Phytomedicine 10: 688699, 2003 Urban & Fischer Verlag http://www.urbanfischer.

de/journals/phytomed

Phytomedicine

REVIEW

A review of clinical and experimental observations about antidepressant actions and side effects produced by Hypericum perforatum extracts
J. F. Rodrguez-Landa and C. M. Contreras
Laboratorio de Neurofarmacologa, Instituto de Neuroetologa, Universidad Veracruzana and Instituto de Investigaciones Biomdicas, Universidad Nacional Autnoma de Mxico, Xalapa, Veracruz, Mxico

Summary
Hypericum perforatum is an herbaceous perennial plant, also known as St. Johns wort, used popularly as a natural antidepressant. Although some clinical and experimental studies suggest it has some properties similar to conventional antidepressants, the proposed mechanism of action seems to be multiple: a non-selective blockade of the reuptake of serotonin, noradrenaline and dopamine; an increase in density of serotonergic and dopaminergic receptors and an increased affinity for GABAergic receptors; moreover, the inhibition of monoaminoxidase enzyme activity has been involved. In any case, the increase of monoamine concentrations in the synaptic cleft resembles several actions exerted by clinically effective antidepressants. In the present article, we review some of the controversial evidence derived from clinical and experimental studies suggesting that H. perforatum exerts antidepressant-like actions, and we also review some of its side effects, such as nausea, rash, fatigue, restlessness, photosensitivity, acute neuropathy, and even episodes of mania and serotonergic syndrome when administered simultaneously with other antidepressant drugs. All of the foregoing suggests that H. perforatum extracts appear to exert potentially significant pharmacological activity involving several neurotransmission systems supposed to be involved in the pathophysiology of depression. However, little information regarding the safety of H. perforatum is available, including potential herb-drug interactions. There is a need for additional research on the pharmacological and biochemical activity of H. perforatum, as well as its side-effects and its several bioactive constituents to further elucidate the mechanisms of antidepressant actions. Key words: antidepressants, depression, hypericin, hyperforin, Hypericum perforatum, medicinal plants, pseudohypericin, side-effects, St. Johns wort

Introduction
The pharmacotherapy of depression includes tricyclic antidepressants (i.e. clomipramine, imipramine and desipramine), monoaminoxidase inhibitors (i.e. moclobemide, tranilcipromine and fenelcine), and the so-called selective serotonin reuptake inhibitors (i.e fluoxetine, fluvoxamine and paroxetine), among others (Baldessarini, 1985; Majeroni and Hess, 1998). Though efficacious for the treatment of depression, these antidepres0944-7113/03/10/08-688 $ 15.00/0

A review of clinical and experimental observations sant drugs frequently produce side-effects; for instance, dry mouth, mydriasis, constipation, sleepness, temporary fatigue, restlessness and headaches (Dziukas and Vohra, 1991). Although the new synthesized antidepressants (e.g., fluoxetine) produce relatively few side-effects, they are expensive, which creates a need for research directed toward finding alternative solutions for the adequate management of depressive disorders. Such an approach to this problem may be found in natural medicine, which has played a crucial role in keeping people with a low economic status healthy since ancient times (Arnold and Gulumian, 1984; Zolla, 1980). There exists a wide variety of plants popularly reputed to have medicinal properties, those that affect the central nervous system being the best-known (Oliver-Bever, 1983). Phytotherapy based on H. perforatum extracts is employed commonly and widely for the treatment of mild forms of depression, in different countries around the world (Nangia et al. 2000; Greeson et al. 2001). Given the lower cost of phytomedicines, they may play an important role in the management of depressive patients who cannot afford conventional antidepressants or who cannot tolerate the side effects produced by them (Gaster and Holroyd, 2000). Through phytochemical analysis, the stems, leaves and flowers of H. perforatum have been found to contain bioactive substances identified as hypericin and hyperforin. In this article, we review some of the data obtained from clinical and experimental research on the pharmacological actions of H. perforatum extracts, which have been indicated as an alternative treatment in the management of depression. However, in view of some confusing data about its mechanism of action, and well-documented observations of its multiple side-effects, more studies are required before a stronger recommendation can be made.

