St John’s wort: Background. Actions

2010

Common Name

St John’s wort

Other Names

Amber, balsana, devil’s scourge, goatweed, hardhay, hartheu, herb de millepertuis, hierba de San Juan, hypericum, iperico, johanniskraut, klamath weed, konradskraut, millepertuis, rosin rose, sonnenwendkraut, St Jan’s kraut, tipton weed, witch’s herb

Botanical Name / Family

Hypericum perforatum (family Clusiaceae or Guttiferae)

Plant Parts Used

Aerial parts, flowering tops

Historical Note

St John’s wort has been used medicinally since ancient Greektimes when, it is believed, Dioscorides and Hippocrates used it to rid the body of evil spirits. Since the time of the Swiss physician Paracelsus (c. 1493-1541), it has been used to treat neuralgia, anxiety, neurosis and depression. Externally, it has also been used to treat wounds, bruises and shingles. The name ‘St John’s wort‘ is related to its yellow flowers, traditionally gathered for the feast of St John the Baptist and the term ‘wort’ is the old English word for plant. St John’s wort has enjoyed its greatest popularity in Europe and comprises 25% of all antidepressant prescriptions in Germany. In the past few decades its popularity has also grown in countries such as Australia and the United States.

Chemical Components

Naphthodianthrones (including hypericin and pseudohypericin). Flavonoids, mostly hyperoside, rutin, quercetin, isoquercitrin, quercetin and kaemferol, phenolics including hyperforin, procyanidins, essential oil, sterols (beta-sitosterol), vitamins C and A, xanthones and choline.

Manufactured products will vary in the concentrations and proportions of the different plant constituents present because these are influenced by the plant’s place of origin, its harvest time and drying, extraction processes and storage conditions. Hyperforin, in particular, can be present in variable concentrations because it is unstable in light, air and most organic solvents. This is extremely important to remember when comparing studies, as variations in chemical composition could be responsible for differences in results. It also provides a rationale for lack of interchangeability between brands.

Clinical note — Pharmacologically important constituents

It has generally been considered that most of the pharmacological activities of St John’s wort are attributable to hypericin and the flavonoid constituent, hyperforin. Besides contributing to the antidepressant activity, hypericin is the primary constituent responsible for the photosensitivity reactions reported with high intakes. Hyperforin is also a major contributor to the herb’s antidepressant activity and considered the main constituent responsible for inducing the cytochrome P-glycoprotein and thereby producing drug interactions. Besides this, it demonstrates many other pharmacological effects such as antibacterial, anti-inflammatory and antineoplastic activities. Components previously considered void of activity have also been identified as important for pharmacological activity. For example, both procyanidin B2 and hyperoside increase the oral bioavailability of hypericin by 58% and 34%, respectively, and therefore, its clinical effects. A report published in June 2003 demonstrated that an extract devoid of both hyperforin and hypericin still exhibited antidepressant activity. Other constituents with antidepressant activity were identified and include hyperoside, isoquercitrin and miquelianin, and the 3-O-galactoside, 3-O-glucoside and 3-O-glucuronide of quercetin.

St John’s wort: Main Actions

Due to the combined effect of several active constituent groups, St John’s wort has many pharmacological actions.

ANTIDEPRESSANT

Although St John’s wort has been investigated extensively in scientific studies, there are still many questions about its pharmacology and mechanisms of action.

Collectively, the data show that St John’s wort extract exerts significant pharmacological activity within several neurochemical systems believed to be implicated in the pathophysiology of depression.

Inhibits synaptic reuptake of several neurotransmitters

Preclinical animal studies have found that St John’s wort inhibits the synaptic reuptake system for serotonin, noradrenaline and dopamine. Studies using specific isolated constituents have demonstrated potent uptake inhibition of GABA and L-glutamate in vivo. These effects appear to be non-competitive, dose-dependent and mediated via sodium channels. Studies with hyperforin have shown it acts by reducing the pH gradient across the synaptic vesicle membrane, resulting in diffusion of uncharged monoamines out of the vesicular compartment into the cytoplasm. The increase in cytoplasmic concentration in turn decreases the transmembrane gradient of the neurotransmitters causing an ‘apparent’ inhibition of synaptosomal uptake by hyperforin. This is a novel mechanism of action, which differs from conventional antidepressant drugs.

Although hyperforin is the main constituent responsible for these effects, tests now show that a number of others are also involved, such as adhyperforin, which has demonstrated a strong inhibitory effect on neurotransmitter uptake, and the oligomeric procyanidins fraction, which has demonstrated weak to moderate effects.

GABA receptor binding

St John’s wort extracts have been shown to bind at GABA-A and -B receptors, to inhibit GABA reuptake, to evoke GABA release from synaptosomes and to exert an anxiolytic effect that is blocked by the benzodiazepine antagonist flumazenil.

Upregulation of serotonin receptors

St John’s wort significantly up-regulates both 5-HT1A and 5-HT2A receptors and has a significant affinity for opiate sigma-receptors, which may contribute to the antidepressant effect.

Dopamine beta-hydroxylase inhibition

Studies on isolated constituents showed that hypericin and pseudohypericin can inhibit the enzyme dopamine-beta-hydroxylase in vitro.

Inhibition of catechol-o-methyltransferase

This has been demonstrated in test tube studies.

Suppresses IL-6 synthesis

Various extracts from St John’s wort produce a potent and dose-dependent inhibition of substance-P-induced IL-6 synthesis, which may also contribute to the herb’s overall antidepressant effect.

