between Hypericum and the other synthetics in the remaining four studies. The results of the trials conducted to date show no major differences in efficacy of the alcoholic extracts. Taking all the results into account, it can be assumed that the threshold dose for efficacy against individual symptoms and complaints that occur in the course of the depressive illness could be about 300 mg of extract per day. In the medically supervised treatment of mild to moderate depression, doses of approximately 500-1000 mg of extract per day of these preparations of St. John's Wort are of comparable efficacy to standard antidepressants in their normally prescribed dosages. Clinical trials with hypericum extracts in patients with depression--results, comparisons, conclusions for therapy with antidepressant drugs. Schulz V. Phytomedicine 2002 Jul;9(5):468-74

St. John’s Better than Placebo in Large 35^th Study: Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. Lecrubier Y, Clerc G, Didi R, Kieser M. Paris, Am J Psychiatry 2002 Aug;159(8):1361-6. 375 patients with mild-moderate depression. Hypericum 300 tid. 6 weeks.

St. John’s as Good as Sertraline (Zoloft) for MDD in DB, 36th Study: In a DB study of 87 patients with major depressive disorders in Montreal, sertraline 50-100 mg/day was compared to hypericum 900-1800 mg/day. St John's wort or sertraline? Randomized controlled trial in primary care. van Gurp G, Meterissian GB, Haiek LN, McCusker J, Bellavance F. Can Fam Physician 2002 May;48:905-12

Disadvantage: CYP 3A4 Induction: 12 healthy young adults in 14 day trial of St. John’s wort. Strong induction of liver enzyme CYP 3A4 that plays a role in the metabolism of up to 50% of all prescription medicines. Half-life of alprazolam cut from 12 hr to 6 hr. Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang JS, Chavin KD. JAMA. 2003 Sep 17;290(11):1500-4

Equal to Fluoxetine in DB: A phyto-industry conducted DB study of 70 Germans with mild-moderate depression found no significant difference although slight favoring of fluoxetine with 50% and 58% achieving 50% decreases in HAM-D. Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression. Behnke K, Jensen GS, Graubaum HJ, Gruenwald J. Adv Ther 2002 Jan-Feb;19(1):43-52 

Continuation Treatment: Randomized controlled trial. Efficacy of continuation treatment with hypericum perforatum in depression. Brenner R, Madhusoodanan S, Pawlowska M. J Clin Psychiatry 2002 May;63(5):455

Hyperfolin Helps: In a 6-week DB PC study of mild-mod depression using placebo or 300 mg/day with 0.5% hyperfolin or 300 mg with 5.0% hyperfolin, HAM-D depression scores were significantly more decreased with higher dose but not low dose (10.3 vs. 8.5 vs. 7.9). Laakmann, U Munchen, Pharmacopsychiatry 6/98;31 Suppl 1:54-9

St. John’s Wort Helps Somatiform/Somatization Disorder in DB: In a multicenter, randomized, placebo controlled, 6-week trial comparing the efficacy of St. John's wort (LI 160) (600 mg/day) to placebo in 151 out-patients suffering from somatization disorder (ICD-10: F45.0), undifferentiated somatoform disorder (F45.1), or somatoform autonomic dysfunctions. superior effectiveness concerning the primary outcome criterion HAMA-SOM [decrease from 15.39 to 6.64 in the Hypericum group and from 15.55 to 11.97 in the placebo (P=0.001)] was found. 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, HAM-D, SCL-90-R, University of Jena, St John's wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial. Volz HP, Murck H, Kasper S, Moller HJ. Psychopharmacology (Berl) 2002 Nov;164(3):294-300

Equal to 150 mg/day of Imipramine: In a 6-week, 324 patients DB study of 150 mg of imipramine vs. 250 mg hypericum extract twice a day for mild-moderate depression, researchers found no difference. Side-effects occurred in 39% of St. John's vs. 63% of imipramine patients and 3% vs. 16% dropped out due to side-effects. BMJ 2000 Sep 2;321(7260):536-9. The article notes St. John's wort is also used for anxiety in Europe.

Helps Severe Depression vs Imipramine: DB PC 6 wk 1800 mg/d extract LI 160 vs imipramine found both equally effective with HAM-D 25.3-15.6 for St John’s and 26.1-14.5 for imipramine. Fewer S-E with St. John’s. Vorbach, Darmstadt. Pharmacopsychiatry 9/97;30 Suppl 2:81. Refers to several earlier DB studies where successful.

Helps Equal to Amitriptyline: DB PC multicenter 6 wk LI 160 900mg/d vs amitrip 75mg/d. No difference although amitriptyline was favored by a slight trend. S-E worse with amitrip. London, Pharmacopsychiatry 9/97;30 Suppl 2:77-80

No Benefit Either St. John’s or Sertraline in DB: 200 MDD > 4 week with HAM-D >19 DB PC. St.John 300 tid or qid. 8 weeks. No signif diff. Response in 27% St. John’s vs 19% placebo. Shelton, Vanderbilt, JAMA 01;285:1978

No Benefit for St. John or Sertraline in DB: 340 patients with Major Depression in a DB PC study of hypericum 900-1500 mg/day vs. sertraline 50-100 mg/day vs. placebo for 8 weeks with 18 added weeks for responders found no benefit for either treatment. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. Hypericum Depression Trial Study Group. JAMA 2002 Apr 10;287(14):1807-14. Ed: This was a "failed study." Obviously, sertraline usually does better than placebo, but not in every study.  The same is true of St. John's wort.  A test of blood samples well after the study was over found that 16% of the people on placebo actually had hypericum in their blood, suggesting that they had purchased it on their own and were taking it despite being involved in the study.  Of the people who were supposed to be taking hypericum, 17% had none in their blood test, suggesting that they were not taking it.  All of the sertraline patients had sertraline in their blood. J Clin Psychopharmacol. 2005 Jun;25(3):243-249.

