Wort (Hypericum perforatum L.) - Nature

Molecular Psychiatry (1999) 4, 333–338  1999 Stockton Press All rights reserved 1359–4184/99 $15.00

MECHANISMS OF DRUG ACTION

The experimental and clinical pharmacology of St John’s Wort (Hypericum perforatum L.) PJ Nathan Brain Sciences Institute, Swinburne University of Technology, 400 Burwood Road, Hawthorn 3122, Victoria, Australia Hypericum (St John’s Wort) is a plant that has been used for centuries as a medicinal herb. Pre-clinical animals studies suggest that hypericum is effective in three major biochemical systems relevant for antidepressant activity, namely the inhibition of the synaptic re-uptake system for serotonin (5-HT), noradrenaline (NA) and dopamine (DA). It is the only antidepressant capable of inhibiting the re-uptake of 5-HT, NA and DA with similar potencies. The potencies for monoamine re-inhibition and chronic changes in receptors are also consistent with changes seen with known antidepressants. Behavioral studies suggest that hypericum is active in pre-clinical animal models of depression with comparable effects to known antidepressants. Supporting the pre-clinical pharmacology and efficacy, many clinical studies have shown that hypericum has superior efficacy compared to placebo and comparable efficacy to standard antidepressants in the treatment of mild-to-moderate depression. The advantage of hypericum over other antidepressants may result from its favorable side-effect profile. Although pre-clinical and short-term clinical studies demonstrate antidepressant activity, the lack of long-term use and efficacy, and the heterogeneity of patients, interventions, extract preparations from previous clinical studies suggests that more careful and controlled studies are needed to determine the long-term efficacy of hypericum in mild-to-moderate depression. Keywords: pharmacology; hypericum; St John’s Wort; mechanism; antidepressant; mild-moderate depression; clinical efficacy; herbal remedies

Introduction St John’s Wort refers to the plant Hypericum perforatum, and has been used for centuries as a medicinal herb for anti-inflammatory, sedative, analgesic, diuretic, antimalarial, antidepressant and vulnerary action. Traditional indications have included trauma, burns, rheumatism, hemorrhoids, neuralgia, gastroenteritis, snakebite, ulcers, contusions, sprain, diarrhea, menorrhagia, hysteria and depression.1,2 Its efficacy in depression has been supported in recent times with implication for its use in the treatment of mild-tomoderate depression.3–5 Today, hypericum extracts are among the most widely used antidepressants in Germany, with more than 3.7 million prescriptions in 19976 and a market share of more than 25% of all antidepressant prescriptions in 1997.7 While evidence suggests that hypericum has antidepressant potential, the exact mechanism for the antidepressant effect remains to be resolved. The aim of this article is to illustrate some of the possible mechanisms that may underlie hypericum’s antidepressant action and review its clinical efficacy in the treatment of mild-to-moderate depression.

Dr PJ Nathan, Brain Sciences Institute, Swinburne University of Technology, 400 Burwood Rd, Hawthorn 3122, Victoria, Australia. E-mail: pnathan얀bsi.swin.edu.au Received 29 January 1999; revised and accepted 19 March 1999

About hypericum Hypericum perforatum belongs to the Guttiferae family. The genus Hypericum encompasses approximately 400 species of which Hypericum perforatum itself is divided into four subspecies that are distinguished by the size of their septals.8 Hypericum perforatum is found in many areas of the world including Europe, Asia, North America and North Africa. The name St John’s Wort comes from the fact it flowers around St John’s day. The crude drug, called herba hyperici, consists of the upper aerial parts of the plant, which are harvested before or during the flowering period. Chemical constituents of hypericum The commercially available products of St John’s Wort contain hypericum dry extracts, the pharmacological agent prepared from the upper aerial parts of the plant with either 60% ethanol or 80% methanol. These extracts differ to varying degrees in the content of six major natural product groups: naphthodianthrones (hypericin and pseudohypericin), acylphloroglucinols (hyperforin and adhyperforin), flavonol glycosides (quercetin, quercitrin, isoquercitrin, rutin, hyperoside, kampferol, leteolin, myricetin), biflavones (13,118-biapigenin, 13⬘,118-biapigenin (amentoflavon), proanthocyanidins (procycanidin B2) and phenyl propanes (chlorogenic acid and caffeic acid).9,10 Flavonol glycosides, biflavones, proanthcyanidins, and phenylpropanes, as biogenetically related compounds, together