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Phytochemistry of Hypericum perforatum

The phytochemical analysis of H. perforatum aerial parts has revealed the presence of a diversity of substances with biological activity. Phenylpropanes, flavonoids, proanthocyanidins, xanthones, phloroglucinols, some amino acids, essential oils, procyanidin B2 and the naphthodianthrones are some of the identified compounds contained in H. perforatum (Butterweck et al. 1998; Nahrstedt and Butterweck, 1997). Hypericin (Fig. 1a) and pseudohypericin (Fig. 1b) are two naphthodianthrones identified by means of highperformance liquid chromatography coupled to mass spectrometry in extracts from dried flowers of H. perforatum (Piperopoulus et al. 1997). It has been proposed that these two compounds, together with hyperforin (Fig. 1c), exert pharmacological actions resembling those of synthetic antidepressants (Butterweck et al. 1997; Chatterjee et al. 1998a, b). The H. perforatum extract most often used is known as LI 160; it contains 0.3% hypericin and exerts antidepressant-like actions, both clinically and experimentally (Butterweck et al. 1997; Vorbach et al. 1997). In fact, it has been reported that depressed patients receiving WS 5572 and WS 5573 extracts, which contain 5% and 0.5% hypericin, respectively, showed lower scores on the Hamilton Depression Scale in a randomized, double-blind, placebocontrolled, multicenter study (Laakmann et al. 1998).

Behavioral animal studies

Some antidepressant-like actions of H. perforatum extracts have been identified from animal experiments (Table 1). Stress is considered as one of the factors fre-

Fig. 1. Chemical structure of hypericin (a), pseudohypericin (b), and hyperforin (c). This bioactive substance from H. perforatum produces antidepressant-like actions, both clinically and experimentally.

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J. F. Rodrguez-Landa and C. M. Contreras and fluvoxamine) typically increase the swimming efforts of the animal seeking a solution to the problem (Porsolt et al. 1977, 1978). Some examples of these drug groups are: tricyclic antidepressants, serotonin 5HT1A receptor agonists and selective serotonin reuptake inhibitors, among others (Porsolt et al. 1977, 1978; Borsini et al. 1989; Kostowski et al. 1992; Redrobe et al. 1996; Detke et al. 1997; Snchez and Meier, 1997; Rodrguez-Landa and Contreras, 2000; Contreras et al. 2001). Some extracts from the aerial parts of H. perforatum significantly reduce immobility in rats forced to swim (Butterweck et al. 1997), to a level lower than that produced by imipramine or fluoxetine (De Vry et al. 1999); of these extracts, the one known as LI 160 also produces anxiolytic-like effects in a specific subset of defensive behaviors, particularly those related to generalized anxiety, such as in the elevated T-maze (Flausino et al. 2002). The extract known as IIIc also reduces immobility in rats forced to swim, an effect blocked by the previous administration of sulpiride, a dopaminergic antagonist (Butterweck et al. 1998). Interestingly, the anti-immobility effect of desipramine can likewise be canceled by sulpiride systemically or locally administered in the nucleus accumbens of the rat (Cervo and Samanin, 1987); thus, common sites of action may be supposed. It has also recent-

quently related to the depressive disorder (Akil and Morano, 1995). Animals, mainly rats or mice, submitted to inescapable stressful situations for long periods, develop a behavioral deficit in paradigms of learning and escape (De Montis et al. 1995), as well as signs interpreted as anhedonia, e.g., a lower consumption of sweet water, less attention to cleanliness and lowered sexual activity, among others (Ghiglieri et al. 1997). This is relevant since anhedonia is one of the main symptoms of depression (American Psychiatric Association, 1994). Stress-induced changes in behavior may be reduced by chronic treatment with clinically effective antidepressants such as imipramine and fluoxetine (Gambarana et al. 1995, 1999b). In the same way, the hydro-alcoholic extract of H. perforatum blocks the stress-induced effect in rats, i.e., they do not develop the behavioral deficit but maintain their capability for obtaining positive reinforcement (Gambarana et al. 1999a). In the forced swimming test, an experimental model for testing the efficacy of antidepressant drugs, the animal develops a learned helplessness syndrome characterized by a lowered motivation for escaping, as evidenced by increased periods of immobility (Porsolt et al. 1977). Clinically effective antidepressants (i.e. clomipramine, imipramine, desipramine, fluoxetine

Table 1. Similarity between the pharmacological actions of H. perforatum and those produced by some synthetic antidepressants. Hypericum extracts LI 160 and IIIc extracts reduce immobility in rats forced to swim (Butterweck et al. 1997,1998). The anti-immobility effect of the IIIc extract in rats forced to swim was antagonized by the dopamine antagonist sulpiride (Butterweck et al. 1998). A crude H. perforatum extract inhibits the activity of monoaminoxidase enzymes, types A and B (Cott, 1997). Synthetic antidepressants Desipramine, imipramine, buspirone and fluoxetine decrease immobility in rats forced to swim (Kostowski et al. 1992; Porsolt et al. 1977; Snchez and Meier, 1997). Bilateral injection into the nucleus accumbens of the rat blocks the decrease in immobility produced by the tricyclic antidepressant desipramine (Cervo and Samanin, 1987). Some antidepressants such as moclobemide, cimoxatone and brofaromine are monoaminoxidase inhibitors, type A (Baldessarini, 1985).

