Adaptation to stress

Published animal studies, mostly conducted in the Far East and Eastern Europe, consistently demonstrate the adaptogenic effect of Eleutherococcus under a wide variety of stressful conditions. In his original work with mice, Brekhman found that Eleutherococcus increased stamina by up to 70%.²⁰ Severely stressed rats show enlarged adrenal glands, reduced thymus and spleen size and damage to the gastric mucosa.²¹ Eleutherococcus significantly reduced this adrenal hypertrophy and adrenal ascorbic acid depletion.¹⁵ These and other effects suggested that Eleutherococcus modified the physiological response to stressors (general adaptation syndrome) to help the organism better to withstand prolonged stress.

Additional research found that Eleutherococcus could increase the resistance of animals to stressors such as heat, cold, immobilisation, trauma, surgery, blood loss, increased or decreased barometric pressure, narcotics, toxins and bacteria.^22,23 Eleutherococcus also appears to exert an immune-enhancing action in immune-compromised mice.²⁴

Oral administration of water extract of Eleutherococcus and its components, eleutheroside B and eleutheroside E demonstrated protective effects on behavioural, functional and biochemical changes in mice subjected to acute or chronic stress (exhaustion).²⁵ Oral administration of this extract (500 mg/kg per day) for 7 weeks led to improvements in learning and memory in the active avoidance rat model.²⁶

Addition of an aqueous extract of Eleutherococcus (0.1 mg/mL) caused significant liberation of adrenocorticotropic hormone (ACTH) and luteinising hormone from isolated rat pituitary glands in vitro. In vivo experiments indicate that a single intraperitoneal dose of standardised aqueous extract (3 mg/mL) enhanced the liberation of corticosterone, while subchronic administration (3 mg/mL, ip, or 500 mg/kg, oral) did not alter ACTH or corticosterone levels, body or organ weight after 7 weeks. However, elevations of corticosterone serum levels induced by mild stress were significantly suppressed in animals treated either subchronically by oral administration or by intraperitoneal injection of standardised Eleutherococcus extract.²⁷

Some studies have shown stimulant rather than adaptogenic effects. An American investigation of the adaptogenic effects of Eleutherococcus in stressed mice did not confirm improved stamina, and instead demonstrated aggressive behaviour for mice given unlimited quantities of the root.²⁸ Rats given Eleutherococcus show increased brain levels of noradrenaline (norepinephrine) and serotonin and adrenal levels of adrenaline (epinephrine), which may explain the increased aggressive behaviour observed above.²⁹

Eleutherococcus may exert some of its effects by inducing enzyme activity. It inhibited metabolism of the sedative hexobarbitol in mice to produce a longer sleep period.³⁰ In one study, the stress of swimming for 15 minutes inhibited RNA polymerase in the liver and skeletal muscle of rats; prior injection of eleutherosides delayed the RNA polymerase inhibition and accelerated its restoration during rest.³¹ Another study suggested that the effects of swimming stress in inhibiting NK activity and corticosterone could be countered by eleutheroside E.³²

Experiments conducted in stressed BALB/c mice using oral doses (30, 90 and 180 mg/kg) of a proprietary combination of extracts from Eleutherococcus senticosus, Schisandra chinensis and Rhodiola rosea found increased endurance.³³ In addition, repeated administration of the adaptogen formulation dose-dependently increased basal serum levels of the heat shock protein Hsp72, which was even stronger than the effect of stress on this measure. Based on their findings, the authors suggested that the increased tolerance to stress induced by adaptogens is associated with stimulation of Hsp72 production and release into the systemic circulation. Hsp72 is a known mediator of the stress response involved in protein maintenance and repair. This finding implies that adaptogens could be acting as hormetic agents.

Resistance to radiation and chemical carcinogens

The independent application of Eleutherococcus extract (given orally and prophylactically, 5 g/kg) and a chemical radioprotector (adeturone) demonstrated a favourable effect on rats subjected to radiation injury. This favourable effect was only demonstrated on the course of the recovery processes. The two agents mutually potentiated each other and provided a high degree of protection.³⁴

Eleutherococcus given to mice by injection prior to radiation treatment improved self-repair rather than exerting a direct protective effect. This further supports the concept of its non-specific activity.³⁴ Up to 80% of mice given Eleutherococcus beforehand survived a lethal dose of radiation. When Eleutherococcus was administered as late as 12 hours after irradiation the survival rate was 30%.³⁵ The stimulation of red blood cell production by the spleen was considered to be responsible for this sustained effect.³² An in vitro study using isolated mammalian cells exposed to gamma radiation found that Panax ginseng increased their resistance to irradiation whereas Eleutherococcus did not.³⁶ The above studies suggest that Panax confers a direct resistance to cells by altering cell physiology, whereas the improved survival from Eleutherococcus is via an indirect action on the whole organism.

In their early seminal review of Eleutherococcus, Brekhman and Dardymov found that it inhibited both spontaneous malignant tumours and those induced by a number of carcinogens. Evidence was obtained of a decreased transplantability of tumours in mice and an inhibition of metastases occurred in some cases.¹⁵ An earlier study indicated a decreased incidence of lung cancer in mice when Eleutherococcus was given for several weeks with or after the administration of a carcinogenic agent.³⁷ Further in vitro research found that components of Eleutherococcus exerted an antiproliferative action upon murine cancer cells; the effect of some cytotoxic drugs was also potentiated by Eleutherococcus, thereby reducing the amount of drug needed.³⁸ Eleutherococcus lowered the occurrence of chromosomal mutations and increased the survival rate of plants exposed to mutagens.³⁹

Immune effects

Resistance to bacterial infection is increased in mice and rabbits by prior dosing with Eleutherococcus. However, simultaneous administration with the infecting organism increased the severity of the disease.⁴⁰ This work and clinical experience in Russia have led to the notion that use of Eleutherococcus should be discontinued during acute infections, although it has been used in combination for such conditions.⁴¹ Antiviral immunity is also stimulated in vivo and in vitro by prior administration of Eleutherococcus.⁴² Preparations of Eleutherococcus were analysed and found in vitro to selectively inhibit COX-2 enzymes and lipid peroxidation which are elevated in inflamed or cancerous conditions.⁴³

Normalising actions

Brekhman and Dardymov demonstrated that Eleutherococcus impeded both hypertrophy and atrophy of the adrenal and thyroid glands, reduced blood sugar level in hyperglycaemia and increased it in hypoglycaemia. A normalising action was also observed in both leucopenia and leucocytosis.¹⁵

Cardiovascular effects

Eleutherococcus countered the effects of cerebral ischaemia in rats,⁴⁴ and in other studies increased their resistance to coagulant drugs.⁴⁵ Rats recovering from heart damage demonstrated increased repair of heart muscle: Eleutherococcus was found to increase the number of mitochondria in the cardiac muscle, resulting in better oxygen metabolism and increased conversion of fat into glycogen for energy.⁴⁶

Other activity

Eleutherococcus displayed a marked benefit in diabetic rats by increasing insulin and lowering glucagon.⁴⁷ The eleutherosides had an insulin-like activity in diabetic rats⁴⁸ and the eleutherans are hypoglycaemic.¹³ There is some evidence of hypoglycaemic effects in healthy adults,⁴⁹ but no such benefits have been observed in diabetes patients.⁵⁰

Eleutherococcus has demonstrated anabolic effects, with improved egg weight and yield in hens, increased reproductive capacity in bulls, and weight gain in growing rabbits⁵¹ and in rats.⁵² It is claimed to have a gonadotropic effect in young male mice, with 1 g of root (by intraperitoneal injection) being equivalent to 6 mg of testosterone (by intramuscular injection).⁵³ However, components of an Eleutherococcus extract only demonstrated a modest affinity for steroid receptor sites in an in vitro study.⁵⁴

An antitoxic effect has been demonstrated in vivo for the simultaneous administration of drugs and toxins with Eleutherococcus.⁵⁵

Effect on healthy or stressed individuals

Studies (mostly from Russia) of Eleutherococcus in individuals without pathology have indicated an increased capacity to adapt to changed environmental and working conditions. In healthy humans, Eleutherococcus improved short-term memory and light and colour perception.^56,57 The herb has been reported as improving the performance and stamina of explorers, sailors, deep sea divers, mine and mountain rescue workers, truck drivers, pilots, factory workers and even cosmonauts in open label trials and case observations.⁵⁸ Improved mental and physical output is noted, for example proof-readers were quicker and made fewer errors, cognitive performance increased in the elderly,⁵⁹ and labourers improved work capacity.⁶⁰

In a double blind study of 1000 workers in a Siberian factory who received Eleutherococcus daily for 30 days, a 40% reduction in lost work days and a 50% reduction in general illness over a 1-year period was reported.⁶¹ A Japanese single blind crossover study with six adolescent male athletes demonstrated that Eleutherococcus improved maximal work capacity by 23.3% in male athletes compared with a 7.5% increase in the placebo group.⁶² In another study on athletes, Eleutherococcus also improved the strength of larger muscles, but its effect was weaker than Panax.⁶³

The results of a study comparing Eleutherococcus (4 g/day), Panax (2 g/day) and placebo on endurance athletes showed that over 6 weeks there was no effect on immune cell markers, but in the Eleutherococcus group (not Panax) the testosterone/cortisol ratio decreased by almost 30% (mostly due to increased cortisol). The authors suggest this is consistent with animal research suggesting a threshold of stress below which Eleutherococcus increases the stress response and above which it decreases the stress response.⁶⁴ They went on to propose that Eleutherococcus may competitively engage stress hormone receptors that function to mobilise energy reserves in activity.⁶⁵ This again implies hormetic activity for the herb.

