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St John's wort

4-hypericum-perforatum3300
Hypericum perforatum
Hypericaceae
St John's wort
Perforate St John's-wort, Common Saint John's wort
Flowers

St. John’s wort is one of the most researched herbal medicines. Its efficacy has been proven beyond doubt in many studies.

St John’s wort is just as effective as pharmaceutical antidepressants in mild to moderate depression without significant side effects.

St John’s is used in traditional herbal medicine for excitability, neuralgia, fibrositis, and sciatica. Topically it was use for wounds. The British Herbal Pharmacopoeia lists its specific indication as menopausal neurosis. It was probably this old fashioned term, which let researcher to focus on its antidepressant effects. Herbalists consider St John’s wort a nervine tonic, useful for stress, tension, depression and anxiety.

The EU community monograph on St John’s wort confirms that it is more effective than placebo and comparable to standard antidepressants in the treatment of mild to moderate depressive episodes.

The monograph further states that St John’s wort can be used to prevent a relapse of depressive symptoms.

The compound known as hyperforin may cause drug interactions. Only extracts with higher than usual levels of hyperforin may cause adverse drug interactions. Regular extract with low to normal levels of hyperforin are unlikely to cause significant drug interactions.

High levels of hyperforin are not needed. Products with low to normal levels of hyperforin are still effective in the treatment of depression.

hypericum perforatum glands

St John’s wort is a perennial, aromatic herb growing to one m high with woody stems that die back in autumn. The rhizomes are slender and leaves pale green and dotted with numerous tiny oil glands and it produces golden yellow flowers throughout summer. A native of Europe and Asia but has been naturalised in the Americas and many countries.

The genus name Hyperieum comes from the greek words "hyper eicon", "above the icon", as supposedly a bundle of St. John’s wort fixed above the picture of some deity would chase away bad spirits.

The species name perforatum (perforated) refers to a typical feature of the leaves: against the light they appear to have hundreds of tiny perforations. In reality these half-transparent spots are the locations where the plant stores its oil.

The St. John part of the herb’s name is related to the time of the flowering and collection. St. John’s wort has traditionally been collected at full flowering, which coincides with the day St. John the Baptist used to be celebrated – June 24th.

St John’s wort contains naphthodianthrones including hypericin and pseudohypericin. Flavonoids including hyperoside, rutin and quercetin, phenolic compound including hyperforin, procyanidins, essential oil and xanthones.

constituents

The timing of harvesting is critical

The time of harvesting makes a difference with respect to the constituents. The optimal time of harvesting the plant for its antidepressant effects is not known, but traditionally, St John’s wort is harvested when in full flower. Hyperforin, the compound known to be responsible for the increased metabolism of certain pharmaceutical drugs, can be increased by waiting to harvest the plant at a late stage of withering and fruit formation.1

constituents dried plant

The figure above shows that the level of hyperforin can be manipulated by selecting the plant at different times. Traditionally, St John's wort is collected when the level of hyperforin is very low (yellow). Late harvesting produces a raw material high in hyperforin (blue).

 constituents extract

High-hyperforin extracts are produced from St John's wort harvested late in the season when the level of hyperforin is very high (blue).

 

There are three basically different St. John’s wort preparations:

Oilhypericum oil

The red oil, mostly extracted with the aid of olive oil by maceration, which turns red upon exposure to sunlight. It is traditionally applied against skin inflammation.

Regular extracts

Regular extracts of the fully flowering herb: They have been shown efficacious against mild to moderate depression.

Special extracts

Special extractions of the herb post flowering, enriched with hyperforin: They are also efficacious against depression, but the high hyperforin content also causes interactions with other, concomitantly taken medications by lowering the blood levels of these drugs.2 Hyperforin contents have been limited to maximally 6 % by the European pharmacopoeia.

Known bioactive compounds in St John's wort represent approximately 50-70% of the known phytochemical constituents. Thirty to fifty percent of the compounds present in St John's wort extracts are as yet not structurally assigned – among them could be further constituents directly or indirectly contributing to the overall clinical efficacy. The total extract must still be regarded as the active constituent of St John's wort.

Clinical studies have shown antidepressant activity for different types of extracts. Obviously, it is the total extract and not a specific constituent, which is responsible for the efficacy.

