Elsevier

Pharmacological Research

Volume 47, Issue 2, February 2003, Pages 101-109
Pharmacological Research

Review
Current St. John’s wort research from mode of action to clinical efficacy

https://doi.org/10.1016/S1043-6618(02)00266-9Get rights and content

Abstract

Preparations from St. John’s wort extracts are used in the treatment of depression in many countries and represent an accepted alternative to synthetic antidepressants or behavioural therapy. St. John’s wort extracts are therefore used in a therapeutic area which extends well beyond the traditional field of herbal medicine. The current status of preclinical and clinical research is summarised. St. John’s wort extract has a clear inhibitory effect on the neuronal uptake not only of serotonin, noradrenaline, and dopamine but also of gamma-aminobutyric acid (GABA) and l-glutamate. No other antidepressant shows an approximately equally broad inhibitory profile. In good agreement with the effects in various biochemical models of antidepressant action, many effects in a number of behavioural pharmacology models of antidepressant efficacy could also be demonstrated for St. John’s wort extract. Similar doses of John’s wort also cause changes in the above-mentioned neurotransmitter systems in the brain. Out of all individual substances of St. John’s wort only hyperforin and its structural analogue adhyperforin inhibit the re-uptake of the investigated neurotransmitters. However, hyperforin does not act as a competitive inhibitor at the transmitter binding sites of the transporter proteins but it affects the sodium gradient which then leads to an inhibition of uptake. The broad spectrum of action which characterises St. John’s wort extracts has only been described for the pure substance hyperforin. Over the past year a number of good clinical studies have been carried out which confirm the efficacy and tolerability of St. John’s wort extracts in mild depressive disorders, even if the therapeutic efficacy has recently been questioned by an American study. All studies have confirmed the good tolerability of St. John’s wort extract and the very low frequency of adverse events. However, some drug interactions have been found to occur with St. John’s wort extract, a number of which are of clinical relevance. In summary, pharmacological activity and therapeutic efficacy of St. John’s wort extract as an antidepressant are supported by a large number of scientific publications. Within the wide range of components in St. John’s wort extract, hyperforin plays an important, if not an outstanding role.

Introduction

Preparations from St. John’s wort extracts have become widely used in the treatment of depression in many countries and represent an accepted alternative to synthetic antidepressants or behavioural therapy, particularly for mild to moderate disorders [1], [2], [3], [4], [5], [6]. St. John’s wort extract preparations are therefore not only used for a common and potentially life-threatening disease (risk of suicide) but also for patients suffering enormously and for a disorder which is extremely expensive for our insurance system (medical consultations, medication, days off work, sick leave). St. John’s wort extracts are therefore used in a therapeutic area which extends well beyond the traditional field of herbal medicine. In view of this, it appears completely appropriate to require that the use of St. John’s wort preparations should comply with the criteria of rational drug therapy, which are defined in terms of activity, efficacy and safety by the legal authorities. The current status is summarised in the present communication.

Section snippets

The role of noradrenaline and serotonin for the mechanism of action of antidepressants

Today, it is known that almost all antidepressants influence the synaptic communication of the neurotransmitters serotonin and noradrenaline in the CNS, although different biochemical pathways are involved. The majority of antidepressants lead, at least initially, to an increased availability of noradrenaline and serotonin at the respective synapses (Fig. 1). One possible mode of action is the inhibition of the intra- and extraneuronal enzyme monoamine oxidase (MAO), a pathway which is

St. John’s wort extract has a broad spectrum of action

St. John’s wort extract has a clear inhibitory effect on the synaptosomal uptake not only of serotonin, with a mean inhibitory concentration of 2 μg/ml (Table 1). To our surprise, and in clear contrast to the characteristics of all other antidepressants, we found similar inhibitory effects on the synaptosomal uptake also not only for noradrenaline and dopamine but also of gamma-aminobutyric acid (GABA) and l-glutamate [8] (Table 1). From the comparative data (Table 1), it can be seen that none

Influence on neurotransmission in vivo

For the understanding of St. John’s wort extract as an antidepressant it is particularly significant that a number of authors also found changes in the central concentrations of the three neurotransmitters, noradrenaline, serotonin and dopamine or their metabolites, in the CNS of experimental animals after acute or chronic treatment. As for the synthetic antidepressants, the data are not uniform, but different effects are observed depending on the dose, the duration of treatment and the brain

Effects on the density of β- and 5-HT2-receptors

We could also confirm an influence on noradrenergic and serotoninergic mechanisms in vivo by showing that sub-chronic treatment of rats with imipramine or St. John’s wort extract resulted in a significant reduction in β-receptor density in the frontal cortex [7]. These findings obtained with the rater less selective ligand 3H-DHA were recently confirmed using a β-selective radioligand (3H-CGP 1277) [13].