In healthy people exposed to heat stress, Eleutherococcus caused faster activation and greater intensity of perspiration.⁶⁶ In a study on 225 volunteers to assess microvascular reactions in the skin from UV light and after application of low pressure cupping, Eleutherococcus taken over 30 days showed significant benefits over placebo.⁶⁷

Due to such reports and its local reputation, Eleutherococcus was widely used in Russia by track and field athletes, gymnasts and weight lifters.^68,69 There is, however, some modern contention about the reliability of some of the earlier studies and the effects of Eleutherococcus on athletes are not judged strong enough for it to be a banned drug. A review of the available evidence found serious methodological flaws in the earlier papers and a trend in more rigorous studies to find no effect on endurance.⁷⁰ For example, in a rigorous randomised, double blind crossover study of endurance cyclists, supplementation with 1.2 g Eleutherococcus extract for 7 days did not alter cycling performance.⁷¹ Twenty highly trained distance runners randomly assigned in matched pairs participated in an 8-week double blind study during which they completed five trials of a 10-minute treadmill run at their 10 km race pace and a maximal treadmill test. Following a baseline trial, participants consumed Eleutherococcus extract or placebo daily for 6 weeks. Data from the measured parameters (including heart rate, respiratory parameters and serum lactate) did not support an ergogenic effect of Eleutherococcus supplementation for submaximal and maximal aerobic exercise tasks.⁷²

There is some support for a role for Eleutherococcus in supporting immune function, elaborated further in the next section. A placebo-controlled study of the effect of an Eleutherococcus senticosus extract on quantitative flow cytometric measures of cellular immune status in 36 healthy volunteers showed that over 6 months there was a significant increase in the activity and number of immunocompetent cells, notably helper T lymphocytes and natural killer (NK) cells.⁷³ In another study 50 healthy volunteers were given either Echinacea fresh plant tincture or a liquid preparation containing Eleutherococcus (about 2 to 3 g/day of root) for 30 days. Changes in the Eleutherococcus group were observed for cellular defence and physical fitness, together with significantly decreased total cholesterol (14%), LDL-cholesterol (23%), triglycerides (23%) and glucose levels (11%) (p<0.001).⁷⁴

Nine recreationally trained college male students participated in a small randomised, double blind, crossover trial conducted in Taiwan. Eleutherococcus root and rhizome extract (equivalent to 3.2 g/day) or placebo was taken for 8 weeks, with a washout period of 4 weeks. Participants cycled on a cycle ergometer at 75% of peak oxygen uptake (VO₂ peak) until exhaustion (endurance time). Eleutherococcus increased VO2 peak by 12% and endurance time by 23% from baseline. This response was statistically significant compared with placebo (VO₂ peak and endurance time increased by 3% and 6% from baseline, respectively). Taking Eleutherococcus for 8 weeks allowed participants to tolerate a greater cardiac work load. Plasma free fatty acids were increased and glucose was decreased. These alterations, combined with the significant decrease in respiratory exchange ratio, suggest a shift in metabolism from carbohydrate to fat (thus sparing muscle glycogen).⁷⁵

Effect on unwell individuals

Administration of Eleutherococcus has shown beneficial effects in a wide range of functional and pathological disorders in open label trials and case observation studies. It has been used in both China and Russia to treat diseases of the heart, kidneys and nervous system. It is likely that Eleutherococcus exerts its beneficial effects by improving the overall health of the patient, rather than by any direct effect on the pathological process.

The results of a postmarketing surveillance study of 160 patients using an Eleutherococcus preparation demonstrated a beneficial effect on antibiotic-induced diarrhoea in convalescence, leading to its recommendation as an adjuvant treatment in convalescence after antibiotic therapy to prevent or to clear gastrointestinal complications.⁷⁶

Several studies have looked at the effect of Eleutherococcus on immunological activity. In a double blind, placebo-controlled study involving 93 patients, 75% taking Eleutherococcus dry extract for 6 months (equivalent to 2 g/day) reported an improvement in the duration, severity and frequency of recurrent herpes simplex type II infections, compared with 34% in the placebo group.⁷⁷ Studies with cancer patients given Eleutherococcus while undergoing antitumour treatment demonstrated enhanced innate immunity,⁷⁸ and it also minimised the side effects from radiation, chemotherapy and surgery, and improved healing, well-being and survival time.⁷⁹ Twenty eight patients with stage III-IV epithelial ovarian cancer were given 270 mg/day of a proprietary combination of dried ethanol/water extracts of Leuzea carthamoides, Rhodiola rosea, Eleutherococcus senticosus and Schisandra chinensis for 4 weeks following chemotherapy. Results suggested that the combination may boost suppressed immunity.⁸⁰

Reviews of earlier clinical studies have suggested improved general well-being in a wide range of patients with both mild health disturbances and more serious illness; there was added improvements reported in cardiovascular functions in atherosclerotic patients and those with rheumatic heart lesions, in lung capacity in patients with chronic bronchitis, pneumoconiosis and pneumonia, and in blood pressure in both hypertensive and hypotensive patients.⁸¹ Hypotensive children demonstrated a significant rise of blood pressure and peripheral resistance when given Eleutherococcus.⁸² Children with dysentery responded faster to medical treatment when Eleutherococcus was added.⁸³

A randomised placebo-controlled trial in patients with substantial fatigue for at least 6 months with no identifiable cause was conducted in Iowa. After 2 months there were no significant differences in fatigue relief between placebo or Eleutherococcus (extract corresponding to 2 to 4 g/day of root) among the 76 patients who completed the study. However, in a subset of 45 patients with less severe fatigue there was a significant difference in favour of the herb, suggesting that it may be more efficacious for mild-to-moderate fatigue.⁸⁴ A double blind, placebo-controlled, parallel-group clinical study on Kan Jang (a combination of Andrographis paniculata and Eleutherococcus senticosus) showed positive effects in the treatment of acute upper respiratory tract infections, including sinusitis⁸⁵ and a randomised trial of the same preparation in children with acute respiratory viral infections was well tolerated and effective.⁸⁶ (See the Andrographis monograph for more details of these trials.)

Antiviral and antiretroviral activity

Hypericin, and to a lesser extent pseudohypericin, have been the subject of intense research for their antiviral properties. A review article by Kubin and colleagues²⁵ has been published on this topic. Hypericin and pseudohypericin have demonstrated activity against several enveloped viruses in vitro, including vesicular stomatitis virus, herpes simplex virus types 1 and 2, parainfluenza virus, vaccinia virus,²⁶ murine cytomegalovirus,²⁷ duck hepatitis B virus,²⁸ bovine viral diarrhoea virus, influenza virus type A, parainfluenza virus type 3, radiation leukaemia virus, Moloney murine leukaemia virus, Friend leukaemia virus, vesicular stomatitis virus, Sendai virus, Sindbis virus, equine infectious anaemia virus, bovine immunodeficiency virus and human cytomegalovirus.²⁵ These compounds were inactive against non-enveloped (naked) viruses such as human rhinovirus, adenovirus and poliovirus.^26,29

This suggests that the mechanism of viral inactivation is dependent upon the presence of a viral lipid envelope.²⁹ The antiviral activity was enhanced by exposure to light²⁷ and is directed at both the virions and virus-infected cells.³⁰ Hypericin and pseudohypericin appear to inactivate the viral fusion function via the generation of singlet oxygen upon illumination,³¹ which could also occur in vivo in the absence of light if driven by chemically generated excited states.³² Hypericin and pseudohypericin also interfere with more than one stage in the virus replication cycle (see also below).³³

Both hypericin and pseudohypericin demonstrated potent activity, in vitro and in vivo (by oral administration or injection),^34,35 against several retroviruses, including HIV.³⁶ The antiretroviral activity was enhanced by exposure to light.^30,33 The ring structure, the quinone and phenolic groups were deemed necessary for the antiretroviral activity.³⁶

The antiretroviral effect was postulated to be achieved in a number of ways:

The antiretroviral activity is probably due to a combination of the photodynamic and lipophilic properties of these compounds: hypericin binds cell membranes and crosslinks virus capsid proteins resulting in a loss of infectivity and an inability to retrieve the reverse transcriptase activity from the virion.⁴⁰

Light-independent inhibition of HIV-1 was demonstrated for highly purified fractions of chloroform extracts of Hypericum.⁴¹ Through bioassay-guided fractionation, 3-hydroxylauric acid found in field-grown H. perforatum was identified as inhibiting HIV-1 activity, with little to no cytotoxicity. Similarly, light-independent anti-HIV-1 activity was also observed for Hypericum that lacked detectable levels of naphthodianthrones.

A recent review noted in vitro studies where hypericin inhibited human cytomegalovirus, inhibited the adsorptive ability of foot-and-mouth virus to host cells in a model of BHK-21 cells, with maximal inhibitory rate of 59.7%, and exerted a dose-dependent activity against porcine reproductive and respiratory syndrome virus in a model of Marc-145 cells.⁴² No information was provided about light conditions.

Despite promising results from in vitro studies, the review by Kubin and colleagues suggested tests in mice indicate that the efficacy of hypericin on enveloped viruses requires light illumination for effective in vivo virucidal activity.²⁵ They noted that this was a controversial area, with some results showing positive in vivo antiviral activity in the absence of light. It is possible that marked antiviral activity from the use of Hypericum is only achieved for parts of the body that have access to light, such as the skin. (See the trial in patients with herpes simplex later in this monograph.)