The pharmacology of St John’s Wort PJ Nathan

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represent the main constituents in the dry crude drug of St John’s Wort.9 As hypericum contains numerous compounds with biological activity it is currently not known if one chemical or a combination produces the antidepressant effect. However, hypericum possesses a unique pharmacology in that it displays the pharmacology of many antidepressants in the one drug. This may be related to the multiple bioactive compounds present in hypericum. Experimental pharmacology of hypericum The monoamine hypothesis of depression postulates that symptoms of depression arise from the deficit in the availability of one or another of three biogenic monoamines serotonin (5-HT), noradrenaline (NA) and/or dopamine (DA).11 Most antidepressant drugs exert their pharmacological actions by increasing the concentrations of 5-HT, NA or DA through: (1) the inhibition of the synaptic uptake of these transmitters; or (2) inhibiting the metabolism of these transmitters by monoamine oxidase type A (MAO-A) enzymes; or (3) by blocking pre-synaptic inhibitory receptors such as ␣2-adrenoceptors.12 The final mechanism in the antidepressant effect is the changes in neurotransmitter receptor function, which in turn triggers various second messenger pathways. Receptor function is expressed as either changes in receptor number or the functional activity of the receptor (ie changes in second messenger levels). An increase in receptor number or functional activity is commonly termed upregulation whereas a decrease in receptor number or functional activity is termed downregulation. Some of the common changes in neurotransmitter receptor changes following chronic antidepressant or electro-convulsive therapy (ECT) treatment are shown on Table 1. Effects on monoamine re-uptake Recent reports by Rolli et al16 and Muller et al17 showed that a clinically used hypericum extract (LI 160) like conventional antidepressants, concentration dependently and potently inhibited the synaptic reuptake of 5-HT, NA and DA with an IC50 around

Table 1 Common changes in neurotransmitter receptor function in the rat brain following chronic antidepressants (AD) or ECT. Receptor function denotes changes in receptor number or functional activity. Data summarised from references11,13–15

␣2-adrenoceptors ␣1-adrenoceptors ␤-adrenoceptors 5-HT2-receptors (postsynaptic) 5-HT1A (autoreceptors) 5-HT1A (post-synaptic) GABAB receptors Dopamine (autoreceptors)

Decreased Increased (after AD) Decreased Decreased (after AD) Increased (after ECT) Decreased (for SSRIs and MAOIs) Increased (ECT, TCAs) Increased Decreased

2 ␮g ml−1. While tricyclics (TCAs) such as amitriptyline and imipramine, and serotonin and noradrenaline re-uptake inhibitors (SNRIs) such as duloxetine and milnacipran inhibit the synaptic uptake of 5-HT and NA with about equal affinity, no other compound shows similar potency for all three uptake systems. A recent study has shown that the bioactive substance responsible for inhibiting synaptic re-uptake of monoamines is a constituent of hypericum called hyperforin. This compound potently inhibited uptake of all three monoamines in the concentration range of 80– 200 nmol L−1.18 Hyperforin was also present in the alcoholic extract previously tested (LI-160) by Rolli et al16 and Muller et al.17 The hyperforin present in the alcoholic extract (LI 160) was also shown to inhibit the synaptic uptake of 5-HT, NA and DA in a similar concentration range (24–150 nmol L−1) (Table 2).18 In contrast hypericin, a major constituent of hypericum, that was originally thought to be important for antidepressant action, had no effect on synaptic uptake of monoamines.18 Hypericum’s potency on monoamine re-uptake inhibition is remarkable as previous studies by the same authors have shown that classical antidepressants such as imipramine were also active in these systems with IC50 values around 20 nmol L−1 for the 5HT and NA uptake systems.17 Comparable potencies were also found in the literature for other antidepressants (Table 2). More recently Neary and Bu21 reported the first study on the effects of hypericum on 5-HT and NA transport in intact neuronal cells. In this study it was shown that hypericum inhibited transport of 5-HT by 50%, which was approximately 70% of that observed with paroxetine and fluoxetine, whereas for noradrenaline the main effect was a 4.5-fold reduction in the apparent affinity of noradrenaline for its uptake site.21 Taken together these findings suggest that hypericum is effective in three major biochemical systems relevant for antidepressant activity, namely the inhibition of the synaptic re-uptake system for 5-HT, NA and DA. An important consideration is the relevance of these pharmacological effects seen in animals to the therapeutic doses used in clinical studies for the treatment Table 2 Comparison of the potencies of hyperforin in hypericum (LI-160) and various other antidepressants for the synaptic re-uptake of 5-HT, NA and DA. Data summarised from18–20 IC50 (nmol L−1)