If we treated rats with imipramine under otherwise identical conditions, we could also show

Behavioural pharmacology studies

In good agreement with the effects in various biochemical models of antidepressant action, many effects in a number of behavioural pharmacology models of antidepressant efficacy could also be demonstrated for St. John’s wort extract by a number of different working groups. These models included the reversal of several behaviour patterns induced by reserpine, elimination of the immobilisation time in the Porsolt test and reversal of helpless behaviour in the model of learned helplessness (Table 2

Hyperforin, a “broad-band re-uptake inhibitor”

The marked MAO-A inhibitory effect of St. John’s wort extract, which was subsequently never confirmed, was originally associated with hypericin, a component important for the phototoxic effect. Likewise, MAO inhibition could not be confirmed for hypericin [7]. Furthermore, in our investigations on synaptosomal uptake of serotonin, noradrenaline, dopamine and GABA, pure hypericin was not effective [15].

However, the active ingredient relevant for the synaptosomal uptake inhibition of all five

Molecular mechanism of action of hyperforin

Recently, exciting new aspects with regard to the molecular mode of action of hyperforin have also emerged. Hyperforin does not act as a competitive inhibitor at the transmitter binding sites of the transporter proteins like all the other antidepressants [17], [19], [20], [21], [22], [23] but shows a completely novel mechanism of action. The driving force of all the high-affinity neuronal neurotransmitter transport mechanisms mentioned is the sodium gradient between the high extracellular and

Effects of hyperforin on behaviour

In behavioural pharmacology experiments, the dominating role of hyperforin could also be demonstrated by a number of different authors (Table 3). In our initial findings, the activity of St. John’s wort extract in the immobilisation and the learned helpless paradigms were largely determined by hyperforin [8]. Similar findings have been reported by us and many other groups for many other behavioural models [23], [24], [25], [26]. If hyperforin is removed from the extract, activity can be still

Other active ingredients

As well documented hyperforin may be as the main active principle in St. John’s wort extract, the evidence today is clear that other ingredients are also effective in different pharmacological models. However, the pharmacological properties of these substances are by no means as well or as comprehensively documented as those of hyperforin.

An effect in the Porsolt test has recently been described for hypericin itself [18]. This has not been found by other authors [14] and was not found by the

Clinical efficacy

Although the therapeutic use of St. John’s wort extracts first came from practice, the high acceptance, such as found today in Germany and a few other countries, can only be explained by the fact that over the past years a number of good clinical studies have been carried out which confirm the efficacy and tolerability of St. John’s wort extracts in mild depressive disorders (for reviews [1], [2], [3], [4], [5], [6]).

The therapeutic efficacy has recently been questioned by an American study [35]

A comparison of two most recent clinical studies

The much quoted “negative” American study [35] represents a multicenter, randomised, double-blind, placebo-controlled study in which patients with an initial score on the Hamilton Depression Scale (HAMD) of at least 20 were included. Following a single-blind placebo run-in phase, the double-blind treatment study lasted 8 weeks. The primary assessment criterion was the HAMD, but a series of other self- and third-party assessment scales were investigated in addition.

The essential finding of this

Tolerability and interactions

Both clinical studies mentioned in this review confirmed the good tolerability of St. John’s wort extract and the very low frequency of adverse events. This emphasises once more the undisputed advantage of St. John’s wort in the outpatient treatment of depressive disorders as mentioned in Section 1 [1], [2], [3], [4], [5], [6].

Recently, the assessment of St. John’s wort extract as a generally unproblematic therapy had to be revised in certain respects, as various drug interactions have been

Which interactions are relevant in practice?

The interaction of St. John’s wort extract with the immune suppressant cyclosporin is well documented with regard to the decrease in plasma level as well as the clinical consequences (risk of transplant rejection), so that here a clear contraindication for St. John’s wort is certainly the case. Furthermore, St. John’s wort extract should not be combined with indinavir and possibly not with other protease inhibitors used in HIV therapy, although these interactions (reduction in plasma level)

Assessment of St. John’s wort as an antidepressant

Today, the pharmacological action and therapeutic efficacy of St. John’s wort extract as an antidepressant must be considered as confirmed, despite two negative American studies mentioned. Within the wide range of components in St. John’s wort extract, hyperforin plays an important, if not an outstanding role.

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