Serotonin and noradrenaline reuptake in the brain of the Desipramine and imipramine inhibit noradrenaline reuptake, rat is inhibited by the LI 160 extract and purified hyperforin, and fluoxetine is a selective serotonin reuptake inhibitor respectively (Mller et al. 1997; Singer et al. 1999). (Baldessarini, 1985). The extract LI 160 increases the extracellular concentrations of serotonin in the cerebral cortex of the rat (Calapai et al. 1999). The hydro-alcoholic extract of H. perforatum reverts the behavioral deficit and the anhedonia in rats provoked by unavoidable stress (Gambarana et al. 1999a). Pharmacological actions of H. perforatum extracts are greater after repeated treatment (Mller et al. 1997; Teufel-Mayer and Gleitz, 1997). Fluoxetine increases the availability of extracellular serotonin in the cerebral cortex of the rat (Calapai et al. 1999). Imipramine and fluoxetine revert the behavioral deficit provoked by inescapable stress in rats (Gambarana, et al. 1995, 1999b). Therapeutic actions of antidepressant drugs may be attributed to the biological effects induced by long-term treatment, from two to three weeks (Baldessarini, 1985; Contreras et al. 1990b).

A review of clinical and experimental observations ly been found that other extracts derived from H. perforatum containing flavonoids reduce immobility in the forced swim test, resembling the action of imipramine (Butterweck et al. 2000). In another case, the 4.5% extract of H. perforatum reduced the immobility of rats forced to swim, yielding dose-response plasma concentrations of hyperforin (Cervo et al. 2002). In a recent study some ethanolic and methanolic H. perforatrum extracts were investigated in the forced swimming test and, in almost all cases, the extracts produced strong antidepressant activity. However, one methano-

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lic extract had no effect and HPLC analysis illustrated a reduced concentration of the diglycoside flavonoid rutin, therefore suggesting that the antidepressant activity of these extracts is related to the rutin contained in the plant (Noldner and Schotz, 2002). To summarize, some H. perforatum extracts reduced immobility in the forced swim test in a manner similar to clinically effective antidepressant drugs such as fluoxetine, paroxetine, sertraline, imipramine, desipramine, maproptiline, buspirone, mianserine and imprindole, among others (Table 2).

Table 2. Immobility reduction in rats forced to swim and treated with H. perforatum extracts and some clinically effective antidepressants. Drugs Hypericum perforatum extracts Hypericin Total extract Fraction II of total extract Fraction IIIc of total extract ZE 117 extract LI 160 extract Serotonin selective uptake inhibitor Fluoxetine Fluoxetine Fluoxetine Paroxetine Sertraline Tricyclic antidepressants Imipramine Imipramine Desipramine Desipramine Noradrenaline uptake inhibitors Maprotiline Maprotiline Dopamine uptake inhibitors Nomifensine Dopaminergic drugs Bupropion 5-HT Agonists Buspirone Gepirone GABAergic drugs Muscimol Atipical antidepressant Mianserine Mianserine Iprindole Treatment form 1 1 2 2 2 2 3 2 4 2 2 2 2 2 3 2 2 2 1 1 2 2 2 2 2 Dosage Variable evaluated a a a a a a b a a b b a a a b a b a a c b a a a a Immobility reduction* 35% 57% 59% 64% 41% 32% 33% 57% 59% 40% 52% 50% 38% 34% 36% 58% 51% 46% 57% 12% 20% 51% 39% 33% 36% Reference

0.23 mg/kg 500 mg/kg 23.6 mg/kg 1.25 mg/kg 20 mg/kg 20 mg/kg 5 mg/kg 10 mg/kg 1 mg/kg 20 mg/kg 20 mg/kg 30 mg/kg 15 mg/kg 15 mg/kg 5 mg/kg 30 mg/kg 20 mg/kg 5 mg/kg 20 mg/kg 0.06 mg/kg 20 mg/kg 2 mg/kg 15 mg/kg 15 mg/kg 40 mg/kg