A phase I dose escalation study of patients with chronic hepatitis C virus failed to show any significant antiviral activity. Hypericin was given orally in liquid doses of 0.05 or 0.10 mg/kg for 8 weeks. Seven of 12 patients treated with the 0.05 mg/kg dosage, and all seven treated with the 0.1 mg/kg dosage. experienced photosensitivity reactions judged to be probably related to hypericin, including paraesthesia, dermatitis, darkened colour of exposed skin and pruritic nodules.⁴³

Similarly, a phase I dose escalation study of hypericin as a potential antiretroviral drug against HIV was unable to confirm its value in this context. In fact, phototoxic reactions severe enough to cause participants to discontinue treatment were observed. Thirty HIV-infected patients with CD4 counts less than 350 cells/mm³ were treated with intravenous hypericin (0.25 or 0.5 mg/kg twice weekly or 0.25 mg/kg three times weekly) or oral hypericin (0.5 mg/kg/day). Of the 30 patients who were enrolled, 16 discontinued treatment early because of toxic effects. Severe cutaneous phototoxicity was observed in 11 of 23 evaluable patients, and dose escalation could not be completed. Virological markers and CD4 cell count did not significantly change.⁴⁴

Antidepressant activity

The exact mechanisms of action and key constituents of Hypericum that play a role in its antidepressant activity have yet to be fully elucidated. Hypericin was previously thought to be the only active constituent in depression,^45–48 but more recent interest has focused on other constituents including hyperforin, an unstable compound shown in in vitro and in vivo studies to have antidepressant activity.^17–22 The flavonoids have also received attention in this context.^49,50 However, the total extract appears to be more effective than isolated constituents⁵¹ in terms of the antidepressant effect of Hypericum, and most of the data to date suggest that multiple mechanisms exhibited by several groups of active compounds may be involved in the antidepressant action of Hypericum.^52,53

Support for hyperforin as a key antidepressant component is derived from several sources. In vitro research found that the potency of Hypericum products at inhibiting uptake of serotonin depended on their hyperforin content.⁵⁴ Furthermore, the effects of two different Hypericum extracts in behavioural despair and learned helplessness in a rodent model closely correlated with their hyperforin content.¹⁸ A randomised, controlled trial comparing the clinical efficacy and safety of 900 mg/day of two different extracts of Hypericum found the low-hyperforin extract (0.5%) was ineffective over placebo compared with the high-hyperforin extract (5%) over a 42-day period.²⁰ However, there is still considerable debate concerning the relevance of hyperforin to the antidepressant effects. One review of the evidence for different compounds in depression cited six studies using hyperforin-free Hypericum extracts that were able to demonstrate clinical efficacy.¹¹ Specifically, clinical studies have clearly demonstrated low-hyperforin extracts (1.5% to 3%) to be superior to placebo or equivalent to fluoxetine in the treatment of mild-to-moderate depression.⁵⁵ In addition, many positive findings were reported from clinical trials on Hypericum for the treatment of depression prior to 1998, when the extraction process used to make the most clinically tested extract was modified to target higher levels of hyperforin.¹¹

Evidence for the relevance of other constituents to the antidepressant activity has been demonstrated using the tail suspension test in mice, where step by step removal of either hyperforin or hypericin did not result in a loss of pharmacological activity.⁵⁶ An extract fraction containing a high amount of flavonoids significantly reduced immobility time in the forced swimming test. The effect was comparable to that of imipramine.⁴⁹

The pathophysiological mechanisms underlying the complex disorder of depression are still not well understood. As well as neurotransmitter deficiency, an inflammatory response (elevated pro-inflammatory cytokines), and activation of the hypothalamic-pituitary-adrenal (HPA) axis (elevated levels of corticotropin-releasing hormone, ACTH (adrenocorticotropic hormone) and cortisol) have also been observed in depressed patients. Hence, the following mechanisms that have been observed for Hypericum extracts and/or its constituents are of some relevance, albeit keeping in mind the limitations of in vitro models.

Anxiolytic activity

In vitro studies suggest that Hypericum components can interact with receptors that mediate anxiolytic effects. For example, hypericin reduced GABA-activated chloride currents in vitro, while pseudohypericin had the opposite effect.¹⁰¹ Both hypericin and pseudohypericin inhibited the activation of NMDA receptors.¹⁰¹

In vivo studies reporting on the anxiolytic effects of whole extracts of Hypericum have revealed mechanisms that may be of relevance. Further details of these studies are provided here as follows:

Anxiolytic activity was exhibited for a Hypericum extract (0.54% TH) administered orally to rats at the dose of 10 mL/kg, but not by protohypericin or a fraction containing hypericin and pseudohypericin. The activity was blocked by pretreatment with the benzodiazepine antagonist flumazenil, suggesting benzodiazepine receptor activation may be involved.¹⁰¹

Anxious/depressive-like behaviour, induced in a mouse model by 7 weeks of corticosterone administration, was reversed by exogenous administration of a methanolic extract of Hypericum (0.34% hypericin, 4.1% hyperforin, 5% flavonoids) at a dose of 30 mg/kg ip for 3 weeks. Treatment with Hypericum also prevented the corticosterone-induced decrease in hippocampal cell proliferation and ameliorated the associated reduced spine density, suggesting that morphological adaptations occurring in mature hippocampal neurons might underlie resilient responses to chronic stress and contribute to the therapeutic effects of Hypericum.¹⁰⁵

The above mechanistic studies are supported by a number of models consistently demonstrating anxiolytic activity for Hypericum extracts.

A 50% ethanolic extract of Hypericum (100 and 200 mg/kg, oral) administered to rats for 3 consecutive days showed consistent and significant anxiolytic activity for all the experimental paradigms used, and resulted in a significant increase in social interaction.¹⁰⁶

An infused Hypericum lyophilised aqueous extract devoid of hyperforin showed a clear sedative effect at doses ranging from 10 to 100 mg/kg administered intraperitoneally to mice, and at 5 mg/kg produced an anxiolytic effect.¹⁰⁷ Hypericum (100 and 200 mg/kg, oral) showed significant antistress activity, qualitatively comparable to Panax ginseng (100 mg/kg, oral), against a variety of behavioural and physiological perturbations induced by chronic stress over 14 days in albino rats. Adrenal gland and spleen weights were attenuated dose-dependently by Hypericum and Panax.¹⁰⁸

Oral administration of Hypericum (LI 160 at 62.5 to 500 mg/kg) exerted anxiolytic-like effects in rats for a specific subset of defensive behaviours, particularly those related to generalised anxiety. Acute treatment (125 mg/kg) impaired elevated T-maze inhibitory avoidance, indicating an anxiolytic effect. Neither acute nor chronic treatment (250 mg/kg) impaired escape performance.¹⁰⁹

Putative anxiolytic effects of Hypericum extract were demonstrated in induced hyperthermia in mice, where oral administration of doses of 250 and 500 mg/kg significantly reduced body temperature (deltaT) while higher (750 and 1000 mg/kg) and lower doses (125 mg/kg) had no effect. Among the individual constituents, hypericin (0.1 mg/kg, oral) administered 60 min prior to testing significantly decreased deltaT (p<0.05).¹¹⁰

Anxiolytic activity of Hypericum was suggested by findings from acute, subchronic (7 days), and chronic (21 days) administration of LI 160 (150 and 300 mg/kg) to mice submitted to the mouse defence test battery. The dose of 300 mg/kg for 21 days reduced flight reaction to the presence of a predator, suggesting a possible anti-panic effect. However, perceived risk assessment (the main index of anxiety) was not affected, suggesting that both effects were only mild.¹¹¹

Hypericum extract (LI 160) administered orally to rats (150 to 500 mg/kg) 24, 18 and 1 h before the forced swim test demonstrated anxiolytic and anti-panic effects, with no impact on locomotor activity. Subacute treatment (300 mg/kg) exerted a partial anxiolytic-like effect, while administration of 300 mg/kg for 7 days induced anxiolytic (decreased inhibitory avoidance) and anti-panic effects (increased one-way escape).¹¹²

Neuroprotective and cognition-enhancing activities

In vitro and in vivo studies suggest that Hypericum extracts and hyperforin have cognition-enhancing and memory-facilitating properties, as well as neuroprotective effects.¹¹³ Mechanisms of potential relevance to the neuroprotective activity of Hypericum and its components are summarised here as follows:

The implication of these findings for Alzheimer’s disease have been expanded in a comprehensive review by Griffith and colleagues, published in 2010, of the neurobiological effects of hyperforin.¹¹³

Results from further in vivo studies of Hypericum or its components demonstrate improvements in learning, memory retention and spatial memory, protective effects against memory impairment generated by amyloid-beta and prevention of the deleterious effects of stress on memory and learning.

Oral administration of Hypericum extract (50 mg/kg/day) and hyperforin sodium salt (1.25 mg/kg/day) to rats considerably improved learning ability in conditioned avoidance response models, and memory retention of the acquired responses. A single oral dose (1.25 mg/kg) of hyperforin, but not the total Hypericum extract (25 mg/kg), improved memory acquisition and consolidation and almost completely reversed scopolamine-induced amnesia in mice.¹²⁷ It was suggested by the authors that Hypericum extract could be a novel type of antidepressant with memory enhancing properties, while pure hyperforin may be a more potent anti-dementia agent than antidepressant.

Similarly, Hypericum was proposed as a possible treatment for the depression commonly associated with dementia. This was based on findings that acute administration of a Hypericum extract (1% TH, 3% hyperforin) to mice at doses of 4 to 25 mg/kg ip enhanced retrieval memory, but failed to reverse scopolamine-induced amnesia. Pretreatment of the animals with a range of neurotransmitter receptor antagonists revealed the involvement of adrenergic and serotonergic 5-HT_1A receptors in the facilitatory effect of Hypericum extract on retrieval memory.¹²⁸

Pretreatment of Wistar rats with a 12:1 Hypericum extract (1% TH, 3% hyperforin) at doses of 4 to 12 mg/kg, ip, subsequent to the administration of 1.4 mg/kg of scopolamine to impair retrieval memory, resulted in an antioxidant effect through altering brain malondialdehyde, glutathione peroxidase and/or glutathione level/activity.¹²² The authors suggested that, since oxidative stress is implicated in the pathophysiology of dementia, low doses of Hypericum extract may be of value for patients exhibiting elevated brain oxidative status.