St. John’s wort has been granted the clinical evidence grade 1a in the treatment of mild to moderate depression: the efficacy has been confirmed in clinical double blind trials, and re-confirmed in meta-analyses of these clinical trials.3

References

1.         Azizi M, Betti G, Schmidt M. Study of the phytochemical variability of the essential oil of Hypericum perforatum in relation to vegetative stage. 53rd Annual Congress of the society of Medicinal Plant Research, Florence (Italy). 2005;21.-24. August.

2.         Mai I, Bauer S, Perloff ES, et al. Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction. Clinical pharmacology and therapeutics. 2004;76(4):330-340.

3.         Nahas R, Sheikh O. Complementary and alternative medicine for the treatment of major depressive disorder. Canadian family physician Medecin de famille canadien. 2011;57(6):659-663.

61 Hypericum perforatum LSt John’s is used in traditional herbal medicine for excitability, neuralgia, fibrositis, and sciatica. Topically it was use for wounds. The British Herbal Pharmacopoeia list its specific indication as menopausal neurosis. It was probably this old fashioned term, which let researcher to focus on its antidepressant effects. Herbalists consider St John’s wort a nervine tonic, useful for stress, tension, depression and anxiety.

The World Health Organisation (WHO) lists St John’s wort as being indicated for symptomatic treatment of mild and moderate depressive episodes. Externally for the treatment of minor cuts, burns and skin ulcers. Topically for viral infections

ESCOP, the European Scientific Cooperative On Phytotherapy suggests St John’s wort for episodes of mild depressive disorders or mild to moderate depressive episodes.

Mrs Grieve, in her book, A Modern Herbal, describes St John’s wort as having the following properties: aromatic, astringent, resolvent, expectorant and nervine. It was used in all pulmonary complaints, bladder troubles, in suppression of urine, dysentery, worms, diarrhoea, hysteria and nervous depression, haemoptysis and other haemorrhages and jaundice. For children troubled with incontinence of urine at night an infusion or tea given before retiring will be found effectual; it is also useful in pulmonary consumption, chronic catarrh of the lungs, bowels or urinary passages. 

depressionDepression, stress and anxiety

Herbalists consider St John’s wort a nervine tonic, useful for stress, tension, depression and anxiety.

The majority of research has focused on the treatment of depression.

The World Health Organisation (WHO) lists St John’s wort as being indicated for symptomatic treatment of mild and moderate depressive episodes.

ESCOP, the European Scientific Cooperative On Phytotherapy suggests St John’s wort for episodes of mild depressive disorders or mild to moderate depressive episodes.

Externally, St John’s wort is also used for the treatment of minor cuts, burns and skin ulcers.

Menopausal symptoms

Depression is a typical symptom of the menopause. In a recent meta-analysis Liu et al. (2013) compared the efficacy of St- John’s wort and placebo used for the treatment of menopausal women. Extracts of St John’s wort and its combination with other herbs were found significantly superior to placebo in the treatment of menopause. Adverse events (not necessarily with causality by the study medication) occurred in 17.4 % patients on St. John’s wort preparations and 15.4 % patients on placebo, which conforms the excellent safety of application of St. John’s wort preparations.1 St John’s wort is often combined with black cohosh (Actaea racemosa, previously known as Cimicifuga racemosa) in to relieve menopausal symptoms of stress, tension, mood swings and depression.

Reference

1 Liu YR, Jiang YL, Huang RQ, Yang JY, Xiao BK, Dong JX. Hypericum perforatum L. preparations for menopause: a meta-analysis of efficacy and safety. Climacteric : the journal of the International Menopause Society. 2013.

capsulesThe German Commission E listed the daily dose as extracts equivalent to 2 to 4 gram of dried St John’s wort.

A dose of 500 to 1000 mg of St John’s wort preparations has been shown to be comparable to synthetic antidepressants in the treatment of mild to moderate depression.{Schulz, 2002 #981}

St John’s wort is unlikely to cause any significant side effects when taken at the recommended dosage, even when taken long term.

Adverse effects

safetyThe most frequently reported adverse events in clinical trials are gastrointestinal symptoms, nausea, vomiting, skin reactions including rash, fatigue, nervousness and dizziness. Very high dosages of hypericin may cause photosensitivity reactions.

St John’s wort has a much better safety profile compared with pharmaceutical antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI) or MAO-inhibitors.

There is legitimate concerns about herb-drug interactions due to high levels of hyperforin in some St John’s wort products, however, similar interactions may be caused by the synthetic antidepressants. Switching from St John’s wort to synthetic antidepressants would not lead to a better safety regarding concomitant intake of other drugs.

