St John's Wort (Hypericum perforatum)

(Beers et al, 2006).

The Use of St John's Wort for Depression

Traditionally St Johns Wort was used for a number of conditions not least for depression. Nicholas Culpeper extolled the virtues of the herb as an aperient (laxative), detersive (depurative), diuretic, anti-parasitic and vulnerary for wounds and bruises. He also writes succinctly, ‘A tincture of the flowers in spirit of wine, is commended against the melancholy and the madness’ indicating his use of the herb as an antidepressant and for other associated disorders such as anxiety (Potterton, 1983). In modern times, as is the case with other herbal medicines, it was the Germans who recognized the merit of Hypericum, almost exclusively prescribing it until the end of 1980 (Kasper, 2001).

Over the years a number of studies have tested the efficacy of St John’s Wort in the treatment of depression. In 1996 Linde and colleagues published a groundbreaking systematic review and meta-analysis of the literature describing 23 randomised trials on the efficacy of Hypericum in treating mainly mild to moderate depression in a total of 1757 outpatients. They concluded, not only that extracts of the herb were significantly more successful in the treatment of mild to moderate depression than placebo, but that it was just as effective as standard antidepressants with far fewer side effects experienced (Linde et al, 1996).

Since then a number of other reviews have emerged in the clinical and more complementary literature supporting the use of St John’s Wort for mild to moderate depression. A cross section of those reviews is included:

• A systematic review conducted by Gaster and Holroyd (2000) concluded that St John’s Wort was more effective than placebo in the treatment of mild to moderate depression but less effective than tricyclic antidepressants and that more research was required on its efficacy when compared to other synthetic antidepressants. Given that tricyclic antidepressants are rarely prescribed for depression anymore (they do have other indications such a neuralgia) and have quite debilitating side effects (Beers et al, 2006) this would appear to be a non-consequential conclusion. This review was quite small, only eight studies were included, however this may reflect the stringency of the criteria used to include studies. It is an important study because it was published in Archives of Internal Medicine, one of the journals of the American Medical Association suggesting a high readership, hence reach.
• A review of clinical studies by Kasper (2001) stated that despite its limitations (mainly its use for more severe depression) and contraindications it was safer and more tolerable than synthetic antidepressants but with comparable efficacy. (Kasper, 2001).
• In 2006 Clement and colleagues published a systematic review in Holistic Nursing Practice concluding that Hypericum was successful in the treatment of mild to moderate depression and that further study on the most appropriate preparations and dosage were required (Clement et al, 2006).

Almost ten years after the original review on the efficacy of Hypericum Linde et al (2005) published another systematic review on the effectiveness and safely of the herb in treating depression. The review included 37 double blind randomised controlled trials reporting on the treatment of patients with depression by Hypericum when compared with a placebo and/or antidepressants. Recognised valid and reliable tools such as the Hamilton Depression Scale were used as clinical outcome measures and tolerability was assessed by drop-out rates (Linde et al, 2005). The review was published in the Cochrane Database of Systematic Reviews which is recognised as the gold standard for reviews due to the rigor and quality required of the reviews ultimately approved for publication.

The results of the review are summarised in Table 2:

Table 2: Results of Systematic Review by Linde et al (2005)

A recent study by Randlov and colleagues tested St Johns Wort on dysthymia, the subclinical version of depression but by comparing its effects to those with mild to moderate depression. Hypericum elicited no significant effect on this condition (as opposed to those experienced by the depression group). The labelling of individuals as being dysthymic is a controversial issue due to the identification of personality traits as the indictors for diagnosis (Randlov et al, 2006).

Side Effects

Side effects experienced from taking Hypericum are generally mild and rare (around 3%). Effects include nausea, constipation, diarrhoea, tiredness, restlessness, photosensitivity and sometimes allergic reactions of the skin (Gaster and Holroyd, 2000; Kasper, 2001). Another study testing the safety of St John’s Wort via ECG found no changes in parameters even at very high doses. There is no record of death from ingesting Hypericum in the literature (Kasper, 2001).

How Does it Work?