Other studies in rats have suggested that Hypericum has the potential to prevent the deleterious effects of stress on learning and memory disorders. Administration of an extract (350 mg/kg/day, oral for 21 days) standardised to 0.3% TH content prevented non-spatial and/or spatial memory impairments due to chronic restraint stress and exogenous corticosterone at 5 mg/kg/day for 21 days. It also significantly improved recognition memory (p<0.01) compared with controls.¹²⁹ These results were subsequently confirmed under the same conditions in male Wistar rats with another Hypericum extract, standardised to 0.2 mg TH, at the same dose. The extract significantly improved hippocampus dependent spatial working memory (p<0.01) and alleviated some other negative effects of stress on cognitive function.¹³⁰ In a follow-up study, Hypericum was found to significantly (p<0.05) increase levels of the synaptic plasticity proteins neuromodulin (GAP-43) and synaptophysin in the hippocampus and prefrontal cortex, which may account for its effect of alleviating stress- and corticosterone-related memory impairments.¹³¹

Acute administration of a standardised 50% ethanolic extract of Hypericum (100 and 200 mg/kg/day, oral for 3 days) to rats demonstrated a possible nootropic action comparable with that induced by piracetam (500 mg/kg).^132,133 Memory retention was facilitated, but a minimal effect was observed on learning acquisition in various learning and memory paradigms.

The effects of acute (500 mg/kg) and chronic (200 mg/kg/day for 3 days) oral administration of Hypericum extract (80% ethanol extract, 1% TH, 3% hyperforin, >20% flavonoids) and hyperforin were tested on prepulse inhibition (PPI) of an acoustic startle response in rats, a paradigm for sensorimotor gating processes. Disruption of PPI resulted with both the chronic dose of the extract and hyperforin, suggesting potential for a possible limitation of cognitive disturbance in psychotic and Huntington’s disease patients manifesting PPI deficit.¹³⁴

In an early randomised, double blind trial, the effect of Hypericum extract (2.7 mg/day TH equivalent) was compared with maprotiline on resting EEG and evoked potentials in 24 healthy volunteers. Results indicative of cognitive function were observed, particularly for the Hypericum treatment.¹³⁵

Anticancer activity

The constituents of Hypericum receiving the most research attention for potential anticancer activity are hypericin and, more recently, hyperforin. The results of in vitro, in vivo and clinical studies are outlined separately below. Much of the recent interest in hypericin in the context of cancer has focused on its role as a photosensitiser in photodynamic therapy (PDT), an increasingly accepted and promising therapeutic modality for the treatment of many types of tumours. Studies on PDT are included separately and only briefly, because of their lesser relevance to the potential herbal use of Hypericum.

Hypericin has demonstrated potent antitumour activity in vitro against several tumour cell lines. Early mechanistic experiments demonstrated that H directly inhibits epidermal growth factor receptor and protein tyrosine kinase activity.¹³⁶ (Epidermal growth factor is a cellular plasma membrane receptor possibly involved in the loss of inhibitory constraint on cell growth, a factor in tumour formation.) Phosphorylation of proteins on tyrosine residues is a key biochemical reaction mediating a large variety of cellular signals, including control of the cell cycle and cell differentiation. Enhanced protein tyrosine kinase activity is also involved in the transformation of normal cells into tumour cells.

In a study on bovine vascular endothelial cells, non-photoactivated hypericin inhibited several key steps of the angiogenic process, including bovine endothelial cell proliferation, formation of tubular-like structures, migration and invasion, as well as extracellular matrix degrading urokinase.¹³⁷

Other in vitro research has found that the hypericins in the lipophilic extract of Hypericum induced apoptosis in cultured T24 and NBT-II bladder cancer cell lines, suggesting that pure hyperforin does not seem to contribute significantly to the cytotoxicity activity.¹³⁸

In vivo studies have supported antimetastatic activity for hypericin in the absence of light. Intraperitoneal injection of 10 mg/kg hypericin significantly reduced the growth rate of metastases in two murine models: breast adenocarcinoma (DA3) and squamous cell carcinoma (SQ2). Long-term animal survival in DA3 tumour-excised groups increased from 15.6% in controls to 34.5% following supplementary treatment with hypericin. In mice bearing SQ2 tumour metastases, therapy with hypericin increased animal survival from 17.7% in controls to 46.1%.¹³⁹

Significant reduction in the growth of a human prostatic carcinoma cell line and the number of metastases was observed with a Hypericum methanolic extract (containing 0.3% TH and 3.8% hyperforin) in orthotopically implanted nude mice.¹⁴⁰ Treatment administered intraperitoneally at a dose of 15 mg/kg for 25 days inhibited tumour growth by 70%. Regional lymph node metastasis was observed in 100% of controls compared with 30% of the mice treated with Hypericum (p<0.01), with no side effects observed in any of the treated mice.

Antibacterial activity

Hyperforin is considered to be the main antibacterial constituent of Hypericum,^165,166 although evidence exists that hypericin, but not the flavonoids, can significantly inhibit the growth of selected micro-organisms.¹⁶⁷ Extracts of other Hypericum species with a low level of hypericin and hyperforin were also found to possess some antimicrobial activity,¹⁶⁸ suggesting that, while these are the main antimicrobial components, they are probably not the only ones responsible for such activity. Hyperforin is the main ingredient of a complex preparation of polyphenolic components, mostly from dianthrone and flavonoid groups, isolated by water-alkali extraction of Hypericum. This preparation has shown antimicrobial properties and has been proposed to be more stable than hyperforin itself.¹⁶⁹

A variety of preparations of Hypericum have demonstrated antibacterial activity in vitro against more than 40 micro-organisms including Staphylococcus Oxford, Staphylococcus aureus, Streptococcus mutans, Streptococcus sanguis, Escherichia coli, Proteus vulgaris, Bacillus cereus, Bacillus subtilis and Nocardia gardene.^169,170 Extracts of the aerial parts have shown activity against Helicobacter pylori (MIC 1.95 to 250 μg/mL).¹⁶⁶ A comprehensive review of the antibacterial activity of Hypericum published in 2010 reported that methanolic/ethanolic extracts have been found to possess more pronounced activity than aqueous extracts.¹⁷⁰ The highest inhibitory properties against Enterococcus faecium, Bifidobacterium animalis, Lactobacillus plantarum and E. coli isolated from the human large intestine were obtained with a 30% ethanol solution, compared with 10% ethanol and pure water extracts.¹⁷⁰ The essential oil has also demonstrated potent antibacterial activity in vitro against a variety of bacterial strains, although it occurs at quite low levels in the herb.^{170,171–173} Water-soluble formulations of hypericin have also shown promise as sensitisers in antibacterial photodynamic therapy for inactivating Staphylococcus aureus infections in wounds.¹⁷⁴

The infused oil of Hypericum has antibacterial activity. Three lipophilic ointments containing this oil (30%, 40% and 50%) demonstrated inhibition of bacterial growth against Streptococcus pyogenes, Streptococcus viridans, Micrococcus luteus ATCC 9341 and Moraxella catarrhalis, but not Lactobacillus acidophilus, with the antibacterial effect correlated with the quantity of oil.¹⁷⁵

The antibacterial activity of Hypericum against methicillin-resistant Staphylococcus aureus (MRSA) has been demonstrated by several research groups.^165,166,176 Hyperforin at concentrations of 0·1 to 100 mg/mL showed antibacterial activity against resistant Staphylococcus aureus.¹⁶⁵ Aqueous solutions of Hypericum teas were also found to be effective against MRSA (MIC 1.3 to 2.5 mg herb per mL).¹⁶⁶ However, subsequent research supported the superiority of the ethanolic extract against eight clinical and one standard strain of MRSA, with the most pronounced effect observed for 0.5 mg/mL of extract.¹⁷⁷ The extracts were more effective against MRSA than methicillin-sensitive S. aureus.