Butterweck et al. 1998 Butterweck et al. 1997 Butterweck et al. 1997 Butterweck et al. 1997 De Vry et al. 1999 De Vry et al. 1999 Detke et al. 1997 De Vry et al. 1999 Contreras et al. 2001 Detke et al. 1995 Detke et al. 1995 De Vry et al. 1999 Borsini et al. 1989 Borsini et al. 1989 Detke et al. 1997 Borsini et al. 1989 Detke et al. 1995 Borsini et al. 1989 Butterweck et al. 1998 Kostowski et al. 1992 Detke et al. 1995 Borsini et al. 1989 Borsini et al. 1989 Porsolt et al. 1977 Porsolt et al. 1977

* Immobility reduction is an approximate value. 1 Single doses; 2 24, 5 and 1 h before swimming test; 3 14-day treatment; 4 21-day treatment; a Total time of immobility; b Counts of immobility; c Active behaviors (swimming).

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J. F. Rodrguez-Landa and C. M. Contreras Matteo et al. 2000), similarly to the tricyclic antidepressant desipramine (See et al. 1992). In addition, a hyperforin-rich extract equally inhibited the sodiumdependent uptake of the monoamine neurotransmitters serotonin, dopamine and norepinephrine in rat brain synaptosomes. Hyperforin inhibited uptake of those monoamines noncompetitively, in marked contrast to the competitive inhibition exerted by fluoxetine or desipramine on the reuptake of these monoamines (Roz et al. 2002). Similarly, hyperforin non-competitively inhibited the uptake of serotonin, dopamine and norepinephrine tritiated in rat brain synaptic vesicles. These data support the assumption that hyperforin interferes with the storage of monoamines in synaptic vesicles, rather than behaving as a selective inhibitor of either synaptic membrane or vesicular monoamine transporters (Roz et al. 2002). The actions of H. perforatum may be attributed to the augmented availability of monoamines in the synaptic cleft, probably resulting from the reuptake inhibition of these neurotransmitters (Mller et al. 1997). Thus, serotonin reuptake is also reduced by H. perforatum extracts containing hyperforin, in a manner similar to those pharmacological actions produced by conventional antidepressants, including tricyclics, mono-aminoxidase inhibitors and selective serotonin reuptake inhibitors (Chatterjee et al. 1998a, 1998b; Singer et al. 1999). In any case, this multiplicity of actions may represent a danger, given that the imprudence in prescribing a certain combination of antidepressants has been widely recognized (Majeroni and Hess, 1998). For instance, in a case in which one drug acting through the inhibition of monoaminoxidase is combined with another, producing an increased availability of neurotransmitters at the synaptic cleft, the result may be fatal (Kline et al. 1989). It should be pointed out that the functional changes in the neuronal membrane receptors related to the administration of different H. perforatum extracts exert their maximum effect after 15 days of treatment (Mller et al. 1997; Teufel-Mayer and Gleitz, 1997). This phenomenon is in accordance with clinical and experimental experience and suggests that repeated treatment is required for the full development of antidepressive effects (Baldessarini, 1985; Bonhomme and Esposito, 1998; Contreras et al. 1993; Contreras et al. 1990a; Detke et al. 1997). It seems that some processes of neuronal plasticity are involved in the effects of H. perforatum extracts; this also happens clinically and experimentally under treatment with antidepressants available for the pharmacological therapy of depression, such as clomipramine, desmetilimipramine and fluoxetine, among others (Contreras et al. 1990b; Duman et al. 1997).