Monoamine oxidase (MAO) inhibition

Inhibition of MAO by hypericin demonstrated in vitro was believed to be the primary mode of action; however, this has not been confirmed in several subsequent studies that have shown only weak inhibitory activity at doses in excess of usual therapeutic levels.

ANTIRETROVIRAL AND ANTIBACTERIAL

Although in vitro and studies in animal models have identified antiretroviral activity for hypericin and pseudohypericin, two clinical trials could not confirm these effects, even when larger doses of hypericin were administered.

The mechanism involved is not known; however, it is suspected to involve direct inactivation of the virus or prevention of virus shedding, budding or assembly at the cell membrane. The presence of light is an important requirement for antiretroviral activity to be demonstrated as the effect appears to be photoactivated.

Hyperforin has also demonstrated antiviral and antibacterial activity. Hyperforin exhibits effective antibacterial activity against MRSAand other Gram-positive bacteria, but no growth-inhibitory effect on Gram-negative bacteria or Candida albicans.

ANXIOLYTIC

Several in vivo studies confirm theanxiolytic effects of St John’s wort extract. Activity at the GABA receptors and an increase in circulating GABA levels are likely to be involved.

ANTI-INFLAMMATORY AND ANALGESIC

Both in vitro and in vivo testing has identified anti-inflammatory and analgesic activities for St John’s wort. It potently inhibits binding to mu-, delta- and kappa-opioid receptors. In vivo tests also identify modulation of COX-2 expression for hypericum extract. Studies with the isolated constituent hyperforin have shown it potently inhibits COX-1 and 5-lipo-oxygenase in vitro. Quercetin and other flavonoids contribute to the anti-inflammatory effect.

ANTICANCER EFFECTS

Emerging evidence clearly indicates that hypericin is a promising tool in the photodynamic treatment of cancers. St John’s wort appears to selectively photosensitise tumour cells. More recently, evidence suggests that when hyperthermia is combined with this approach, the antitumour effects of hypericin are strengthened. Hyperforin also exhibits antineoplastic potential based on the sum of its anticarcinogenic, antiproliferant, pro-apoptotic, anti-invasive and antimetastasic effects. Hyperforin has been shown to effectively decrease the proliferation rates of a number of mammalian cancer cell lines, induce apoptosis of tumour cells and inhibit angiogenesis both in vitro and in vivo. Besides hypericin and hyperforin, polyphenolic procyanidin B2 has also demonstrated an inhibitory effect on the growth of leukaemia cells, brain glioblastoma cells and normal human astrocytes in vitro. Further, the inhibitory effects on leukaemic cell growth were synergistically strengthened when hypericin and hyperforin were tested together.

Clinical note — Photodynamic therapy for tumour cells

Photodynamic therapy is primarily an experimental treatment designed to destroy tumour cells without damaging surrounding normal tissues. This treatment involves the combination of a photosensitising substance, which is taken up and stored within tumour cells, and then the application of visible light at a wavelength matching the absorption spectrum of the photosensitising substance. This combination approach results in the production of cytotoxic oxygen singlets within the tumour that cause irreversible cellular damage and tumour destruction.

REDUCES ALCOHOL INTAKE

Several reports indicate comorbidity between depression and ethanol abuse and that depressive disorders and ethanol abuse may be associated with similar changes in the activity of central neurotransmitters. In vivo studies using St John’s wort in animal models of alcoholism have found that it does not alter food and water intakes, or the pharmacokinetics of alcohol, but a reduction in ethanol intake occurs.

COGNITIVE EFFECTS

St John’s wort extracts and hyperforin improve cognitive function in experimental models; however, clinical studies have been less convincing. In vivo studies with hyperforin have found it induces release of acetycholine from cholinergic terminals in the hippocampus and striatum, providing an explanation for the observed effects.

St John’s wort: Other Actions

INDUCTION OF CYP3A4 ACTIVITY IN THE INTESTINAL WALL

Human studies have identified CYP3A4 and 2C19 induction effects for standard St John’s wort extracts (e.g. LI 160), but no effects on CYP1A2, CYP2C9 or CYP2D6.

Human studies have failed to identify significant CYP3A4, 2D6, 2C9, 1A2 or2C19 induction for low-hyperforin St John’s wort extracts, such as ZE 117, using the appropriate probe drugs.

Hyperforin is a potent ligand for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the CYP3A4 mono-oxygenase. Although it is considered the chief constituent responsible for the pharmacokinetic interactions reported, there are other, less potent constituents in St John’s wort which also modulate cytochrome enzymes.

Results from an open label clinical study suggest that the effects of standard St John’s wort (LI 150) on CYP3A4 enzymes may be biphasic, where the initial dose leads to a minor inhibition, followed by significant induction during long-term use.

INCREASES LEVELS OF INTESTINAL P-GLYCOPROTEIN

St John’s wort extract produced a 3.8-fold increase of intestinal P-glycoprotein (P-gp) expression in vivo. Hyperforin has been identified as the key constituent responsible for P-gp induction effects, although in vitro tests suggest other less potent constituents also exist such as quercetin, hypericin, biapigenin and kaempferol.

Once again, low hyperforin St John’s wort extracts do not appear to significantly induce P-gp.

In vitro and in vivo tests further indicate that P-gp effects caused by standard St John’s wort (LI 150) are biphasic with an initial inhibitory effect followed by induction after longer exposure.

ANTISPASMODIC

St John’s wort exhibits antispasmodic activity, according to research conducted with an experimental animal model, most likely mediated via GABA activity.