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Hypericum perforatum (St John's Wort): A non-selective reuptake inhibitor? A

review of the recent advances in its pharmacology

Article  in  Journal of Psychopharmacology · April 2001

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Journal of Psychopharmacology 15(1) (2001) 47–54
©2001 British Association for Psychopharmacology (ISSN 0269-8811)
SAGE Publications, London, Thousand Oaks, CA and New Delhi
0269–8811[200103]15:1; 47–54; 015984

Hypericum perforatum (St John’s Wort): a non-selective reuptake

inhibitor? A review of the recent advances in its pharmacology
Pradeep J. Nathan
Brain Sciences Institute, Swinburne University of Technology, Hawthorn Victoria, Australia.

Hypericum possesses a unique pharmacology in that it displays the pharmacology of many classes of
antidepressants and new mechanisms not typical of standard antidepressants. The most potent of all its
action is the moderate to high potency for inhibition of the reuptake of monoamines, serotonin, dopamine
and noradrenaline and the amino-acid neurotransmitters GABA and glutamate. Unlike standard reuptake
inhibitors, hypericum exerts this reuptake inhibition non-competitively by enhancing intracellular Na+ ion
concentrations. At a receptor level, chronic treatment with hypericum downregulates β1-adrenoceptor,
upregulates post-synaptic 5-HT1A receptors and 5-HT2 receptors. Although the major constituent
responsible for the antidepressant effect is thought to be hyperforin, other constituents such as hypericin,
pseudohypericin, flavonoids and oligomeric procyanidines may also play a direct or indirect role. While
reuptake inhibition may more than likely be responsible for most of the antidepressant effect, other
mechanisms may also contribute alone or in combination to exert the overall antidepressant action.
Key words: depression; dopamine; GABA; glutamate; hypericum; noradrenaline; pharmacology; reuptake inhibitor;
serotonin; St John’s Wort

Introduction possible mechanism of action, with inclusion of the findings

For centuries, St John’s Wort (Hypericum perforatum and
Hypericum anustifolia) has been used as a medicinal herb. The
current popularity of hypericum comes from recent clinical trials
and reviews on its clinical efficacy and pharmacological potential.
Hypericum is a popular antidepressant drug in many European
countries including Germany where it is available by prescription,
while in the USA and Australia, St John’s Wort is regulated as a
dietary supplement.
Hypericum contains numerous compounds with biological
activity, such as napthodiathrones (0.05–0.15%) including hypericin
and pseudohypericin, tanins and proanthocyanidins (6–15%),
flavonoids (2–5%) and phloroglucinol derivatives (up to 5%
hyperforin). Other constituents found include phenolic acids,
coumarins, monoterpenes, sesquiterpenes, sterols, xanthones,
vitamin C and A and volatile oils (Leung and Foster, 1996). There
are a number of different extractions of hypericum available, and
the active constituents vary in concentration among different
extracts, mainly due to factors such as variations in plant genetics,
growing conditions and preparation and processing procedures.
This makes research into the pharmacology and efficacy of
hypericum and comparison across the board difficult. However,
many recent studies have been conducted on well-defined
hypericum extracts, with the identification of key constituents and
their mechanism of action.
The aim of this short review is to summarize some of the
predominant pharmacological effects of hypericum and identify its
presented at the recent and first meeting on ‘Pharmacology of St
John’s Wort (Hypericum perforatum L.) and its constituents’ in
Germany, February, 2000.
Pre-clinical and clinical evidence for
efficacy
Clinical studies have shown a superior efficacy of hypericum
extracts compared to placebo in mild to moderate depression
(Hansgen et al., 1994; Harrer et al., 1994; Hubner et al., 1994;
Laakmann et al., 1998; Schrader et al., 1998). Recent studies have
shown equivalent efficacy of hypericum extracts compared to
tricyclic antidepressants (TCA) such as maprotiline, imipramine
and amitriptyline (Vorbach et al., 1994; Harrer et al., 1994;
Vorbach et al., 1997; Weatley et al., 1997; Philipp et al., 1999), and
the serotonin reuptake inhibitors (SSRI) fluoxetine and sertraline
(Brenner et al., 2000; Schrader et al., 2000) in mild to moderate
depression. In a systemic review and meta-analysis by Linde
(1996), it was stated that hypericum had a 63.9% response rate
compared to 58.5% for other antidepressants and 22.3% for
placebo.