Neurochemical animal studies

H. perforatum constituents exert multiple actions on the membrane receptors and on enzymatic neuronal processes. Many of these constituents have been shown to bind neuroreceptors in the brain and to inhibit the uptake of various neurotransmitters thought to be involved in depression. For instance, a crude extract of H. perforatum has a high affinity for GABAA and GABAB receptors, as well as for the benzodiazepine receptors, and inhibits the catecholamine-degrading enzymes, monoaminoxidase A and B (Cott, 1997), leading to an increased availability of these neurotransmitters at the synaptic cleft. Nevertheless, purified hypericin had affinity only for the NMDA receptors (Cott, 1997). Other constituents of H. perforatum, such as procyanidin B2, are essential for hypericin to exert its anti-immobility actions in the rats forced to swim (Butterweck et al. 1998). The LI 160 extract inhibits both serotonin and noradrenaline uptake (Perovic and Mller, 1995; Mller et al. 1997) in a dose-dependent manner (Neary and Bu, 1999). At the same time, it inhibits dopamine reuptake and the activity of enzyme monoaminoxidase (Mller et al. 1997), although several studies have shown that the relative inhibitory potential of H. perforatum extracts on monoaminoxidase is very low (Thiede and Walper, 1994; Mller et al. 1997; Bladt and Wagner, 2000). In addition, long-term treatment with LI 160 extract increases the density of both 5-HT1A and 5-HT2A receptors in the brain of the rat by 50% as compared to the control group, whereas the affinity of both serotonergic receptors remains unaltered (Teufel-Mayer and Gleitz, 1997). Subchronic treatment with said extract led to a significant decrease in -adrenergic receptors and to a significantly enhanced activity of 5-HT2A receptors in the prefrontal cortex of the rat (Mller et al. 1997). Furthermore, the administration of LI 160 and Ph50 (containing 0.3% hypericin and 50% flavonoids) extracts increases the serotonin extracellular concentrations in the cerebral cortex of the rat in a manner similar to that produced by the antidepressant fluoxetine (Calapai et al. 1999). However, the described actions of H. perforatum extracts are confusing and multiple. Both the LI 160 and the Ph-50 extracts increased noradrenaline, serotonin and dopamine content in the diencephalon (Calapai et al. 1999). Hyperforin, another constituent of H. perforatum increased the extracellular concentrations of dopamine, noradrenaline, serotonin and glutamate in the locus coeruleus (Kaehler et al. 1999); and the hydro-ethanolic extract of H. perforatum stimulated in vitro the liberation of dopamine in the nucleus accumbens (Di

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Human studies
Some clinical studies (Table 3) have evaluated the effects of H. perforatum extracts and compared them with antidepressant drugs such as maprotiline, imipramine, sertraline, and fluoxetine (Harrer et al. 1994; Vorbach et al. 1997; Brenner et al. 2000; Schrader, 2000; Volz and Laux, 2000; Schulz, 2002). In mild to moderately depressed patients diagnosed according to DSM-III-R criteria, the administration of the LI 160 extract significantly reduced the total score on the Hamilton Depression Scale (from 20.2 before treatment to 8.8 points after 6 weeks of administration). This reduction was similar to that produced in imipramine-treated patients (from 19.4 before treatment to 10.7 after the administration of the tricyclic), but with fewer side-effects, as compared with those of the imipramine group (Vorbach et al. 1994, 1997). Positive results were also found in another randomized, double-blind, multicenter study in which an H. perforatum extract, ZE 117 (250 mg twice daily for six weeks), produced the same therapeutic effects as imipramine (75 mg twice daily for six weeks) in treating mild to moderate depression, and patients tolerated this extract better (Woelk, 2000). Similarly, in a double-blind, randomized 12-week trial including eightyseven men and women with major depression, sertraline (50 to 100 mg/d) and H. perforatum (900 to 1800 mg/d) produced similar antidepressant actions, but significantly more side-effects were reported in the sertraline group than in the H. perforatum group; hence the authors concluded that the more benign side-effects of H. perforatum make it a good first choice for this pa-

tient population (van Gurp et al. 2002). These data agree with those from other studies in which patients diagnosed as depressive and treated with H. perforatum extracts reduced the total score on the Hamilton Depression Scale by more than 40%, with better therapeutic effects than those obtained with placebo treatment (Lenoir et al. 1999; Linde et al. 1996). However, a recent study comparing the efficacy of a standardized extract of H. perforatum with placebo in outpatients with major depression showed the extract to be ineffective in reducing depressive symptoms (Shelton et al. 2001). In another randomized, double-blind, placebo-controlled multicenter study on depressed patients, the WS 5573 and WS 5572 extracts of H. perforatum (which contain hyperforin), administered consecutively during 42 days, diminished the total score on the Hamilton Depression Scale by about 50% versus day zero of the treatment and the placebo group (Laakmann et al. 1998). The greatest antidepressant effect was observed with the extract WS 5572, which contains a higher concentration of hyperforin, suggesting that the efficacy of this H. perforatum extract depends on its hyperforin content (Laakmann et al. 1998). Additionally, in a double-blind, placebo-controlled trial, an H. perforartum extract identified as WS 5570, administered to male and female adult outpatients with mild to moderate major depression, produced a greater reduction in the total score on the Hamilton Depression Scale and significantly more responsive patients as compared to the placebo group; thus it may be concluded that the WS 5570 extract is safe and more effective than placebo for the treatment of mild to moderate depression (Lecrubier et al. 2002).