Some of the literature indicates that Hypericum extracts and its components have a higher antibacterial activity against Gram-positive (MIC 0.1 to 1.0 μg/mL) than Gram-negative bacteria.^166,170,178 However, other research groups have found activity against both Gram-positive and Gram-negative bacteria. Methanol-acetone extracts from the aerial parts of two subspecies of Hypericum (H. perforatum L. subsp. perforatum, H. perforatum L. subsp. veronense (Schrank) Ces.) were found to be active against two Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and two Gram-negative bacteria (E. coli and Pseudomonas aeruginosa).¹⁶⁸

Aqueous extracts were also effective against both Gram-positive (S. aureus ATCC 12600) and Gram-negative bacteria (E. coli ATCC 8677 and P. aeroginosa ATCC 9721). Seasonal variation in antimicrobial activity was noted, with samples collected later in the summer (August) conferring good antimicrobial activity, while those collected in July were inactive.¹⁷⁹ Nikolic and Zlatkovic observed that the antimicrobial activity reached two maximum values during the harvesting season, the first during the budding period, and the second during the period of mass flowering when hyperforin is accumulated in the flowers.¹⁶⁹

Antifungal activity

Several in vitro studies have investigated the antifungal activity of the flavonoids, essential oil and/or ethanolic extracts of H. perforatum. An investigation of the six known flavonoids in the herb showed 6″-O-acetyl quercetin 3-O-beta-D-alloside, quercitrin and quercetin were inhibitory towards the growth of the phytopathogenic fungus Helminthosporium sativum, with MIC values of 25, 50 and 100 μg/mL, respectively, while, 6″-O-acetyl quercetin, 3-O-beta-D-alloside and quercitrin also inhibited the growth of Fusarium graminearum Schw. (MIC 100 μg/mL).¹⁷⁰

Ethanolic extracts of Hypericum have shown fungistatic activity against the fungi Fusarium oxysporum and Penicillium canescens, with the concentration high of 45 mg/mL ethanolic extract showing the highest fungistatic activity using a spore counting method.¹⁸⁰ Activity was also demonstrated against Penicillium canescens, Fusarium oxysporum, Alternaria alternata, Aspergillus glaucus and Phialophora fastigiata using the disk diffusion method, at amounts of 20 to 25 mg/disk.¹⁸¹ The essential oil and water-soluble fraction of an alcohol extract of Hypericum both exhibited in vitro antifungal activity against Microsporum gypseum, Trichophyton rubrum, Aspergillus flavus, Curvularia lunata and Fusarium vasinfectum.¹⁸²

Wound healing/anti-inflammatory activities

The wound healing effect of Hypericum may be attributable to its antibacterial and/or anti-inflammatory activities. When pure constituents were tested in vitro for anti-inflammatory activity in RAW264.7 macrophage cells, flavonoids, amentoflavone, hyperforin and light-activated pseudohypericin all displayed activity, but the anti-inflammatory activity observed for whole plant extracts was light-independent.¹⁸³

Hyperforin has been found to act as a dual inhibitor of 5-lipoxygenase (5-LOX) and cyclo-oxygenase (COX)-1 in intact cells.¹¹⁴ Extracts of Hypericum have shown inhibitory effects on COX-2 expression in vitro.¹⁸⁴ In two different human epithelial cell lines, alveolar A549/8 and colon DLD-1 cells, H. perforatum extract concentration-dependently inhibited human inducible nitric oxide synthase (iNOS) expression, which resulted from transcriptional inhibition.¹⁸⁵ Hyperforin inhibited the generation of ROS as well as the release of leucocyte elastase (degranulation) in human isolated polymorphonuclear leucocytes challenged by the G protein-coupled receptor ligand N-formyl-methionyl-leucyl-phenylalanine.¹¹⁷

In embryonic fibroblasts from fertilised chicken eggs, Hypericum extract was shown to increase the stimulation of fibroblast collagen production and the activation of fibroblast cells that play a role in wound repair by closing the damaged area.¹⁸⁶

In vivo research using pleural exudate formation in carrageenan-treated rats showed that hyperforin significantly suppressed leukotriene B4 formation, suggesting it may act as a novel type of 5-LOX inhibitor.¹¹⁵ Hyperforin (4 mg/kg) was administered ip 30 minutes before carrageenan. Topical Hypericum extracts provoked a dose-dependent reduction of croton-oil-induced ear oedema in mice (lipophilic extract > ethyl acetate fraction > hydroalcoholic extract). The pure compounds amentoflavone, hypericin, hyperforin dicyclohexylammonium (DHCA) salt and adhyperforin exhibited anti-inflammatory activity that was more potent than or comparable to indomethacin, whereas isoquercitrin and hyperoside were less active.¹⁸⁷ The lipophilic extract contained no hyperoside, hypericin or pseudohypericin, but contained 27% hyperforin and 5.2% adhyperforin.

In early research, oral administration of Hypericum tincture (0.1 mL of 1:10 tincture) demonstrated improved wound healing in rats. This activity was believed to be due to the facilitation of the collagen maturation phase of wound healing, enhanced new skin growth and an influence on epithelial cell proliferation and migration.¹⁸⁸

A standardised 50% aqueous ethanolic extract of the Indian variety of H. perforatum showed significant anti-inflammatory and analgesic activity in animal models at oral doses of 100 and 200 mg/kg.¹⁸⁹ Additionally, the Hypericum extract potentiated the anti-inflammatory activity of indomethacin (20 mg/kg, ip) and analgesic activities of pentazocine (10 mg/kg, ip) and aspirin (25 mg/kg, ip).

Topical application of Hypericum ointment and its metabolite hyperforin inhibited the allostimulatory capacity of epidermal cells in vivo and the proliferative effect of T lymphocytes on epidermal cells isolated from treated skin, as well as the proliferation of peripheral blood mononuclear cells in vitro, in a dose-dependent manner. This may provide a rationale for the traditional treatment of inflammatory skin disorders with Hypericum extracts.¹⁹⁰

Hypericum extract (containing 0.27% TH and 2.5% of hyperforin) administered orally to mice at 200 mg/kg significantly inhibited the formation of carrageenan-induced paw oedema (p<0.05). The extract inhibited both iNOS and COX-2 expression, suggesting that the anti-inflammatory effect could be in part related to modulation of COX-2 expression.¹⁸⁴

In order to determine the active wound healing ingredients, the aerial parts of Hypericum were extracted with ethanol. The ethanolic extract was then submitted to successive solvent extractions with n-hexane, chloroform and ethyl acetate. The ethyl acetate sub-extract was found to be the most active, inhibiting wounds by between 17.9% and 100% in an excision model and between 9.4% and 100% in an incision model. Based on this, the flavonoids and hypericins were suggested as the active components.¹⁹¹

Hypericum extract (50 to 300 mg/kg/day, ip) was found to have a protective effect on inflammatory bowel disease induced in rats by 2,4,6-trinitrobenzene sulphonic acid, which the authors postulated was probably due to anti-inflammatory and antioxidant mechanisms.¹⁹² Blood glutathione levels significantly increased for all doses of Hypericum (p<0.001).

Spasmolytic activity

A strong association has been suggested between depression and urinary incontinence. In vitro research found Hypericum extract, hyperforin and, to a lesser extent, the flavonoid kaempferol inhibited excitatory transmission of the rat urinary bladder and also directly inhibited smooth muscle contractility. This could involve opioid receptors, at least in part, as the effect was significantly reduced by the opioid receptor antagonist naloxone.¹⁹³

Spasmolytic activity was also demonstrated in mice for Hypericum crude ethanol extract, ethyl acetate extract, aqueous extract/infusion (50 g dried powdered herb in 500 mL hot water for 15 minutes) administered as a 1% aqueous solution ip (10 mL/kg body weight) for each extract. All extracts significantly reduced intestinal motility.¹⁹⁴ A crude extract of Hypericum at a dose of 500 mg/kg caused a 20% protection against castor oil-induced diarrhoea in mice and a 60% protection at 1000 mg/kg (p<0.05 versus saline).¹⁹⁵

Sexual function

Findings from in vitro research on Hypericum extract (1 to 300 μM) showed a dose-dependent inhibition of contractions in both the rat and human vas deferens for the whole extract, and for hyperforin but not hypericin or the flavonoids. It was suggested that these results could explain the delayed ejaculation sometimes described in patients receiving Hypericum treatment.¹⁹⁶

Later in vivo research on the expulsion phase of ejaculation in anesthetised rats suggested that a hyperforin-enriched extract of Hypericum may be a potential treatment for premature ejaculation (see also under Clinical trials).¹⁹⁷

A study conducted in healthy volunteers (6 men and 6 women) found that 14-day administration of Hypericum extract (LI 160) at 900 mg/day did not significantly alter the concentrations of most circulating androgens (testosterone, dihydrotestosterone, dehydroepiandrosterone sulphate, sex hormone-binding globulin and the combined concentrations of androsterone sulphate and epiandrosterone sulphate) (p>0.05) in men or women.¹⁹⁸ However, the combined concentrations of the 5-alpha-reduced steroids, androsterone sulphate and epiandrosterone sulphate, significantly declined following treatment in all participants (p=0.02) and in the men (p=0.04).

Eye diseases

Intravitreal injection of hypericin demonstrated antitumour activity against proliferative vitreoretinopathy (PVR) in pigmented rabbits.¹⁹⁹ Hypericin in doses of 1 μM, 10 μM and 100 μM significantly inhibited PVR after day 5 (p<0.05). Histological examination of the hypericin-treated control eyes disclosed no morphological change, and electroretinogram analysis revealed no significant functional change.

The antiangiogenic effects of Hypericum or hypericin were investigated for their potential application in ocular neovascularisation, a leading cause of blindness in ischaemic retinopathies.²⁰⁰ In a mouse model of oxygen-induced retinopathy, oral administration of Hypericum (15 mg/kg/day) or hypericin (15, 45 or 135 μg/kg/day) for 5 days from post-natal day 12 to day 17 significantly inhibited the degree of retinal neovascularisation, but did not affect the area of retinal vaso-obliteration.

Hypericin was shown to be a highly potent inhibitor of angiogenesis in several ocular models examined in rat eyes.²⁰¹ Extensive angiogenesis induced in the cornea and iris by intraocular administration of the fibroblast growth factor (FGF)-2 was effectively inhibited by a minimum of four dose regimens of hypericin (2 mg/kg) administered via the intraperitoneal route at 48 h intervals. Maximal inhibition was achieved when treatment with hypericin was initiated 48 h prior to inoculation of FGF-2.²⁰¹

Sedative and hypnotic effects

An aqueous ethanolic extract of Hypericum (26.5 mg/kg, oral) induced marked sedation in vivo similar to diazepam controls. None of the isolated fractions from this extract exhibited the same sedative activity as the whole extract.²⁰²

The effects of Hypericum ethanol extract (A), ethyl acetate extract (B) and aqueous extract/infusion (50 g dried powdered herb in 500 mL hot water for 15 minutes) (C) on pentobarbital-induced sleep time, intestinal motility and analgesic activity were investigated in mice, who received a 1% aqueous solution (10 mL/kg body weight, ip) of each extract. Extracts A and B exhibited significant stimulatory and antidepressant effects on the CNS and prolonged pentobarbital-induced sleep, increasing the time up to more than 25 min. Extract B exhibited strong analgesic activity. All extracts exhibited spasmolytic activity, significantly reducing intestine motility.¹⁹⁴

The effect of a single dose of Hypericum was examined at two dosages (0.9 mg TH and 1.8 mg TH equivalent) on the sleep polysomnogram of healthy volunteers using a placebo-controlled, crossover design.²⁰³ At both doses, Hypericum significantly increased the latency to REM sleep (placebo 69 and 64 min versus 84 min (p=0.030) and 104 min (p=0.031) for the low and high doses, respectively), without producing any other effect on sleep architecture. The mean increase in REM latency over placebo was not statistically greater in the participants who received the higher dose of Hypericum (p=0.15).