The clinical evidence has been supported by many pre-clinical
studies in animal models of depression. The forced swim test
(FST) in rats is a well established behavioural animal model for the
evaluation of antidepressant drugs that correlates well with their
clinical efficacy (Porsolt et al., 1977; Willner, 1985). In this model,
48
Table 1 Comparisons of the potencies of hyperforin in hypericum (LI-160) and various other antidepressants for the synaptic reuptake of
serotonin, noradrenaline, dopamine, GABA and gutamate
Uptake inhibition IC50 (nmol/l)
Antidepressant 5-HT Noradrenaline
Hypericum (LI-160) 67 123
(hyperforin)
Imipramine 20 21
Amitriptyline 39 24
Milnacipran 203 100
Venlafaxine 210 610
Fluoxetine 6.8 620
Data summarized from Muller et al. (1998); Chatterjee et al. (1998a); Hyttel (1994); Briley and Moret (1998); Wonnemann et al. (2000c). IC50 values; the
lower the IC50, the greater the potency.
an antidepressant effect of hypericum extracts has been demon-
strated within a dose range of 250–500 mg/kg (Butterweck et al.,
1997; Bhattacharya et al., 1998).
Antidepressant activity of hypericum has also been demon-
strated in other animal models capable of predicting antidepressant
response, such as the learned helplessness test (Chatterjee et al.,
1998b) and the chronic escape deficit model of depression
(Gambarana et al., 1999). In the former studies, the efficacy of the
hypericum extract was correlated with the hyperforin contents
(Butterweck et al., 1997; Bhattacharya et al., 1998), suggesting
that the hyperforin content may be an important active constituent
in hypericum extracts responsible for antidepressant activity.
However, there is also evidence that other constituents of
hypericum such as solubilized hypericin and pseudohypericin are
active in the FST (Butterweck et al., 1997, 1998b). In addition,
recent studies also show that flavonoids and xanthones have also
been shown to be active in the FST (Butterweck et al., 1997, 2000
Muruganandam et al., 2000).
However, despite its proven pre-clinical and clinical efficacy,
the mode of action of hypericum is still not fully understood.
Hypericum possesses a unique pharmacology in that it displays the
pharmacology of many classes of antidepressants and new
mechanisms not typical of standard antidepressants. This may be
related to the multiple bioactive compounds present in hypericum
which independently or synergistically exert their pharmacological
actions (Nathan, 1999).
Effects of monoamine oxidase a activity
The first study indicating a possible antidepressant action of
hypericum extracts was reported by Suzuki et al. (1984) who
showed that hypericin, the major constituent of hypericum acts as a
reversible inhibitor of monoamine oxidase A activity (MAOI). On
this evidence hypericin was considered the active constituent of
hypericum, and hypericum extracts were standardized to this
compound. However, subsequent findings have not confirmed this
effect (Bladt and Wagner, 1988; Demishch et al., 1989; Thiele et
al., 1994a; Cott, 1995). The positive result of the Suzuki et al.
(1984) study may be related to the fact that the sample of
hypericum used was only 80% pure and one or more constituents
in the remaining 20% of the fraction may have accounted for the
inhibition of MAO (Cott, 1995). Supporting this theory, Bladt and
Wagner (1994) reported that the greatest MAO inhibition was
found in fractions with the greatest amounts of flavonoids. While
JOURNAL OF PSYCHOPHARMACOLOGY 15(1)
Dopamine GABA Glutamate
24 184 143
17 000 – –
5300 – –
> 1000 – –
> 1000 – –
> 5000 – –
flavonoids, quercetin and quercitrin, have been reported to inhibit
MAO-A activity (Sparenberg et al., 1993; Bladt and Wagner,
1994), their therapeutic action remains questionable due to their
low plasma levels (in the µM to mM range). Muller et al. (1997)
showed that the IC50 values of hypericum as an inhibitor of MAO-
A or MAO-B activity exceeded 100 µg/ml (100 times higher than
the IC50 for inhibition of monoamine reuptake), making it unlikely
that both these mechanisms are involved in the antidepressant
action of hypericum. These findings suggest that hypericin at
clinically relevant doses is not an inhibitor of MAO, but evidence
exists to suggest that the effects on MAO inhibition may be dose-
related (Kako et al., 1993).