Table 3. Clinical effects of some derivatives of H. perforatum. H. perforatum derivate LI 160 Effects The administration of this extract to depressed patients for six weeks reduces the symptoms of depression according to the Hamilton Depression Scale; apparently it is more effective and produces fewer and milder side-effects as compared to the tricyclic antidepressant imipramine (Vorbach et al. 1994, 1997). In depressed patients it diminishes the symptoms of depression in comparison with those patients receiving only the placebo treatment (Laakmann et al. 1998). It eliminates symptoms of depression and its effects are greater as compared to those produced by the extract WS 5573 (Laakmann et al. 1998). In depressed patients, different doses of preparations containing hypericin reduce the point value on Hamilton Depression Scale by about 50% versus day zero of treatment and the placebo group (Lenoir et al. 1999). The administration of these extracts increases plasmatic concentrations of the growth hormone and decreases prolactin levels in healthy male volunteers, suggesting that the dopamine system may be involved in the antidepressant-like actions of these extracts (Franklin et al. 1999).

WS 5573 WS 5572 Hyperiforce

Jarsin 300

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J. F. Rodrguez-Landa and C. M. Contreras tations; allergic reactions; tiredness and restlessness are beginning to emerge (Woelk et al. 1994); photosensitivity, which produces changes in skin pigmentation (Brockmoller et al. 1997), and serotonergic syndrome, when administered together with paroxetine (Gordon, 1998) or in patients sensitive to compounds of H. perforatum extracts (Parker et al. 2001). Isolated cases of mania associated with the administration of H. perforatum extracts have been reported (Nierenberg et al. 1999). This effect seems to depend on the age of the patients, since those who developed mania episodes ranged between 53 and 70 years old (Moses and Mallinger, 2000). Nonetheless, a 35-yearold woman treated with H. perforatum during four weeks developed an acute neuropathy upon being exposed to sunlight. A diagnosis of subacute toxic neuropathy associated with demyelination of cutaneous axons was obtained (Bove, 1998). Therefore, the H. perforatum extract was withdrawn and the symptoms began to improve after 3 weeks, gradually disappearing over the next two months. These same symptoms of acute neuropathy have also been observed to develop in some patients treated with Perazine (a phenotiazine antipsychotic drug), in whom a process of demyelination of the nerve fibers was confirmed (Roelcke et al. 1992). Hypericin has been shown to exert phototoxic actions (Vandenbogaerde et al. 1998; Bernd et al. 1999; Jacobson et al. 2001), cytotoxic effects and to produce free radicals when exposed to light (Duran and Song, 1986), which in turn damage the myelin covering on

On the other hand, the administration of the LI 160 extract (Jarsin 300 ) to healthy male volunteers increased the plasmatic concentrations of the growth hormone and reduced the concentrations of prolactin. These findings suggest that the dopamine system is involved in the pharmacological actions of this H. perforatum extract (Franklin et al. 1999); as has also been shown in studies using rats (Butterweck et al. 1998; Di Matteo et al. 2000), suggesting similarity of actions with tricyclics as such as desipramine (Cervo and Samanin 1987). Nevertheless, there is still a need for additional studies in order to test different doses of the extracts from H. perforatum in well-defined groups of patients. The aim should be the full identification of the antidepressant potential attributed to this plant, as well as any side-effects that might be associated with its administration.

Side effects associated with H. perforatum administration

Clinical studies claim that H. perforatum extracts exert antidepressant actions in depressed patients (Vorbach et al. 1994, 1997; Kim et al. 1999; van Gurp et al. 2002), with few side-effects (Sommer and Harrer, 1994; Hansgen et al. 1994; Vorbach et al. 1994,1997; Lecrubier et al. 2002). However, as the use of H. perforatum extracts is increasing, more side-effects are being reported (Table 4), such as: gastrointestinal irri-