In an uncontrolled trial with 13 healthy volunteers, a significant increase in nocturnal melatonin plasma concentration was observed after 3 weeks of administration of Hypericum extract (0.5 mg/day TH equivalent).²⁰⁴

Models of alcoholism and drug-dependency

In a 2008 review of Hypericum for substance dependence, it was proposed that the inhibitory effects on ethanol withdrawal syndrome may be explained by serotonergic mechanisms or a central inhibition of nitric oxide synthase (NOS).²⁰⁵ Hypericum extracts (6 to 24 mg/kg) blocked both nicotine (1 mg/kg) and caffeine (16 mg/kg) induced locomotor hyperactivity in mice. These effective doses of Hypericum did not have any significant impact on locomotor activity when administered alone, suggesting that the effect was not related to a non-specific effect such as sedation or muscle relaxation. Additionally, in a second study, pretreatment with L-arginine (1 g/kg) a NO precursor reversed the inhibitory effect of Hypericum (6 mg/kg) on caffeine (16 mg/kg) induced locomotor activity in mice, without producing any significant effect on locomotor activity when administered alone. This implies that the effect may indeed be related to NOS inhibition.

A 2005 review of potential natural treatments for alcoholism reported several preclinical studies indicated Hypericum extracts might reduce the voluntary intake of alcohol in several strains of alcohol-preferring rats. Hyperforin has been suggested to be a compound of relevance in reducing alcohol intake. The ability of extracts of Hypericum to affect serotonergic, dopaminergic and opioidergic systems in mesolimbic regions in the CNS, directly or indirectly, might help to explain this activity.²⁰⁶

Oral administration of Hypericum extracts dose-dependently and significantly reduced alcohol intake in two genetic animal models of human alcoholism. Similar results were seen after the rats were deprived of alcohol for 20 h and the extract was administered 30 minutes prior to the return of alcohol. Compared with the control group, Hypericum extract (0.6 mg/kg) significantly prevented the alcohol deprivation-induced rebound in alcohol intake.²⁰⁷

Doses of a Hypericum CO₂ extract high in hyperforin reduced ethanol intake at 31 or 125 mg/kg, but not at 7 mg/kg. When the opiate receptor antagonist naloxone at 1 mg/kg was combined with the three doses of Hypericum extract, the attenuation of ethanol intake was more pronounced than for the extract alone.²⁰⁸ Chronic (once a day for 12 days) oral administration to rats of the same Hypericum extract, given alone or combined with naltrexone, markedly reduced ethanol intake (offered 2 h/day) at the dose of 125 mg/kg, but not at 7 mg/kg. The effect of 125 mg/kg was observed from the first day of treatment and remained constant across the 12 days.²⁰⁹ At oral doses of 31 or 125 mg/kg, but not 7 mg/kg, the same Hypericum extract significantly reduced ethanol self-administration in rats.²¹⁰

A randomised, double blind, placebo-controlled, crossover study investigated the interaction of Hypericum extract with alcohol. Thirty-two volunteers received either Hypericum extract (2.7 mg/day TH equivalent) for 7 days or placebo. At the end of the treatment period they underwent several tests following consumption of alcohol. No interaction between Hypericum and alcohol with respect to cognitive capabilities was observed.²¹¹

A study investigating the effects of Hypericum extract and clonidine on morphine withdrawal syndrome in morphine-dependent rats showed that clonidine was more effective than the lower dose of Hypericum extract (fed to rats orally by a nasogastric tube at 0.4 mL/200 g). However, there was no significant statistical difference between the mean frequency of withdrawal signs for Hypericum extract at the dose of 0.8 mL/200 g compared with clonidine (0.2 mg/kg, ip), and at 1.2 mL/200 g the Hypericum was significantly stronger than clonidine in attenuating the morphine withdrawal syndrome.²¹²

Oral administration of an extract of Hypericum was shown to attenuate nicotine withdrawal signs in mice.²¹³ Hypericum extract at doses of 125 to 500 mg/kg administered in combination with, or immediately after, nicotine administration (2 mg/kg, four injections daily) abolished the locomotor activity reduction induced by nicotine withdrawal, and also significantly and dose-dependently reduced the total nicotine abstinence score when injected after nicotine withdrawal.

Other activity

In animal models of metabolic syndrome, Hypericum extract was found to significantly lower total cholesterol and low- density lipoprotein cholesterol in normal rats and inhibit weight gain in high-fat- and fructose-fed rats. It also normalised dyslipidaemia and improved insulin sensitivity.²¹⁴ Hypericum extract (3% hyperforin and 0.3% TH) was orally administered at the doses of 100 and 200 mg/kg/day for 15 consecutive days. The same extract and doses over 14 days were investigated for antidiabetic activity in alloxan-induced diabetic rats.²¹⁵ Treatment with Hypericum led to significant falls (p<0.01) in elevated blood glucose levels and also reversed the weight loss associated with alloxan treatment.

Evidence of persistent thermal and chemical antinociceptive activity of Hypericum mainly mediated by PKC-inhibiting mechanisms was obtained from research in which a dried extract of Hypericum induced an effect that persisted for 120 minutes after oral administration to mice.²¹⁶ The presence of hypericin was fundamental to both thermal and chemical antinociception, through inhibition of PKC activity, whereas hyperforin selectively produced a thermal opioid antinociception.

In research by the same group, Hypericum extract (hypericin 0.06 mg/kg, hyperforin 0.978 mg/kg, quercetin 0.249 mg/kg, hyperoside 1.905 mg/kg and amentoflavone 0.016 mg/kg per 30 mg/kg dose of Hypericum) acutely administered at low doses (30 to 60 mg/kg, oral) relieved neuropathic pain and reversed mechanical hyperalgesia in rat models, being effective up to 180 min after injection of oxiplatin.²¹⁷ Hyperforin and hypericin were responsible for this action, whereas flavonoids were ineffective.

Auditory evoked potentials (AEP) provide a correlate of cognitive dysfunction in schizophrenia. In a double blind, randomised, crossover design, treatment with either 1500 mg/day LI 160 or placebo for 1 week in 16 healthy volunteers reversed changes in AEP induced by infusion with ketamine. The influence of ketamine and the effect of Hypericum on the oculodynamic test showed similar (non-significant) trends. Provided that ketamine mimics cognitive deficits in schizophrenia, it was suggested that Hypericum might be effective to treat these symptoms.²¹⁸

Antiretroviral and antiviral activities

In the first reported case studies of HIV-positive patients who had been taking Hypericum preparations (0.35 to 1.2 mg/day TH), nine (of 11) patients demonstrated successful treatment, as evidenced by symptomatic relief of fatigue, nausea, mild peripheral neuropathies and abatement of swollen lymph glands. Changes in CD4 cell counts and p24 antigen levels were slower to occur. One patient became asymptomatic.²²⁹

In 1990, an uncontrolled study was carried out investigating 26 HIV-positive patients self-administering an over-the-counter Hypericum extract (1 mg/day TH equivalent). At the end of 4 months, p24 antigenaemia disappeared in two of six initially positive patients, both of whom were also using the antiretroviral drug AZT. In 10 patients who had never taken AZT, the mean CD4 cell count increased 13% after 1 month and maintained this increase for 4 months. In those using AZT and Hypericum, CD4 cell counts fell significantly after an initial mild rise. Liver enzyme elevations occurred in five patients, which returned to baseline after 1 month without Hypericum.²³⁰

In another early uncontrolled trial, 16 HIV patients at various stages of the disease process were treated by intravenous injection and oral doses of Hypericum.²³¹ Over 40 months of observation, patients showed stable or increasing CD4 cell counts and only two patients encountered an opportunistic infection. None of the known viral complications due to cytomegalovirus, herpes or Epstein-Barr virus were encountered. There were no cases of toxoplasmosis, neurological symptoms or photosensitivity.

A substantial decline in viral load was observed in most of 18 AIDS patients undergoing a similar treatment regime (intravenous injection and oral Hypericum) for 4 to 6 years. In those patients who experienced an increase in viral load, there was no effect on the clinical outcome of viral cytomegalovirus, herpes or Epstein-Barr viral complications.²³² Twenty-four HIV-infected patients in Thailand participated in a study to determine the maximum tolerated effective oral dose (MTD) of hypericin that demonstrated antiviral activity with minimal phototoxic effects. The MTD was found to be 0.05 mg/kg.²³³ In a toxicological study involving 10 HIV-positive homosexual men, daily dosages of 0.5, 2.0, 4.0 and 8.0 mg hypericin were each administered for 12 weeks. No early, marked anti-HIV activity was found.²³⁴ There have also been two phase I/II studies of synthetic hypericin in HIV-infected subjects, investigating phototoxicity, pharmacokinetics and antiviral activity by oral or intravenous administration.^232,235 A consistent change in antiviral endpoints was not seen with intermittent intravenous dosing. Pharmacokinetic data indicated that chronic oral dosing would achieve sustained blood levels within an antiretroviral range.²³²

In patients with hepatitis C virus (HCV), purified hypericin had no impact on levels of HCV or liver enzymes.²³⁶ Twelve patients received low-dose hypericin (0.05 mg/kg/day) for 2 months, while the remaining seven received high-dose hypericin (0.1 mg/kg/day) for 2 months. Seven of 12 patients receiving low-dose hypericin and all seven who received the high-dose hypericin developed side effects, predominantly photosensitivity reactions.