Hypericum as a non-selective reuptake
inhibitor
An effect of hypericum on reuptake inhibition of monoamines was
first reported by Rolli et al. (1995) and Muller et al. (1997). The
clinically used hypericum extract (LI-160), similar to conventional
antidepressant concentration, dependently and potently inhibited
the synaptic reuptake of serotonin (5-HT), noradrenaline and
dopamine with an IC50 around 2 µg/ml. While other anti-
depressants have similar affinity for either 5-HT and noradrenaline
or noradrenaline and dopamine reuptake inhibition, no other
compound shows similar potency for all three uptake systems.
While there may be number of constituents in hypericum extracts
that maybe responsible for inhibition of monoamine reuptake, a
study by Chatterjee et al., (1998a) indicated a role for hyperforin.
In this study, hyperforin potently inhibited the reuptake of all
three monoamines in the concentration range of 80–200 nmol/l.
In addition, hyperforin also demonstrated antidepressant properties
in animal models of depression (Chatterjee et al., 1998b; Muller et
al., 1998). Hyperforin was also present in the alcoholic extract
previously tested (LI-160) by Rolli et al. (1995) and Muller et al.
(1997), and was also shown to inhibit the synaptic uptake of 5-HT,
noradrenaline and dopamine in a similar concentration range
(24–150 nmol/l) (Muller et al., 1998) (Table 1).
Unlike other antidepressants that inhibit reuptake of
monoamines by binding to the monoamine transporters, hyperforin
has been shown to possess a unique mechanism of action. Singer et
al. (1999) reported that hypericum’s effect on reuptake inhibition is
non-competitive (decrease in Vmax and Km) compared to other
reuptake inhibitors which display competitive inhibition (increase
in Km, no change in Vmax). Furthermore, hyperforin’s effect on
P. J. NATHAN: ST JOHN’S WORT: A NON-SELECTIVE REUPTAKE INHIBITOR?
monoamine uptake inhibition may be mediated by increasing free
intracellular Na+ ion concentrations. Singer et al. (1999) suggest
that an initial decrease in H+ ion concentrations and pH followed
by elevations in intracellular Na+ ion concentrations may be
secondary to an activation of Na+/H+ exchanger (Singer et al.,
1999, 2000). This hypothesis is supported by observations that the
sodium ionophore monensin, which elevates Na+ concentrations by
promoting Na+/H+ exchange (Katsuyoshi and Yoshihiko, 1991;
Sandeaux et al., 1982), is also a potent inhibitor of the
synaptosomal reuptake of monoamines (Reith and O’Reilly, 1990;
Singer et al., 1999). Although hyperforin has some similarities in
its mechanism of action to monensin, it has a reverse U-shaped
dose response curve and does not increase Na+ concentrations up
to the extracellular levels as monensin (Singer et al., 1999). It has
been suggested by Singer et al. (1999) that the effect on Na+
concentrations may be associated with one of the cellular ion
exchanging mechanisms.
The potency of hyperforin and hypericum on monoamine
reuptake 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 for the 5-HT and noradrenaline uptake systems
(Muller et al., 1997). Comparable potencies were also found in the
literature for other antidepressants (Table 1).
While most studies have shown inhibition of reuptake of
monoamines in synaptosomal preparations, a recent study by
Neary and Bu (1999) reported for the first time an effect of
hypericum on 5-HT and noradrenaline 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.