Non-competitive Reuptake Inhibition of NE, 5HT, and DA: inhibited with equal potencies the sodium-dependent uptake of all 3 monoamine neurotransmitters noncompetitively, in marked contrast with the competitive inhibition exerted by fluoxetine, GBR12909 or desipramine. Israel, Life Sci 2002 Sep 27;71(19):2227-37

Cytochrome P450 CYP3A4 Inducer: induced expression of the cytochrome P450 CYP3A4 isoform. lowering of serum concentration of a number of concomitant drugs, including warfarin, digoxin, theophylline, cyclosporin, and indinavir. Also JAMA. 2003;290:1500-1504 saying cut half life alprazolam in half and that 50% of medicines are metabolized by CYP3A4 system.

St. John's Lowers Level of Many Medications: SJW has been shown to lower the plasma concentration (and/or the pharmacological effect) of a number of drugs including alprazolam, amitriptyline, cyclosporine, digoxin, fexofenadine, indinavir, irinotecan, methadone, nevirapine, simvastatin, tacrolimus, theophylline, warfarin, phenprocoumon and oral contraceptives. Induction of P-glycoprotein and/or cytochrome P450 (CYP) enzymes (particularly CYP 3A4) by SJW could explain such pharmacokinetic interactions. When combined with serotonin reuptake inhibitor, antidepressants (e.g. sertaline, paroxetine, nefazodone) or buspirone, SJW can cause serotonergic syndrome. Int J Clin Pharmacol Ther. 2004 Mar;42(3):139-48

St. John’s Better than Fluoxetine for Mild-Moderate: 240 pt HAM-D average 19.5 DB fluoxetine 20/d vs St. John’s 250mg BID. 6 weeks. 60% responded to St. Johns vs. 40% fluoxetine. Side-effects 8% St. Johns, v. 23% fluox. CGI better for St. Johns and slightly greater decrease HAM-D. In Germany, 25% antidepressant rx St. John’s. Schader, Int Clin Psychoph 00;15:61

St. John’s Wort: Med Letter 11/21/97. Plant Hypericum perforatum. Hypericin, a naphthodianthrone, considered active ingredient. Inhibits uptake serotonin, NE, DA, and binds GABA receptor in vitro. Half-life 25 hr. Metabolized ? 23 randomized trials 1757 mild-mod depr x 2-4 wk superior to placebo and about as effective as standard antidepr (BMJ 313:253, ’96). Quality of studies were low. No serious side-effects. Some dry mouth, dizzy, constip, confusion, GI symptoms. Photosensitivity reported rarely. From ancient Greeks through Victorian times. 8 of trials against anti-depressant meds. Lower S-E and dropout rate than anti-depressants. 100-300 mg TID. Photodermatitis, delayed hypersensitivity, GI upset, dizzy, dry mouth, restless, constip. Not use in preg, lactation, or pheochromocytoma. Wong. Up to 2.7mg hypericin per day in studies. Half-life 25 hr. Apparently no value to multiple dosing although this is standard.

St. John’s Wort OK in Children: A post-marketing surveillance study of 101 children under 12 given hypericum 4-6 weeks 300-1800 mg/d. physicians rating effectiveness as 'good' or 'excellent' was 72% after 2 weeks, 97% after 4 weeks and 100% after 6 weeks. The ratings by parents were very similar. No adverse side-effects reported. Experience with St John's Wort (Hypericum perforatum) in children under 12 years with symptoms of depression and psychovegetative disturbances. Hubner WD, Kirste T. Phytother Res 2001 Jun;15(4):367-70

Hypericum Concentration Varies Dramatically: 5 batches each from 8 German manufacturers compared. Wide variations both between brands and, for some but not all manufacturers, between batches. Comparison of German St. John's wort products according to hyperforin and total hypericin content. Wurglics M, Westerhoff K, Kaunzinger A, Wilke A, Baumeister A, Dressman J, Schubert-Zsilavecz M. J Am Pharm Assoc (Wash) 2001 Jul-Aug;41(4):560-6

Higher Dose Might Help More: Extracts of Hypericum perforatum St. John's wort, have been used since antiquity for the treatment of depressive symptoms. In 25 controlled clinical trials where hypericum extract was compared with placebo and established antidepressants, improvement was obtained in 61 percent of patients on low-dose treatment (< 1.2 mg hypericum extract), and in 75 percent of patients treated with a higher dose (2.7 mg). The side effects were mild and occurred at lower frequency than did those of other antidepressants. Sweden. Lakartidningen 1997 Jun 18;94(25):2365-7

Interactions: Decreased cyclosporine and can cause transplant rejection. Interferes with warfarin. 57% reduction HIV-1 protease inhibit indinavir, 25% decrease dignoxin, breakthru bleeding with contraceptives, lower theophylline and anitrip. Serotonin syndrome with SSRI or nefazodone. Med Let 6/26/00

No Problem in Mice Babies: Mice given St John’s prenatal and no impact on behavior tho lower birth weights. Am J Obstet Gynecol 2000 Nov;183(5):1225-31

2 Cases Induced Heart Transplant Rejection: Both resolved with the stopping of St. John’s. Lancet 00;355:548

Decreases Myelosuppressive Irinotecan: Colon cancer treatment of 5 patients in a study with added St. Johns 300 mg TID found a 42% decrease in the blood level of irinotecan, an anti-cancer drug they were receiving, due to the St. John's. J Natl Ca Inst 02;94:1247

Thomas E. Radecki, M.D., J.D.

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