Table 4. Some side-effects associated with H. perforatum extracts treatment. Side effects Photosensitivity that provokes changes in skin pigmentation when it is exposed to sun. Serotonergic syndrome when administered simultaneously with paroxetine, a selective serotonin reuptake inhibitor, or in sensitive patients. Mania episodes associated with the administration of the total extract of H. perforatum to patients more than 50 years old. Acute neuropathy after exposure to sun in a patient treated with the extract of H. perforatum; her symptoms suggest demyelination of axons as reported by patients after sun exposure and being treated with perazine (an antipsychotic drug), in which neural biopsies confirmed demyelination and axonal degeneration. Hepatic cytochrome P450 pathway activation, producing significantly decreased plasma concentrations of some drugs and reducing their therapeutic actions. Reference Brockmoller et al. 1997 Gordon, 1998 Parker et al. 2001 Moses and Mallinger, 2000 Nierenberg et al. 1999 Bove, 1998

Ernst, 1999 Piscitelli et al. 2000 Mai et al. 2000 Ruschitzka et al. 2000 Karliova et al. 2000 Henney, 2000 Schey et al. 2000

In the presence of light, hypericine can induce changes in lens protein from calves that could lead to the formation of cataracts.

A review of clinical and experimental observations nerve fibers (Bongarzone et al. 1995). It has also been reported that hypericin produces singlet oxygen and other excited-state intermediates, which indicates that it must be very phototoxic to the eye. Since it absorbs UV radiation, it could damage lens and retina. Therefore, in the presence of light, hypericin is capable of inducing changes in lens protein that could lead to the formation of cataracts, as has been found to occur in calves (Schey et al. 2000). There is evidence that H. perforatum extracts activate the hepatic cytochrome P450 pathway, roughly doubling its metabolic activity (Ernst, 1999); consequently, significantly decreased plasma concentrations of some drugs have been found in patients treated with H. perforatum extracts (Bilia et al. 2002). Since many drugs used to treat heart disease, depression, seizures, cancer, or to prevent transplant rejection or pregnancy are metabolized through the cytochrome P450 pathway, special care should be taken regarding this potential drug interaction. For instance, the co-administration of LI 160 extract of H. perforatum with amitriptyline led to a significant decrease in the area under the plasma concentration-time curve of 22% in a group receiving various doses of amitriptyline, and of 41% in one receiving nortriptyline, as well as of all hydroxylated metabolites, probably through the induction of cytochrome P450 enzymes or drug transporters (Johne et al. 2002). Furthermore, H. perforatum extracts decreased the area under the curve of Indinavir plasma concentration (a protease inhibitor used for HIV infection) by about 57% (SD19) and decreased the extrapolated 8-h Indinavir by 81% (16) in healthy volunteers (Piscitelli et al. 2000). A reduction of this magnitude in Indinavir exposure could lead to the development of drug resistance and treatment failure (Piscitelli et al. 2000). It is also known that H. perforatum extracts may cause a sudden decrease of cyclosporine concentration (Mai et al. 2000) and a drop in plasma levels of cyclosporine after heart or liver transplantation (Ruschitzka et al. 2000; Karliova et al. 2000), probably a metabolic activation induced by the cytochrome P450, which may also significantly decrease blood concentrations of other drugs for HIV treatment, such as Amprenavir, Nelfinavir, Saquinavir and Ritonavir (Henney, 2000). Consequently, the concomitant use of H. perforatum extracts and the above-mentioned drugs is not recommended because it may result in suboptimal antiretroviral drug concentrations, leading to loss of virology response, and development of resistance and/or cross-resistance (Henney, 2000). So, even if the safety of the plant has been established, physicians should be aware that H. perforatum administration might interact significantly with other prescribed drugs (Bilia et al. 2002; Johne et al. 2002). The foregoing data lead us to question whether H. perforatum is really a safe antidepressant alternative

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and whether its side-effects are as scarce as reported in some studies. They also point up the need for continued pharmacological and toxicological research on the extracts of H. perforatum, so that their therapeutic actions and the side-effects associated with them can be identified thoroughly.

Comments
The use of medicinal plants is considered an alternative for the treatment of diverse illnesses; it is also a therapeutic option and a source of information for developing new and potent phytomedicine, as in the case of H. perforatum. Nevertheless, this kind of alternative should be thoroughly screened and tested before being made available, in order to avoid the incidental discovery of side-effects that might endanger health. One problem that arises from the use of plant extracts for therapy is the variation in the concentrations of their active principles, which depend on the biological development of the plant, the part employed, the season of harvest and the place of origin. All these data must be taken into account in a systematic study of the therapeutic actions attributed to H. perforatum and to other plant extracts if we are to discover safe and effective alternatives for treating illnesses. Evidently, H. perforatum extracts interact with diverse neurotransmission and neuroendocrine systems in the organism; this constitutes a real challenge in which it is necessary to determine how each system participates in the pharmacological actions, to discern among therapeutic effects and the side-effects that might occur during long-term administration of H. perforatum extracts. Although clinical studies indicate that H. perforatum extracts exert therapeutic actions similar to those of antidepressants, and produce neither physical nor psychological dependence, it is important to carry out more detailed studies so that the side-effects associated with the prolonged administration of these plant extracts may be identified. Likewise, it is necessary to identify their pharmacological interactions with other treatments, in order to evaluate the tolerability of their active principles and to determine with what degree of safety these extracts can be administered to different groups of patients.