A tablet of Hypericum dry extract was compared with placebo in patients suffering from recurrent orofacial herpes (trial 1; 94 patients) or genital herpes (trial 2; 110 patients) in two separate double blind, randomised clinical trials.^237,238 For both trials, the total observation time was 90 days and patients received 3 tablets per day in symptom-free periods and 6 tablets a day during skin outbreaks. Each tablet contained 300 mg of dried extract standardised to contain 0.3% TH. The main measure of efficacy was a symptom score, calculated as a total of the severity ratings of major symptoms (such as presence and number of blisters, intensity of complaints, size of affected area) during the skin outbreak. The total symptom score was significantly lower in the Hypericum group compared with placebo in both trials. Average scores were 20.3 for the herb versus 32.1 for placebo for trial 1 and 15.6 versus 29.4 for trial 2. The herb also led to a superior reduction of the number of patients with herpetic episodes (skin sores) in both trials. Individual symptoms were also noticeably improved by the herbal treatment.

Antidepressant activity

Most studies on Hypericum in the context of depression have been conducted on major depressive disorder (MDD). According to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV),²³⁹ major depression is characterised by at least five of the following symptoms occurring nearly every day over a 2-week period, including either depressed mood or loss of interest or pleasure: depressed mood, markedly diminished interest in most activities, significant weight loss or weight gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate or indecisiveness and recurrent thoughts of death or suicide.

The antidepressant activity of many Hypericum extracts in MDD has been established in mild and moderate cases in observational studies, placebo-controlled trials and comparator studies with standard antidepressant medications. Even relatively early meta-analyses of randomised placebo-controlled clinical trials of Hypericum between 1996 and 2000, including up to a total of 2291 patients, reported that extracts of the herb were superior to placebo for the treatment of mild or moderately severe depressive disorders.^240,241,242 In later meta-analyses of placebo-controlled and comparator trials, superiority over placebo and equivalence to conventional antidepressants was also reported (see below).^{240,243–246} In a 2000 systematic review of eight randomised controlled trials, Gaster and Holyroyd reported the absolute increase in response rate with Hypericum ranged from 23% to 55% higher than with placebo, but 6% to 18% lower than tricyclic antidepressants.²⁴⁷ Other systematic reviews reported similar findings to the ones mentioned above.^248–250 Large-scale observational studies of patients with mild-to-moderate depression, including MDD, reported response rates between 65% and 100%.²⁵¹

A Cochrane review published in 2008 of studies comparing Hypericum extracts with placebo or conventional pharmaceutical antidepressant drugs supported its use in MDD.²⁴³ A total of 29 trials (5489 patients) were included, with 18 of these being placebo-controlled^20,252–268 and 17 active-controlled trials.^{256,261–266,269–278} The standard antidepressant drugs were the older tricyclics (maprotiline (one trial), imipramine (three trials) and amitriptyline (one trial)), and selective serotonin reuptake inhibitors (SSRIs, fluoxetine (six trials), sertraline (four trials), paroxetine (one trial) and citalopram (one trial)). The severity of MDD was identified as mild-to-moderate in 19 trials and moderate-to-severe in nine trials. Dosages ranged from 240 to 1800 mg/day Hypericum extract, but were mostly between 500 and 1200 mg/day.

The Hypericum preparations studied in the trials included LI 160 (Jarsin, Lichtwer Pharma, Berlin, Germany), HYP611 (Felis 650, Biocur Arzneimittel GmbH, Holzkirchern, Germany), STW3-1 (Stegerwald Arzneimittelwerk, Darmstadt, Germany), STW3-IV (Stegerwald), STW3-VI (Stegerwald), LoHyp-57 (Dr Werner Loges and Co., GmbH, Winsen, Germany), WS5572 (Schabe Pharmaceuticals, Karlsruhe, Germany), WS5573 (Schwabe), WS5570 (Schwabe), Iperisan (Labaratorio Marjan, Sao Paulo, Brazil), STEI 300 (Steiner Arzneimittel, Berlin, Germany), Ze117 (Max Zeller Sohn, Romanshorn, Switzerland) and Psychotonin Forte (Steigerwald).

The majority of trials were of high quality. Meta-analysis found that for the placebo controlled trials examined, patients receiving Hypericum extracts were significantly more likely to be responders (RR 1.48; 95% CI 1.23 to 1.77), although study results were highly heterogeneous (I² 75%). For the comparator trials, there were no differences between the groups based on the Hamilton Depression Scale (HAM-D) pooled responder rate (RR) ratio 1.01 (95% CI 0.93 to 1.09; I² 17% based on an intention-to-treat approach) and on the clinical global impressions (CGI), RR 1.01 (95% CI 0.94 to 1.09). Patients allocated to Hypericum were less likely to drop out of studies due to adverse events than patients allocated to either the older standard antidepressants or SSRIs. Side effects of Hypericum extracts were usually minor and uncommon.

Further details of some of the comparator studies reviewed in mild-to-moderate depression are included here. Hypericum extract LI 160 900 mg/day (2.7 mg/day TH equivalent) had comparable efficacy to amitriptyline 75 mg/day on HAM-D and CGI scores in 149 patients with mild-to-moderate MDD over a 6-week period.²⁷³ In a 6-week comparator trial on mild-to-moderate major depression in 324 outpatients from psychiatric and general medical practices, ZE 117 500 mg/day (equivalent to 1 mg/day hypericin) was therapeutically equivalent to imipramine 150 mg/day, but better tolerated.²⁷⁴ Similarly, an 8-week trial in 263 patients with moderate MDD found Hypericum extract STEI 300 at a dose of 1050 mg/day (0.2% to 0.3% TH and 2% to 3% hyperforin) to be more effective than placebo and at least as effective as imipramine 100 mg/day in 263 patients.²⁶⁶ Hypericum extract LoHyp57 at a dose of 800 mg/day was shown to be equivalent to fluoxetine 20 mg/day in mild-to-moderate depression in 149 elderly patients aged 60 to 80 years. Hypericum reduced HAM-D scores from 16.6 to 7.91, while fluoxetine resulted in a reduction from 17.18 to 8.11.²⁷⁶ In 251 outpatients with moderate-to-severe MDD, Hypericum WS 5572 (hydro- alcoholic extract 3:1 to 7:1 extract ratio; 1 mg to 2.5 mg/day TH) at an initial dose of 900 mg/day, increased to 1800 mg/day after 6 weeks in non-responders, was at least as effective as paroxetine and better tolerated. Hypericum resulted in a 57% reduction in HAM-D scores compared with a 45% reduction for the SSRI.²⁷⁷

Placebo-controlled studies covered by the Cochrane review include the following. A 6-week randomised, controlled trial with Hypericum extract WS 5572 at two doses, (600 mg/day and 1200 mg/day, 0.3% TH) in 332 patients with mild-to-moderate major depression found Hypericum to be superior to placebo (p<0.001) at both doses.²⁵⁴ Hypericum extract STW 3-VI at 900 mg/day for 8 weeks was superior to placebo (p<0.001) in mild-to-moderate depression in 140 outpatients.²⁵⁸ In a randomised, double blind trial, 102 outpatients with mild-to-moderate depression received either Hypericum extract LI 160 (2.7 mg/day TH equivalent) or placebo. The total Hamilton score in the Hypericum treatment group fell significantly (p<0.001) further after 4 weeks than in the placebo group.²⁵² The placebo group also responded favourably when switched to active treatment for 2 weeks.

In a study not included in the 2008 Cochrane review, Hypericum extract was found to be superior to placebo in patients with MDD with reversed vegetative signs (RVS) in an exploratory subgroup analysis of a 3-arm study.²⁷⁹ A total of 135 patients were randomised to 12 weeks’ treatment with Hypericum LI 160 (900 mg/day), fluoxetine (20 mg/day) or placebo. Patients with RVS were defined in two steps, according to the DSM-IV. First, patients with melancholy-related vegetative signs were excluded. Secondly, patients had to have at least one score of 2 for items 22 to 26 of the HAMD-28 scale, which are related to hypersomnia and hyperphagia. Twenty-seven patients remained in the group. Post-hoc analysis showed a trend to superiority of Hypericum compared with placebo and fluoxetine. Fluoxetine was not different from placebo.

Anxiolytic activity

Anxiolytic clinical activity of Hypericum extracts has been reported in several published case studies as well as in clinical trials investigating a range of conditions, including MDD with co-morbid anxiety, somatoform complaints, obsessive-compulsive disorder, social phobia, irritable bowel syndrome, seasonal affective disorder, sleep disorders, premenstrual syndrome and menopause. (Refer to the relevant sections for further details of these studies.)

In 2001, Davidson and colleagues described three case reports of benefits of Hypericum extract (standardised to 0.3% TH) in generalised anxiety disorder (GAD) diagnosed by DSM-IV criteria.²⁹⁵ Two of the patients had moderate anxiety and one marked anxiety. Not only did core GAD symptoms improve, but there was an improved ability to cope with daily stress and potential conflicts with others.