Antidepressant

Hypericum (LI160) (hyperforin) Imipramine Amitriptyline Milnacipran Venlafaxine

5-HT uptake

NA uptake

DA uptake

67

123

24

20 39 203 210

21 24 100 610

17 000 5300 ⬎1000 ⬎1000


of depression. The therapeutic dose of antidepressants used is usually 10–20 times less than the doses used in animal studies. For example the standard dose of imipramine (20 mg kg−1) most researchers use for pharmacological studies in animals is about 10 times the clinical dose in man.17,22 Similarly, the dose of hypericum used by most studies is 10–20 times the average clinical dose used for mild-to-moderate depression.3 However, under these conditions most of the pharmacological effects observed with antidepressants are consistent. Furthermore, various pharmacological changes evident from animal studies have been reliably used in the past to predict clinical antidepressant efficacy.22 Effects of monoamine oxidase A activity Initial reports suggested that hypericin, the major constituent of hypericum acts as an inhibitor of MAO-A activity.23 However this finding has not been confirmed by subsequent studies.24–26 Quercetin and Quercitrin, both flavonoide aglykone constituents of hypericum extract have also been shown to inhibit MAO-A,27 although a therapeutic action of these compounds remains questionable because of their low plasma levels. Supporting the negative findings, studies by Muller et al17 showed that the IC50 values of hypericum as an inhibitor of MAO-A or MAO-B activity exceeded 100 ␮g ml−1 (100 times higher than the IC50 for inhibition of monoamine re-uptake), making it unlikely that both these mechanisms are involved in the antidepressant action of hypericum. However the effect of hypericum on MAO-A and MAO-B inhibition may be dose-related as a study by Kako et al28 suggests that extremely high doses of hypericum are needed to actively inhibit MAO. Effects on receptors The downregulation of ␤1-adrenoceptors has been commonly used as a biological marker of antidepressant efficacy. This pharmacological effect is one of the most consistent findings after chronic administration of antidepressants.29 A recent study showed that chronic administration of hypericum downregulates ␤1-adrenoceptors in the frontal cortex, with no change in receptor affinity.17 This finding is similar to binding studies, both in vivo and in vitro showing that chronic but not acute, treatment with antidepressants drugs and ECT downregulates ␤1-adrenoceptors in rat forebrain.29–32 Data from previous studies also suggest that adaptive changes in the 5-HT system may also play a pivotal role in the therapeutic effect of antidepressants. It has been shown that long-term TCA and repeated ECT lead to an enhanced 5-HT neurotransmission through a progressive sensitisation and upregulation of the postsynaptic 5-HT1A receptors in the dorsal hippocampus.33–39 These findings have been further supported by Haddjeri et al40 showing that long-term antidepressant treatments result in a tonic activation of forebrain 5HT1A receptors. A similar mechanism has also been shown for hypericum. Teufel-Mayer and Gleitz41 showed that chronic but not acute administration of

the commercially available hypericum extract, in rats, upregulated post-synaptic 5-HT1A receptors with no changes in receptor affinity. In contrast to most antidepressants, which downregulate 5-HT2 receptors after chronic administration,12,42,43 hypericum has been shown to upregulate 5-HT2 receptors.22,37 A similar upregulation of 5-HT2 receptors has also been shown with repeated treatments with ECT, one of the most effective therapies for depression.12 Recent evidence also suggests the hypericin has modest affinity for sigma receptors.43 The activity of hypericin at sigma receptors is a novel finding and represents potential new insight into the pharmacological action of hypericum. An association between sigma receptors and antidepressant action has been postulated on: (1) the demonstration that several antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and MAOIs have moderate affinity for sigma receptors;44–47 (2) some sigma receptor ligands, despite lacking affinity for serotonergic or noradrenergic receptors or transporter sites, exhibit antidepressant profile in animal models;48 and (3) chronic treatment with certain SSRIs and TCAs downregulate sigma receptors in brain regions associated with emotion such as the limbic regions.49 Hypericum has also been shown to affect several synaptic mechanisms of gamma-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission,50 with moderate affinities for GABAA, GABAB and Nmethyl-d-aspartate (NMDA) receptors.51 Both NMDA receptors and GABA receptors have been implicated in depression,52,53 and affinities for these receptors may also contribute to the overall antidepressant effect of hypericum. Behavioral pharmacology in animals The forced swim test (FCT) in rats is a well established behavioral animal model for the evaluation of antidepressant drugs that correlates well with their clinical efficacy.54 In this model hypericum has been shown to have antidepressant effects with an optimal dose range of 250–500 mg kg−1.55,56 More recently antidepressant activity of hypericum was also observed in the learned helplessness test, which is also used in detecting potential antidepressants.57 The efficacy of the hypericum extract in these two models was correlated with their hyperforin contents,56–58 suggesting that the hyperforin content may be the active constituent in hypericum extracts responsible for antidepressant activity. This also supports recent evidence that hyperforin is also the major bio-active substance responsible for inhibiting synaptic re-uptake of monoamines.18 Clinical pharmacology and efficacy in mild depression Every new antidepressant that is implicated for the treatment of depression needs to be evaluated in terms of its efficacy and potential side-effect profile. In order for St John’s Wort to be considered an effective antidepressant, evidence for its superior efficacy in comparison to placebo and at least equal efficacy in comparison