Up until recently the widely accepted active constituent in Hypericum perforatum was Hypericin, a type of glycoside called an anthraquinone. A glycoside consists of a sugar component (glycone) and non sugar component (aglycone) which has to undergo hydrolysis in the body before the aglycone component can have a therapeutic action. Anthraquinones are yellow pigments which were traditionally used as textile dyes. They are commonly bounded by a phenol or carbon structure and hydrolysed in the bowel to become laxatives. Aloes and Senna are classical examples of this effect. Hypericin is different in that although structurally classified as an anthroquinone glycoside it is a red pigment and does not become hydrolysed in the bowel (Pengelly, 2004), suggesting that it is absorbed into the bloodstream as is. Figure 1 shows the chemical structure of hypericin.

Figure 1: Hypericin

(Pengelly, 2004)

It has always been recognised that Hypericum contains some other key compounds which account for some of the other actions of the herb. These are flavonoids such as quercetin and proanthocyanidins. More recently, however it is recognised that Hypericum contains another compound, hyperforin, which is more important than hypericin in explaining the antidepressant action of the herb. Hyperforin is an acylphloroglucinol which was disregarded in the past because it is highly unstable to light and air. Figure 2 illustrates the structure of Hyperforin.

Figure 2: Hyperforin

It now appears that, although hypericin has some antidepressant activity via dopamine receptors it is the hyperforin responsible for most of the effect because the level of hyperforin contained in the extract correlates closely with the potency of that extract and the antidepressant effect of hyperforin as an isolated extract and as a known constituent of Hypericum is now well documented (Caccia, 2005; Mennini and Gobbi, 2004).

Hypericum also includes a range of polyphenols including the phenylpropane chlorogenic acid which demonstrates no antidepressant effects along with the proanthocyanadins which are poorly assimilated from the gastrointestinal tract. The flavonols however, such as quercetin, hyperoside and rutin, are believed to contribute to the antidepressant effect although further investigation is required on the mechanism by which this occurs (Caccia, 2005). This is a good example of the synergistic effects of the constituents of a herb.

Due to the fact that Hyperforin has only recently become the likely candidate for Hypericum’s antidepressant action there is still much study required on the exact mechanism of action. Originally it was believed that the antidepressant activity of the herb was due to the inhibitory effect of hypericin on Monoamine oxidase, an enzyme responsible for the breakdown of certain neurotransmitters such as dopamine. It is now known that hyperforin has the ability to inhibit the uptake of serotonin, dopamine and noradrenaline at the synapses via changes in the intracellular concentration of hydrogen and sodium ions and in the storage of neurotransmitters in synaptic vesicles. There also appears to be a little understood mechanism whereby Hypericum acts as an agonist to Sigma receptors, receptor proteins responsible for an antidepressant action in mammalian brains (Mennini and Gobbi, 2004).

The common physiological link between the etiology of both depression and pain modulation is a neuropeptide called substance P which has the ability to induce inflammatory proteins such as cytokine interkekin-6 (Fiebich and Mills, 2001). This provides an explanation as to why depressed patients often feel pain (eg fibromyagia) and vice versa. Fiebich and Lieb have demonstrated in vitro that Hypericum has the ability to inhibit the synthesis of substance P dependant interleukin-6 (Fiebich and Mills, 2001). This also gives some clue as to the documented anti-neuralgic effects of the herb.

Interactions

Unfortunately Hypericum is a herb which has well studied interactions with other herbs and drugs so in prescribing the practitioner needs to be, not only wary of combining it with other herbs, but careful to take a detailed listing of the patients medication and be aware of when it needs to be avoided. The main issue appears to be regarding the bioavailability of the drug. A systematic review of 19 pharmacokinetic trials conducted by Mills et al (2004) found that 17 of those trials demonstrated a decrease in the systemic bioavailability of the studied conventional drug (determined by a >20% in AUC) when combined with St John’s Wort (Mills et al, 2004). The mechanism by which this occurs is due to the herb dependant inhibition of drug metabolising enzymes (particularly CYP3A4) in the liver and intestine and/or of drug transporters such as P-glycoprotein (PgP).It is therefore, those drugs that are specifically broken down by these enzymes that appear to be affected whilst drugs that are metabolised by other enzymes, such as theophylline by CYP1A2 appear unchanged by the administration of Hypericum (Mannel, 2004; Zhou et al, 2004).