Adverse events of SJW are mostly mild and reversible. Generally the adverse events observed in clinical trials are not distinctly different from those observed in the placebo arms of controlled clinical trials. Adverse effects attributed to the intake of SJW preparations are generally non-specific, and may rather be regarded as nocebo effects than as real adverse effects caused by a pharmacodynamic interaction.6,41-48

In addition one has to be aware that many of the more frequently mentioned “adverse effects” of St John’s wort (e.g., tiredness) may actually be part of the symptom picture of depression.

Drug interactions

Much has been written about the drug interactions with St. John’s wort.

The discussion was triggered by the observation that combining St John’s wort and some pharmaceutical medicines produced reduced blood levels of the drug and therefore a potential reduced efficacy of the drug.

Reports on pharmacokinetic interactions between St John’s wort extracts and concomitantly applied drugs such as digoxin, immunosuppressants, antiviral agents or contraceptives have been published in the recent years, and extensively reviewed.1-25 New case reports and clinical interaction trials with St John’s continue to be published.

Unfortunately the clinical importance of the reported interactions has confused health practitioners, regulators and the public alike.

It is now known that the compound responsible for the drug interactions is hyperforin.14

hyperforin PXR activaton

The above figure clearly show that of all the constituents tested in St John's wort, it is hyperforin, which is responsible for the activation of the pregnane X receptor.

pregnane X receptor

Hyperforin increases drug metabolism via activation of the Pregnane X Receptor (PXR) also called steroid X receptor (SXR) and by activation of drug transporter (P-glycoprotein)


The site of the interaction is not the liver, as generally assumed, but the intestinal metabolic systems.

The EU monograph states that products containing less than 1 mg hyperforin does not increase P450 enzyme activity.26 Such product shouldn’t even need a label warning of possible drug interactions.

Pharmacokinetic interaction studies of St John’s wort extracts with low to normal levels of hyperforin does not produce drug interaction via the drug metabolizing cytochrome P450 isoforms nor the drug transporter (P-glycoprotein).

herb drugBottom line on drug interactions

Only a few of the interactions hitherto detected can be considered clinically important. In all of these cases, such as patients treated with the immunosuppressant cyclosporine after organ transplantations, the patients are under a high level of surveillance, which contributes to risk minimization.27-30

In summary:

  • St. John’s wort preparations are efficacious and safe on the treatment of mild to moderate depression.
  • Interactions with other drugs have been observed, but their importance is by far not as high as one could conclude from the sheer number of studies.
  • Hyperforin is responsible for the drug interactions attributed to St. John's wort.
  • Clinically relevant interactions can only be expected with hyperforin-enriched products.
  • Standard products containing 1.5-2.5 % hyperforin, on average 18 mg in the daily dose, are unlikely to cause clinically significant drug interactions.
  • The solution is not to avoid St. John’s wort and instead use pharmaceutical antidepressants. The solution is to avoid hyperforin-enhanced SJW preparations and exercise vigilance if drugs metabolised by CYP enzymes are concomitantly prescribed.
  • Health practitioners should demand to be informed about the level of hyperforin in the products they use.

Low-hyperforin extracts are safer

It can be quite safely assumed that the risk of clinically important interactions is low when preparations containing normal extracts, not enriched in hyperforin, are used. St John’s wort preparations with normal levels of hyperforin (typically around 1.5-2.0 %) have been demonstrated not to cause clinically important pharmacokinetic interactions, and thus possess a better safety profile compared to special extracts enriched with hyperforin.31,32

Hyperforin does not seem to be important for the clinical efficacy. To date no clinical study has demonstrated the importance of hyperforin for clinical efficacy in depression treatment.33

St John’s wort and oral contraceptives

The hysteria surrounding the potential drug interaction of St John’s wort is no better illustrated than the press headlines proclaiming “miracle babies” and unwanted pregnancies associated with the use of St John’s wort in women taking oral contraceptives.34,35

Minor increase in breakthrough bleeding has been reported with St John’s wort in women on the oral contraceptive pill,36however, no evidence of ovulation or loss or contraceptive efficacy has been observed.37 even with extracts high in hyperforin.38,39 Extract with low to normal levels of hyperforin does not cause break-through bleeding.40

St John’s wort is not a sedative

SJW extract was shown to have no sedative effect in mental performance and reaction time tests, so no impairment on the ability to drive vehicles or operate machinery is anticipated. In addition, cognition was not impaired further when SJW extract was administered concomitantly with alcohol.