While hyperforin has been shown to be the key constituent
important for uptake inhibition of monoamines, a recent study by
Wonneman et al. (2000b) suggests that other constituents such as
the oligomeric procyanidines (OPC), which are part of the tanin
fraction of hypericum is also a weak to moderate inhibitor of the
uptake for 5-HT, noradrenaline and dopamine (µM range). This
may be an important mechanism of action for certain extracts of
hypericum that do not contain hyperforin. For example, it has been
shown that the hypericum extract ZE117 inhibits the reuptake of
both noradrenaline and 5-HT (Burgi et al., 2000) and demonstrates
clinical antidepressant effects (Schrader, 2000). Taken together, the
available data suggests that hyperforin is the principal active
constituent of hypericum responsible for reuptake inhibition of
monamines in the moderate potency range (in the nM range), while
OPC represents yet another active constituent responsible for weak
to moderate uptake inhibition of monoamines, that may be
important for hypericum’s antidepressant effects.
These studies have been supported by (1) in-vitro and in-vivo
studies in rats showing increased release of monoamines in the
cortex, diencepaholon and brainstem (Calapai et al., 1999; Yu,
2000), locus coeruleus (Kaehler et al., 1999), striatum and nucleus
accumbens (Di Matteo et al., 2000); (2) animal and human
neuroendocrine studies showing increased secretion of growth
hormone and decreased secretion of prolactin (a measure of
dopaminergic function) (Butterweck et al., 1998a; Franklin et al.,
1999) and increased cortisol secretion (a measure or serotonergic
function) (Laakmann et al., 2000) after hypericum administration;
49
and (3) electrophysiological animal and human studies showing
electroencephalographic changes in the alpha frequency (indicative
of serotonergic and dopaminergic modulation) (Dimpfel and
Schombert, 1997; Dimpfel et al., 1998; Schellengerg et al., 1998;
Dimpfel et al., 1999).
While hypericum has similarities with other known
antidepressants, in terms of uptake inhibition of monoamines 5-
HT, noradrenaline and dopamine, it has a unique action not
observed in other antidepressants in that it also has a relatively
high potency (nM range) for the uptake inhibition of the amino
acid transmitters GABA and glutamate (Chatterjee et al., 1998a;
Wonnemann et al., 2000a,c) (Table 1).
In-vivo studies in rats have also shown enhanced release of
glutamate after hypericum administration (Kaehler et al., 1999).
Inhibition of synaptosomal uptake of glutamate and GABA has
been shown with the active constituent hyperforin (Wonnemann et
al., 2000a,c) and OPC (Wonnemann et al., 2000b) (Table 1).
Similar to the mechanism suggested for reuptake inhibition of
monoamines, the mechanism for GABA and glutamate uptake,
inhibition has also been suggested to be non-competitive (decrease
in Vmax, no change in Km) and due to an increase in intracellular
concentrations of Na+ ions (Wonnemann et al., 2000a,c). Authors
suggest that the mechanism responsible for this effect could be due
to the activation amiloride sensitive Na+ channels and/or the
Na+/H+ exchanger (Wonnemann et al., 2000c).
Effects on monoamine receptors
Chronic treatment with antidepressant drugs lead to long-term
changes to various receptors in the brain (Table 2). A commonly
used biological marker of antidepressant efficacy is the
downregulation of β1-adrenoceptors after chronic administration of
most antidepressants (Vertulani and Sulser, 1975). Binding studies,
both in vivo and in vitro indicate that chronic but not acute
treatment with antidepressants drugs and electroconvulsive therapy
(ECT) downregulates β1-adrenoceptors in rat forebrain (Vertulani
and Sulser, 1975; Beer et al., 1987; Heal et al., 1989; Hosada and
Duman, 1993). Similarly, hypericum has also been shown to
downregulate β1-adrenoceptors in the frontal cortex, with no
change in receptor affinity (Muller et al., 1997, 1998).