Some of the classes of drugs whose bioavailability are compromised by St John’s Wort are:

• Cancer:
• Tricyclic Antidepressants
• Anti-coagulants
• Anti-histamines
• Anti- HIV agents
• Immuno-suppressants
• Cardiovascular drugs

The pharmacology, pharmocognosy and pharmakinetics of Hypericum perfortatum is studied with much interest in the research community. It is encouraging to see that a better understanding of the herb is sought in order to aid in its responsible prescribing and to give credence to the traditional and empirical use of this important herb.

References

• Beers, M., Porter, R.S., Jones, T.V., Kaplan, J.L., and Berkwits, M. (Eds) The Merck Manual of Diagnosis and Therapy. Online Edition. http://www.merck.com/mmpe/index.html.

• Caccia, S. (2005) Antidepressant-like components of Hypericum perforatum extracts: an overview of their pharmacokinetics and metabolism. Current Drug Metabolism, 6: 531 – 543.

• Cavarga, I., Brezani, P., Fedorocko, P., Miskovsky, P., Bobrov, N., Longauer, F., Rybarova, S., Mirossay, L., and Stubna, J. (2005) Photoinduced antitumour effect of hypericin can be enhanced by fractionated dosing. Phytomedicine, 12: 680-683.

• Clement, K., Covertson, C., Johnson, M. J and Dearing, K. (2006) St John’s Wort and the Treatment of Mild to Moderate Depression: A Systematic Review. Holistic Nursing Practice, 20: 197-203.
• Fiebich, B.L and Lieb, A.H. (2001) Inhibition of Substance P Induced Cytokine Synthesis by St John’s Wort Extracts. Pharmacopsychiatry, 34: S26-S28.

• Gaster, B. and Holroyd, J. (2000) St John’s Wort for Depression: A Systematic Review. Archives of Internal Medicine, 160: 152-156.

• Kasper, S. (2001) Hypericum perforatum – A Review of Clinical Studies. Pharmacopsychiatry, 34: S51-S55.

• Linde, K., Ramirez, G., Mulrow, C.D., Pauls, A., Weidenhan, W. and Melchart, D. (1996) St John’s Wort for Depression – an Overview and Meta-analysis of Randomised Clinical Trials. BMJ, 313:253-258.

• Linde, K., Mulrow, C.D., Berner. M, and Egger, M. (2005) St John’s Wort for Depression. The Cochrane Database of Systematic Reviews. 2: CD000448.

• Mannel, M. (2004) Drug Interactions with St John’s Wort: Mechanisms and Clinical Implications. Drug Safety, 27: 773-797

• Mennini, T. and Gobbi, M. (2004) The Antidepressant Mechanism of Hypericum perforatum. Life Sciences, 75: 1021-1027.

• Mills, E., Montori, V.M., Wu, P., Gallicano, K., Clarke, M. and Guyatt, G. (2004) Interaction of St John’s Wort with Conventional drugs: a systematic review of clinical trials. BMJ, 329: 27-30.

• Pengelly, A. (2004) The Constituents of Medicinal Plants: An Introduction to the Chemistry and Therapeutics of Herbal Medicine. CABI Publishing: Cambridge.

• Potterton, D. (Ed) (1983) Culpeper’s Colour Herbal. W. Foulsham & Company Ltd: Berkshire.

• Randlov, C., Mehlsen, J., Thomsen, C.F., Hedman, C., von Fircks, H. and Winther, K. (2006) The efficacy of St. John's Wort in patients with minor depressive symptoms or dysthymia--a double-blind placebo-controlled study. Phytomedicine, 13: 215-221.

• Zhou, S., Chan, E., Pan, S.Q., Huang, M. and Lee, E.J. (2004) Pharmacokinetic interactions of drugs with St John's wort. Journal of Psychopharmacology, 18: 262-276.