References

1 Ernst E. Second thoughts about safety of St John's wort. Lancet. 1999;354(9195):2014-2016.

2 Ernst E. St John's Wort supplements endanger the success of organ transplantation. Arch.Surg. 2002;137(3):316-319.

3 Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355  134-138.

4 Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of report reliability. Br.J.Clin. Pharmacol. 2001;52(5):587-595.

5 Ioannides C. Pharmacokinetic interactions between herbal remedies and medicinal drugs. Xenobiotica. 2002;32(6):451-478.

6 Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs. 2001;61(15):2163-2175.

7 Madabushi R, Frank B, Drewelow B, Derendorf H, Butterweck V. Hyperforin in St. John's wort drug interactions. Eur.J.Clin Pharmacol. 2006;62(3):255-233.

8 Tirona RG, Bailey DG. Herbal product-drug interactions mediated by induction. Br.J.Clin Pharmacol. 2006;61(6):677-681.

9 Whitten DL, Myers SP, Hawrelak JA, Wohlmuth H. The effect of St John's wort extracts on CYP3A: a systematic review of prospective clinical trials. Br.J.Clin Pharmacol. 2006;62(5):512-526.

10 Xie HG, Kim RB. St John's wort-associated drug interactions: short-term inhibition and long-term induction? Clin Pharmacol.Ther. 2005;78(1):19-24.

11 Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John's wort. J.Psychopharmacol. 2004;18(2):262-276.

12 Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. 2001;286(2):208-216.

13 Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs. 2009;69(13):1777-1798.

14 Borrelli F, Izzo AA. Herb-drug interactions with St John's wort (Hypericum perforatum): an update on clinical observations. AAPS.J. 2009;11(4):710-727.

15 Dasgupta A. Herbal supplements and therapeutic drug monitoring: focus on digoxin immunoassays and interactions with St. John's wort. Ther.Drug Monit. 2008;30(2):212-217.

16 Di YM, Li CG, Xue CC, Zhou SF. Clinical drugs that interact with St. John's wort and implication in drug development. Curr.Pharm.Des. 2008;14(17):1723-1742.

17 Zhou SF, Lai X. An update on clinical drug interactions with the herbal antidepressant St. John's wort. Curr.Drug Metab. 2008;9(5):394-409.

18 Yang AK, He SM, Liu L, Liu JP, Wei MQ, Zhou SF. Herbal interactions with anticancer drugs: mechanistic and clinical considerations. Curr.Med.Chem. 2010;17(16):1635-1678.

19 He SM, Yang AK, Li XT, Du YM, Zhou SF. Effects of herbal products on the metabolism and transport of anticancer agents. Expert.Opin.Drug Metab Toxicol. 2010;6(10):1195-1213.

20 Saxena A, Tripathi KP, Roy S, Khan F, Sharma A. Pharmacovigilance: effects of herbal components on human drugs interactions involving cytochrome P450. Bioinformation. 2008;3(5):198-204.

21 Shord SS, Shah K, Lukose A. Drug-botanical interactions: a review of the laboratory, animal, and human data for 8 common botanicals. Integr.Cancer Ther. 2009;8(3):208-227.

22 Mills E, Montori VM, Wu P, Gallicano K, Clarke M, Guyatt G. Interaction of St John's wort with conventional drugs: systematic review of clinical trials. BMJ. 2004;329(7456):27-30.

23 Kober M, Pohl K, Efferth T. Molecular mechanisms underlying St. John's wort drug interactions. Curr.Drug Metab. 2008;9(10):1027-1037.

24 Lawvere S, Mahoney MC. St. John's wort. Am.Fam.Physician. 2005;72(11):2249-2254.

25 Meijerman I, Beijnen JH, Schellens JH. Herb-drug interactions in oncology: focus on mechanisms of induction. Oncologist. 2006;11(7):742-752.

26 Länger R. Die HMPC monograph zu Hypericum: Hintergründe, Entstehung, Inhalte. Wiener medizinische Wochenschrift. 2010;160(21-22):557-563.

27 Butterweck V, Derendorf H, Gaus W, Nahrstedt A, Schulz V, Unger M. Pharmacokinetic herb-drug interactions: are preventive screenings necessary and appropriate? Planta Med. 2004;70  784-791.

28 Schulz V. Indicence and clinical relevance of the interactions and side effects of Hypericum preparations. Phytomed. 2001;8  (2):152-160.

29 Schulz V. Keine Aufhebung der kontrazeptiven Wirkung zweier Ovulationshemmer durch Johanniskrautextrakt. Z.Phytother. 2004;25(6):301-302.