Conclusion
There are substantial data about the antidepressant actions of H. perforatum extracts suggesting that they are safe, well-tolerated and probably more effective than placebo; however, it is necessary to carry out further studies so that the side-effects associated with the ad-

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and sertraline in the treatment of depression: a doubleblind, randomized pilot study. Clin Ther 22: 411419 Brockmoller J, Reum T, Bauer S, Kerb R, Hubner WD, Roots I (1997) Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 30: 94101 Butterweck V, Jrgenliemk G, Nahrstedt A, Winterhoff H, (2000) Flavonoids from Hypericum perforatum show antidepressant activity in the forced swimming test. Planta Med 66: 36 Butterweck V, Petereit F, Winterhoff H, Nahrstedt A (1998) Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming test. Planta Med 64: 291294 Butterweck V, Wall A, Lieflander-Wulf U, Winterhoff H, Nahrstedt A (1997) Effects of the total extract and fractions of Hypericum perforatum in animal assays for antidepressant activity. Pharmacopsychiatry 30: 117124 Calapai G, Crupi A, Firenzuoli F, Costantino G, Inferrera G, Campo GM, Caputi AP (1999) Effects of Hypericum perforatum on levels of 5-hydroxytryptamine, noradrenaline and dopamine in the cortex, diencephalon and brainstem of the rat. J Pharm Pharmacol 51: 723728 Cervo L, Rozio M, Ekalle-Soppo CB, Guiso G, Morazzoni P, Caccia S (2002) Role of hyperforin in the antidepressantlike activity of Hypericum perforatum extracts. Psychopharmacology (Berl) 164: 423428 Cervo L, Samanin R (1987) Evidence that dopamine mechanisms in the nucleus accumbens are selectively involved in the effect of desipramine in the forced swimming test. Neuropharmacology 26: 14691472 Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Mller WE (1998b) Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci 63: 499510 Chatterjee SS, Noldner M, Koch E, Erdelmeier C (1998a) Antidepressant activity of Hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry 31: 715 Contreras CM, Marvn ML, Alcal-Herrera V (1993) Sleep deprivation is a less potent agent than clomipramine in increasing firing rate in lateral septal neurons in the rat. Neuropsychobiology 27: 8385 Contreras CM, Marvn ML, Alcal-Herrera V, GuzmnSenz MA (1990b) Chronic clomipramine increases firing rate in lateral septal nuclei of the rat. Physiol Behav 48: 551554 Contreras CM, Marvn ML, Mrquez-Flores C, Chacn L, Guzmn-Senz MA, Barradas A, Lara H (1990a) La plasticidad del sistema nervioso central y el mecanismo de accin de las terapias antidepresivas. Salud Mental 13: 3948 Contreras CM, Rodrguez-Landa JF, Gutirrez-Garca AG, Bernal-Morales B (2001) The lowest effective dose of fluoxetine in the forced swim test significantly affects the firing rate of lateral septal nucleus neurons in the rat. J Psychopharmacol 15: 231236

ministration of these plant extracts may be either identified or dismissed. Only then will it be possible to consider H. perforatum as a definitely safe and efficacious alternative for treating mild to moderate major depression and to remove the present barrier to recommending its use for treatment.
Acknowledgments

The authors wish to thank Warren Haid and Irene Marquina for revising the manuscript. During this investigation JFR-L received fellowships from the Consejo Nacional de Ciencia y Tecnologa (CONACyT, Mxico), Reg. 124885; and partial fellowships from the Direccin General de Estudios de Posgrado de la Universidad Nacional Autnoma de Mxico (DGEP-UNAM).

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Carlos M. Contreras, POB 320, Xalapa 91 000, Veracruz, Mxico Tel./Fax: ++52-228 8-13-51-57; e-mail: ccontreras@uv.mx