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to conventional treatment must be demonstrated. Several placebo-controlled studies have shown a superior efficacy of hypericum extracts compared to placebo in mild-to-moderate depression.59–62 The overall significant superiority of St John’s Wort over placebo was also confirmed by a recent meta-analysis.3 The responder rates for persons receiving hypericum preparations and placebo were 56% and 25% respectively.3 A number of recent studies have also shown equivalent efficacy of hypericum extracts compared to TCAs such as maprotiline, imipramine and amitriptyline in mild-to-moderate depression.63–66 The responder rates in these studies were 50% for hypericum compared to 52% with standard antidepressants.3 The clinical efficacy demonstrated for most of these studies should be interpreted with caution because of a number of methodological weaknesses. The most significant shortcoming is the relatively short duration of the trials. Most studies were conducted over 6–8 weeks, which means that data on the efficacy of hypericum over a longer period of time is fragmentary. Secondly, comparisons with newer antidepressants such as SSRIs or serotonin and noradrenaline re-uptake inhibitors (SNRIs) are lacking. Thirdly, the different trials vary with regard to classification of types of depression used to characterise patients. There is no consistent documentation on the exact diagnosis and severity of illness. Finally, the types of hypericum preparation and the amount of different constituents varied in different trials. Most tested preparations were standardised for hypericin content, but the amount varied from trial to trial (ie from 0.75 mg to 2.7 mg per day). A recent study also suggests that hyperforin content is more important for clinical efficacy and pharmacological action.67 As hyperforin levels varied between hypericum preparations (between 0.5–6%), the pharmacological constituent responsible for the antidepressant effect may have varied from study to study. The different preparations also varied in the amount of total hypericum extract (ranged from 350–900 mg per day). Hence the content of potentially active constituents also would have varied between studies. Future studies with well defined hypericum preparations and well defined patient groups are needed for careful examination of the clinical efficacy of hypericum. An advantage hypericum has over other antidepressants is its favorable side-effect profile. Hypericum has been shown to be well tolerated in patients with the incidence of adverse reactions similar to that of placebo.68 The most common adverse effects reported are gastrointestinal symptoms (8.5%), dizziness/confusion (4.5%) and tiredness/sedation (4.3%). However, the observed adverse effects are after short-term therapy and more long-term studies are desirable.

Conclusion St John’s Wort (hypericum) has a unique pharmacology in that it displays the pharmacology of many different classes of antidepressants. The likely mechanism of action is the inhibition of monoamine re-uptake (5-HT,

NA and DA) with comparable potencies to known antidepressants. Hypericum is also the only antidepressant known that inhibits the uptake of all three monoamines with similar potencies. At a receptor level, chronic treatment with hypericum downregulates ␤1-adrenoceptors (similar to most antidepressants and ECT), upregulates post-synaptic 5-HT1A receptors (similar to TCAs and ECT) and upregulates 5-HT2 receptors (similar to ECT). Moderate affinities for Sigma, NMDA and GABA receptors have also been shown suggesting additional mechanisms for antidepressant effect. It has also been shown that most effects of hypericum in biochemical models of antidepressant activity can be explained by the major constituent hyperforin. Preclinical behavioral studies suggest that hypericum is active in animal models of depression, with comparable potencies to standard antidepressants. Clinical studies show superior efficacy of hypericum compared to placebo and comparable efficacy to conventional antidepressants in the treatment of mild-to-moderate depression. The benefit of hypericum over other antidepressants may result from its favorable clinical sideeffect profile.

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