30 Schulz V. Safety of St. John's Wort extract compared to synthetic antidepressants. Phytomedicine. 2006;13(3):199-204.

31 Müller SC, Majcher-Peszynska J, Uehleke B, et al. The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose. Eur.J.Clin Pharmacol. 2006;62(1):29-36.

32 Müller SC, Uehleke B, Wöhling H, et al. Effect of St John's wort dose and preparations on the pharmacokinetics of digoxin. Clin.Pharmacol.Ther. 2004;75(6):546-557.

33 Butterweck V, Schmidt M. St. John's wort: role of active compounds for its mechanism of action and efficacy. Wiener medizinische Wochenschrift. 2007;157(13-14):356-361.

34 Vegano D. Study shows St. John’s wort might weaken birth control. USA Today 2000 May 1; p. 01.A. 2000.

35 Schwarz UI, Büschel B, Kirch W. Unwanted pregnancy on self-medication with St John's wort despite hormonal contraception. Br.J.Clin.Pharmacol. 2003;55(1):112-113.

36 Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception. 2005;71(6):402-408.

37 Hall SD, Wang Z, Huang SM, et al. The interaction between St John's wort and an oral contraceptive. Clin.Pharmacol.Ther. 2003;74(6):525-535.

38 Fogle RH, Murphy PA, Westhoff CL, Stanczyk FZ. Does St. John's wort interfere with the antiandrogenic effect of oral contraceptive pills? Contraception. 2006;74(3):245-248.

39 Pfrunder A, Schiesser M, Gerber S, Haschke M, Bitzer J, Drewe J. Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial. Br.J.Clin.Pharmacol. 2003;56(6):683-690.

40 Will-Shahab L, Bauer S, Kunter U, Roots I, Brattström A. St John's wort extract (Ze 117) does not alter the pharmacokinetics of a low-dose oral contraceptive. Eur.J.Clin.Pharmacol. 2009;65:287-294.

41 Bilia AR, Galleri S, Vincieri FF. St. John's wort and depression: efficacy, safety and tolerability - an update. Life Sci. 2002;70  3077-3096.

42 Ernst E, Rand JI, Barnes J, Stevinson C. Adverse effects profile of the herbal antidepressant St. John's wort (Hypericum perforatum L.). Eur.J.Clin.Pharmacol. 1998;54(8):589-594.

43 Gaster B, Holroyd J. St John's wort for depression: a systematic review. Arch.Intern.Med. 2000;160(2):152-156.

44 Hammerness P, Basch E, Ulbricht C, et al. St John's wort: a systematic review of adverse effects and drug interactions for the consultation psychiatrist. Psychosomatics. 2003;44(4):271-282.

45 Josey ES, Tackett RL. St. John's wort: a new alternative for depression? Int.J.Clin Pharmacol.Ther. 1999;37(3):111-119.

46 Kim HL, Streltzer J, Goebert D. St. John's wort for depression: a meta-analysis of well-defined clinical trials. J.Nerv.Ment.Dis. 1999;187(9):532-538.

47 Knüppel L, Linde K. Adverse effects of St. John's wort: a systematic review. J.Clin.Psychiatry. 2004;65  (11):1470-1479.

48 Meier B. The science behind Hypericum. Adv.Ther. 1999;16  (3):135-147.

pharmacologyVarious compounds found in St John’s wort extracts have been shown to be active in pharmacological models of depression, including naphthodianthrones hypericin and pseudohypericin, flavonoids and polyphenols, and naphtodianthrones known as hyperforin and adhyperforin.

Hypericin and pseudohypericin are accepted as quality markers and lead constituents in St John’s wort extracts.

Even after more than 25 years of pharmacological research, the mechanisms of action of St. John’s wort and its constituents is still under debate.

Since St John’s work as well as pharmaceutical antidepressants, it has been assumed that St John’s wort work in a similar way, that is, inhibition of the re-uptake of neurotransmitters in nerve cell junctions.

In fact, hyperforin and adhyperforin inhibit the re-uptake of serotonin, adrenalin and dopamine1-3, but then this effect has also been shown in extracts devoid of hyperforin 4 Even in hyperforin-enriched extracts the presence and quantity of hyperforin cannot explain the extent of the overall effect.5

As as yet unidentified constituent must contribute to the antidepressant effect.

The fact that neither the mechanism of action nor the active constituents are fully known should not be considered as a restriction for using St. John’s wort in the therapy of mild to moderate depression.