The serotonergic system and changes to serotonergic receptor
function may also play an important role in the pharmacological
actions of antidepressants. It has been shown that long-term TCA
and repeated ECT lead to an enhanced 5-HT neurotransmission
through a progressive sensitization and upregulation of the post-
synaptic 5-HT1A receptors in the dorsal hippocampus (de
Montigny and Aghajanian, 1978; de Montigny, 1984; Welner et al.,
1989; Blier et al., 1990; Nowak and Dulinski, 1991; Stockmeier et
al., 1992; Burnet et al., 1994;). Supporting these findings, Haddjeri
et al. (1998) showed that long-term antidepressant treatments
results in a tonic activation of forebrain 5-HT1A receptors. A
similar mechanism has also been shown for hypericum. Teufel-
Mayer and Gleitz (1997) showed that chronic but not acute
administration of the commercially available hypericum extract,
upregulated post-synaptic 5-HT1A receptors with no changes in
receptor affinity. However, in contrast to most antidepressants
which downregulate 5-HT2 receptors after chronic administration
(Stolz et al., 1983; Nelson et al., 1989; Leonard, 1995), hypericum
has been shown to upregulate 5-HT2 receptors (Muller et al., 1997;
50
Table 2 Common changes in neurotransmitter receptor function in the rat brain following chronic antidepressants, ECT or hypericum
Type of receptor Antidepressants
α2-adrenoceptors Decreased
α1-adrenoceptors Increased
β-adrenoceptors Decreased
5-HT2 receptors Decreased
(post-synaptic)
5-HT1A (autoreceptors) Decreased
(for SSRIs and MAOIs)
5-HT1A (post-synaptic) Increased
(ECT, TCAs and Lithium)
GABA receptors Increased
Dopamine D2 receptors Decreased
Receptor function denotes changes in receptor number or functional activity.
Teufel-Mayer and Gleitz, 1997). Interestingly, a hyperforin rich
extract did not upregulate 5-HT2 receptors (Muller et al., 1998),
while Chatterjee et al. (1998b) showed evidence for 5-HT2
receptor downregulation with hyperforin. This suggests that
different constituents in hypericum may be responsible for varying
effects of 5-HT2 receptors. The upregulation induced by hypericum
may be due to other constituents present in the extract. Supporting
this, a recent study showed that xanthones induce upregulation of
5-HT2 receptors (Muruganandam et al., 2000). In contrast the
downregulation of these receptors may be influenced by hyperforin
as indicated by Chatterjee et al. (1998b). While the significance of
the upregulation or downregulation is not known, upregulation of
5-HT2 receptors has also been shown with repeated treatments with
ECT, one of the most effective therapies for depression while
downregulation of these receptors is seen with other antidepressant
classes (Leonard, 1995).
While the role of the dopaminergic system in antidepressant
action is less known, a number of antidepressant drugs possess
dopamine reuptake inhibition properties. Similar to other
monoamine receptors, chronic administration of various
antidepressants also downregulates dopamine receptors in the brain
(Leonard, 1995). Although there is limited evidence for an
interaction between hypericum extracts and dopamine receptors, a
recent study showed that xanthones present in hypericum extracts
downregulate D2 receptors following chronic administration
(Muruganandam et al., 2000).
Other pharmacological actions
While the most potent effects of hypericum and its constituents are
on reuptake inhibition of monoamines and amino-acid
neurotransmitters (nM range), other pharmacological actions have
been noted. However, these actions are in the mM to µM range and
at clinically relevant doses may not be responsible for the
pharmacological actions of hypericum. These moderately potent
effects may, however, act synergistically with reuptake inhibition
to produce the overall antidepressant effect.
Nelson et al. (1989) suggest that hypericin has modest affinity
(mM to µM range) for sigma receptors. The activity of hypericin at
sigma receptors is a novel finding and represents potential new
insight into the pharmacological action of hypericum. Sigma
receptors may play an important role in antidepressant action as it
JOURNAL OF PSYCHOPHARMACOLOGY 15(1)
ECT Hypericum and constituents
Decreased Decreased
(extract and hyperforin)
Increased Increased
(extract and xanthones)
Decreased (hyperforin)
Increased
Increased
(extract and hyperforin)
Increased (xanthones)
Decreased (xanthones)
has been shown that several antidepressants such as SSRIs and
MAOIs also have moderate affinity for sigma receptors with
chronic administration leading to downregulation of these
receptors (Klein and Musacchio, 1989; Schmidt et al., 1989; Itzhak
and Kassim, 1990; Shirayama et al., 1993; Matsuno et al., 1996;
Raffa, 1998). In addition, some sigma receptor ligands exhibit
antidepressant profile in animal models despite lacking affinity for
serotonergic or noradrenergic receptors or transporter sites (Rao et
al., 1990).