The mechanisms of action of chemically defined antidepressants are likewise not fully understood, and ultimately the knowledge of mechanisms come secondary to the proof of efficacy in humans.

In this regards there is hardly a better-examined and proven plant medicine than St John’s wort.

References

1.         Buchholzer ML, Dvorak C, Chatterjee SS, Klein J. Dual modulation of striatal acetylcholine release by hyperforin, a constituent of St. John's wort. J.Pharmacol.Exp.Ther. 2002;301(2):714-719.

2.         Jensen AG, Hansen SH, Nielsen EO. Adhyperforin as a contributor to the effect of Hypericum perforatum L. in biochemical models of antidepressant activity. Life Sci. 2001;68(14):1593-1605.

3.         Müller BM. St. John's Wort for depressive disorders: Results of an outpatient study with the Hypericum preparation HYP 811. Adv.Ther. 1998;15  109-116.

4.         Kientsch U, Bürgi S, Ruedeberg C, Honegger UE. St. John's wort extract Ze 117 (Hypericum perforatum) inhibits norepinephrine and serotonin uptake into rat brain slices and reduces ß-adrenoreceptor numbers on cultured rat brain cells. Pharmacopsychiatry. 2001;34(Suppl. 1):S56-S60.

5.         Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci. 1998;63(6):499-510.

clinical study

The EU community monograph on St John’s wort confirms that it is more effective than placebo and comparable to standard antidepressants in the treatment of mild to moderate depressive episodes.

The monograph further states that St John’s wort can be used to prevent a relapse of depressive symptoms.

The monograph also confirms that products containing less than 1 mg hyperforin does not increase P450 enzyme activity and therefore would not even need a label warning of possible drug interactions.1

Comprehensive reviews and meta-analyses of the clinical trials of St John’s wort extracts have been conducted separately by various authors, all coming to the conclusion that St John’s wort is superior to placebo, and has a similar effect to pharmaceutical antidepressants.2-13

References

1.         Länger R. Die HMPC monograph zu Hypericum: Hintergründe, Entstehung, Inhalte. Wiener medizinische Wochenschrift. 2010;160(21-22):557-563.

2.         Hippius H. St John's Wort (Hypericum perforatum) - a herbal antidepressant. Curr.Med Res.Opin. 1998;14(3):171-184.

3.         Josey ES, Tackett RL. St. John's wort: a new alternative for depression? Int.J.Clin Pharmacol.Ther. 1999;37(3):111-119.

4.         Kasper S. Hypericum perforatum - a review of clinical studies. Pharmacopsychiatry. 2001;34 Suppl 1:S51-S55.

5.         Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St John's wort for depression - an overview and meta-analysis of randomised clinical trials. Br.Med.J. 1996;313(7052):253-258.

6.         Linde K, Mulrow CD, Egger M. St. John's Wort for depression. Cochrane.Database.Syst.Rev. 2005(3  ):CD000448.

7.         Röder C, Schaefer M, Leucht S. Meta-Analyse zu Wirksamkeit und Verträglichkeit der Behandlung der leichten und mittelschweren Depression mit Johanniskraut. Fortschr.Neurol.Psychiat. 2004;72:330-343.

8.         Volz HP. Controlled clinical trials of hypericum extracts in depressed patients - an overview. Pharmacopsychiatry. 1997;30 Suppl 2:72-76.

9.         Whiskey E, Werneke U, Taylor D. A systematic review and meta-analysis of Hypericum perforatum in depression: a comprehensive clinical review. Int.Clin Psychopharmacol. 2001;16(5):239-252.

10.       Kasper S, Dienel A. Cluster analysis of symptoms during antidepressant treatment with Hypericum extract in mildly to moderately depressed out-patients. A meta-analysis of data from three randomized, placebo-controlled trials. Psychopharmacology (Berl). 2002;164(3):301-308.

11.       Kasper S, Caraci F, Forti B, Drago F, Aguglia E. Efficacy and tolerability of Hypericum extract for the treatment of mild to moderate depression. Eur.Neuropsychopharmacol. 2010.

12.       Müller D, Niederberger M, Trenckmann U, Volz HP. Laif 900 in der Depressionsbehandlung. Feste Göße in der First Line-Therapie mittelschwerer Depressionen. MMW.Fortschr.Med. 2010;152(48):54-55.

13.       Gastpar M. Hypericum extract WS (R) 5570 for depression - an overview. International journal of psychiatry in clinical practice. 2013;17 Suppl 1:1-7.