Hypericum extracts and hypericin may also have GABAergic
and anti-glutaminergic effects, as moderate affinities for GABAA,
GABAB (Ki = 75 ng/ml and 6 ng/ml) and N-methyl-D-aspartate
(NMDA) (1 µM for hypericin) receptors have been demonstrated
(Cott, 1997; Wonnemann et al., 1997). A recent study also showed
that xanthones, a constituent of hypericum, increased GABA
receptors (Muruganandam et al., 2000). While the significance of
NMDA and GABA receptor binding by hypericum is not known,
there is evidence linking the GABA and NMDA receptors to
antidepressant action. For example, the GABAergic agent
fengabine has antidepressant effects (Nielsen et al., 1990) and
GABAB receptor stimulation enhances β-adrenoceptor down-
regulation (Enna et al., 1986). In addition, reduced levels of
plasma GABA levels have been shown in depression (Petty et al.,
1993).
Similarly, the moderate affinity of hypericum for NMDA
receptors may also play a role in its antidepressant action since
studies have shown that several tricyclic antidepressants such as
imipramine, desipramine and chlormipramine also possesses anti-
glutaminergic properties (Holemans et al., 1993), with chronic
administration leading to downregulation of NMDA receptors
(Nowak et al., 1993). In addition, treatment with NMDA
antagonists results in downregulation of β-adrenoceptors (Paul et
al., 1992). While it appears that hypericum extracts have two
opposing effects (NMDA antagonistic effects and inhibition of
glutamate reuptake), they are mediated by different constituents. In
addition, the antagonistic effect of hypericin on NMDA receptors
(anti-glutaminergic effect) may be independent to the effects of
hyperforin on glutamate reuptake inhibition (glutaminergic
effects). It is possible that antidepressant effect of the latter
mechanism may be via activation of metabotrophic glutamate
receptors, and is independent of the concurrent antidepressant
effect of NMDA receptor antagonism.
Evidence also suggests that hypericum is an inhibitor of
P. J. NATHAN: ST JOHN’S WORT: A NON-SELECTIVE REUPTAKE INHIBITOR?
cytokine expression, particularly interleukin-6 (IL-6), with
moderately potent effects in the µM range (Thele et al., 1994b).
More recent findings suggest that this effect may be mediated by
hyperforin (Fiebich et al., 2000). This mechanism of hypericum
may be of clinical importance since there is increasing evidence for
changes in immune parameters, including overexpression of IL-6
in depression (for a review, see Connor and Leonard, 1998).
Pharmacokinetics of hypericum
Pharmacokinetic studies in humans have shown that, at clinically
relevant doses (900 mg and 1800 mg), peak plasma levels of total
hypericin was observed approximately 4 h after dosage, with
plasma levels in the nM to µM range (Staffeldt et al., 1994; Kerb et
al., 1996; Brockmoller et al., 1997). The elimination of hypericin
has been shown to be slow with an approximate half-life of 25 h
(Staffeldt et al., 1994). Similarly, hyperforin concentrations have
been observed in the nM range, peaking at 3.5 h after dosage
(Biber et al., 1998). Compared to hypericin, hyperforin has been
shown to have a shorter half-life of 9 h. Steady-state levels of
hypericin and hyperforin are achieved after 3–4 days and
concentrations are comparable to the plasma levels achieved by
other antidepressants (Biber et al., 1998).
Recently, a number of pharmacokinetic interactions between
hypericum extracts and other drugs have been reported. Ernst
(1999) suggested that interaction may be due to an effect of
hypericum on liver cytochrome (CYP) P-450 enzymes. Reduced
plasma concentrations of theophylline, cyclosporin, wafarin,
anaesthetics and the oral contraceptives ethinyloestradiol/
desogestrel have been noted with combination with hypericum
extracts (Ernst, 1999; Koupparis, 2000). This is further supported
by other studies showing a reduction in plasma concentrations of
the cardiac glycoside, digoxin (Johne et al., 1999) and the HIV-1
protease inhibitor indinavir (Piscitelli et al., 2000). Interactions of
hypericum with SSRIs have also been suggested with the reported
cases of central serotonin syndrome (Lantz et al., 1999).
The effects of hypericum on CYP enzymes were directly
investigated by Markowitz et al. (2000) using substrate probes for
the CYP 2D6 and 3A4 enzymes. While no significant effect was
found on both enzymes, the results were limited by the small
sample size. However, the authors suggested that in majority of the
subjects tested the maximum concentration of the 3A4 substrate
alprazolam was decreased by 5 h, indicating a possible inductive
effect of hypericum on CYP 3A4. More recent in-vitro and in-vivo
studies have supported the possible inductive effect reported by
Markowitz et al. (2000), showing that hypericum can induce of
CYP 3A4 both after acute and chronic treatments (Moore et al.,
2000; Roby et al., 2000). Furthermore, similar induction of the
enzyme was also shown with the constituent hyperforin (Moore et
al., 2000). In contrast to the above findings, a more recent finding
suggests that hypericum and some of its major constituents are
inhibitors of cytochrome P-450 enzymes (Obach, 2000). In this
study, the flavonoid constituent I3,II8-biapigenin was shown to be
a potent, competitive inhibitor of CYP3A4, CYP2C9 and CYP1A2
(Ki values of 0.038, 0.32 and 0.95 µM, respectively), while
hyperforin was a potent non-competitive inhibitor of CYP2D6 (Ki
of 1.5 µM) and a competitive inhibitor of CYP2C9 and CYP3A4
(Ki values of 1.8 and 0.48 µM). It is possible that the discrepancy
between the studies may be related to one or more of the following
51
factors: (1) multiple and complex effects of various constituents on
cytochrome enzymes; (2) differences in acute versus chronic
effects; and (3) dose–response effects. It is apparent from the
current findings that the effects of hypericum on cytochrome
enzymes may be complex and further studies are warranted before
certain conclusions can be made about the exact nature of the
interaction. However, given that greater the 50% of drugs are
metabolized by the CYP 3A4 enzyme, and many other drugs are
metabolized by CYP2D6, the current findings suggest likely
interactions of hypericum extracts with a number of drugs.
In summary, Hypericum perforatum (St John’s Wort) has a
unique pharmacology in that it displays the pharmacology of many
different classes of antidepressants while possessing new actions
that are not seen with known antidepressants. The most potent of
all its reported actions is the inhibition of monoamine reuptake (5-
HT, noradrenaline and dopamine) with comparable potencies to
known antidepressants. Additionally, hypericum is also a fairly
potent inhibitor of GABA and glutamate uptake, a property not
observed with other antidepressants. Unlike standard reuptake
inhibitors, hypericum exerts this action through the non-
competitive inhibition of reuptake by elevation in intracellular Na+
ion concentrations. At a receptor level, chronic treatment with
hypericum downregulates β1-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 to low affinities for sigma,
NMDA and GABA receptors have also been shown suggesting
additional but less likely 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, although other constituents such as
hypericin, pseudohypericin, flavonoids, xanthones and oligomeric
procyanidines may also play a direct or indirect role. While
hypericum may have a complex but unique pharmacology, the
most potent of its actions are on reuptake inhibition of serotonin,
dopamine, noradrenaline, GABA and glutamate, and thus may be
considered a non-selective reuptake inhibitor.
Acknowledgements
I would like to thank Blackmore’s Ltd. for granting me a travel
scholarship to attend the meeting in Germany, on the
‘Pharmacology of St John’s Wort (Hypericum perforatum L.) and
its constituents’.
Address for correspondence
Brain Sciences Institute
Swinburne University of Technology
400 Burwood Road
Hawthorn 3122, Victoria
Australia
Email: pnathan@bsi.swin.edu.au
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