In a further three positive case reports by Kobak and colleagues in 2003, all patients were treatment naïve, and responded to initial treatment with Hypericum extracts.²⁹⁶ In one case, the patient discontinued treatment due to adverse events and subsequently relapsed. In case 1, optimal treatment efficacy (e.g. much improved on both CGI and Patient Global Impressions of Improvement Scale, PGI) was obtained at 1350 mg/day and in cases 2 and 3 at 900 mg/day.

In a multicentre, placebo-controlled double blind trial, the effect of a highly concentrated Hypericum preparation was investigated on 97 depressed outpatients at doses of 200 to 240 mg/day. The preparation showed an anxiolytic effect on the State-Trait Anxiety Inventory of 38% (STAI X1) and 39% (STAI X2), compared with the placebo, which reduced anxiety by only 19% (STAI X1) and 20% (STAI X2).²⁶⁰

Superiority was shown for LI 160 on anxiety measured on the Hamilton Anxiety Scale (HAM-A) in an 8-week, randomised, double blind, placebo-controlled, multicentre parallel-group trial evaluating the efficacy of Hypericum extract LI 160 (600 mg/day) in 200 patients who met the ICD-10 criteria for mild or moderate depression and had been diagnosed with atypical depression (p=0.01).²⁸⁵ LI 160 was also superior to placebo on the Patient Health Questionnaire (PHQ)-9 (p<0.01) and Clinical Global Impressions-Improvement (CGI-I) scale (p=0.01).

A combination of Hypericum and Piper methysticum (kava) failed to outperform placebo in a randomised, controlled crossover trial in patients with MDD and co-morbid anxiety. Standardised Hypericum tablets (3/day, each containing 1.8 g dried herb equivalent containing 990 μg TH, 9 mg hyperforin and 15 mg flavonoid glycosides), and kava (2.66 g three times daily standardised to 50 mg kava lactones) or placebo were administered to 28 participants in a crossover design, with two controlled 4-week phases.²⁹⁷

The Hypericum extract LI 160 was found to be superior to placebo in somatisation disorder, independent of depressive symptomatology. In a 6-week multicentre, randomised, controlled trial with 151 patients suffering from somatisation disorder (ICD-10: F45.0), undifferentiated somatoform disorder (F45.1) or somatoform autonomic dysfunctions (F45.3), Hypericum was superior to placebo on the Hamilton Anxiety Scale, sub-factor Somatic Anxiety (HAMA-SOM) (p=0.001).²⁹⁸

These findings were subsequently confirmed in a prospective, randomised, placebo-controlled, double blind, parallel group study involving 184 outpatients with somatisation disorder (ICD-10: F45.0), undifferentiated somatoform disorder (F45.1) and somatoform autonomic dysfunction (F45.3), but not major depression.²⁹⁹ Patients received either 600 mg/day Hypericum extract LI 160 or placebo for 6 weeks. In the intention-to-treat population (n=173) for each of six primary efficacy measures, superiority of Hypericum over placebo was demonstrated (p<0.0001).

In a randomised, controlled trial in patients with social phobia, no significant difference was found between Hypericum and placebo on the Liebowitz Social Anxiety Scale (p=0.27). Forty patients with generalised social anxiety disorder without co-morbid depression were randomised to 12 weeks of treatment with a flexible dose (600 to 1800 mg/day) of Hypericum extract LI 160 (n=20) or placebo (n=20).³⁰⁰

Obsessive-compulsive disorder

In an open label exploratory study, 12 patients with a primary DSM-IV diagnosis of obsessive-compulsive disorder (OCD) of at least 12 months’ duration were administered a fixed dose of 900 mg/day LI 160 (extended-release formulation) for 12 weeks. A significant change from baseline to week 12 on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was observed, with a mean change of 7.4 points (p=0.001). Five (42%) of 12 were rated ‘much’ or ‘very much’ improved on the clinician-rated CGI-I scale, six (50%) were ‘minimally’ improved and one (8%) had ‘no change’.³⁰¹

However, such findings were not replicated in a subsequent 12-week randomised controlled trial in 60 patients with OCD using a standardised Hypericum extract (LI 160) at a flexible dose of 600 to 1800 mg/day.³⁰² There was no significant difference between the mean change on the total Y-BOCS with Hypericum treatment (3.43) and placebo (3.60) (p=0.899), or on any of the subscales.

Seasonal affective disorder

In a postal open label survey of mild-to-moderate seasonal affective disorder (SAD), Hypericum extract LI 160 (900 mg/day) for 8 weeks was compared with the same formulation in addition to light therapy. Significant improvements were observed in anxiety, loss of libido and insomnia in both groups. No significant between-group differences were observed on any measure except for sleep, which improved more in the Hypericum plus light group (p<0.01). On an 11-item rating scale, the mean score in the 168 patients using Hypericum alone fell from 21.3 at baseline to 13 at endpoint (p<0.001), while the corresponding figures for the 133 patients using Hypericum plus light therapy were 20.6 and 11.8, respectively (p<0.001), suggesting Hypericum may be an effective treatment for SAD.³⁰³

In an earlier preliminary, single blind trial, 20 patients with SAD were randomised to receive Hypericum extract (2.7 mg/day TH equivalent) combined with either bright or dim light therapy for 4 weeks. A significant reduction of HAM-D scores was observed in both light groups, but with no significant difference between them. The favourable response in the dim light group suggested Hypericum may be an efficient therapy in patients with SAD, as well as in combination with light therapy.³⁰⁴ In another similar single blind trial, 4 weeks’ treatment with Hypericum extract (2.7 mg/day TH equivalent) was associated with a significant reduction in the total Hamilton score. There was no significant additional advantage for bright light treatment over Hypericum.³⁰⁵

Menopause-related symptoms

A 12-week monitoring study on a Hypericum liquid (60 drops/day) in 40 patients compared its efficacy to diazepam (6 mg/day) in 20 patients with climacteric anxiety and depression.³⁰⁶ On the HAM-A, scores reduced by 72% with Hypericum compared with 37% for diazepam. On the Self-rating Depression Scale, scores reduced by 46% and 31% respectively, suggesting a beneficial effect on both anxiety and depression associated with menopause.

In an open, observational study of 111 ‘pre-’ (presumably peri-) and postmenopausal women aged between 43 and 65 years, Hypericum LI 160 was found to significantly improve the psychological (irritability, depressive moods, inner tension, anxiety, sleep and concentration disorders) and somatic symptoms of menopause (hot flushes, sweating, palpitations, dizziness, headaches).³⁰⁷ The total daily dose was 405 to 675 mg extract, standardised to 0.9 mg hypericin, for 12 weeks. On the self-designed sexuality assessment scale, significant improvements were found in the feeling of attractiveness (p<.0.001) and participants’ rating of the importance of sexuality (p<0.001).

A pilot double blind, randomised, controlled trial investigated an ethanolic Hypericum extract (2700 mg/day) against placebo in 47 perimenopausal breast cancer survivors aged 40 to 65 years, experiencing three or more hot flushes per day.³⁰⁸ After 12 weeks, a non-significant difference favouring the Hypericum group was observed in the daily hot flush frequency (p=0.10). Women on the active treatment reported significantly better menopause-specific quality of life (p=0.01) and significantly fewer sleep problems (p=0.05) compared with the placebo group.

A trial involving 100 women investigated a liquid extract of Hypericum for its impact on hot flushes.³⁰⁹ The drops, administered three times daily at an unspecified dose, contained hypericin at 0.2 mg/mL. After 8 weeks, the frequency of hot flushes decreased by 54% with Hypericum compared with 32% for placebo (p<0.001), duration decreased 51% and 23%, respectively (p<0.001) and severity decreased 60% and 26%, respectively (p<0.001).

A combination of Hypericum and Vitex agnus-castus was studied in a 16-week randomised, controlled trial involving 100 late-perimenopausal and postmenopausal women.³¹⁰ No significant effect was found for the herbal combination over placebo on vasomotor symptoms (p=0.42), Greene Climacteric scores (p=0.13) or depressed mood (p<0.42). However, both arms showed significant improvements from baseline on all outcome measures of vasomotor symptoms (p<0.001 and p<0.01 for placebo and study groups, respectively), depressed mood and overall menopausal symptoms measured on the Greene Climacteric Scale, (p<0.001 for both groups). Based on current evidence for their pharmacology, a negative interaction between the two herbs seems unlikely.

Several studies support the benefit of Hypericum in combination with Actaea racemosa (black cohosh) for menopausal complaints.^311–315 In a double blind, placebo-controlled trial of 301 women experiencing menopausal complaints with a pronounced psychological component, the combination was significantly superior to placebo (p<0.001).³¹¹ The dosage regime was two tablets twice daily for 8 weeks, reducing to one tablet twice daily for the following 8 weeks. Each tablet contained Hypericum extract equivalent 245 to 350 mg herb, standardised to 0.25 mg TH and Actaea extract equivalent 22.5 to 41.25 mg rootstock, standardised to 1 mg triterpene glycosides. The mean decrease in scores on the Menopause Rating Scale from baseline to week 16 was 50% in the treatment group, compared with 19.6% in the placebo group (p<0.001). The HAM-D score decreased by 41.8% in the treatment group and 12.7% in the placebo group (p<0.001).

A 6-week double blind, randomised controlled trial of the same combination in 179 women found significant improvement of ‘psychovegetative’ menopausal symptoms such as anxiety, impaired drive, depressive mood, nervousness and irritability, as well as good tolerability and compliance.³¹² Symptoms rated on the Kupperman Index (KI) fell from 31.4 to 18.7 (40% reduction) in the treatment group, compared with 30.3 to 22.3 (26% reduction) in the placebo group (p<0.001).

A large-scale prospective, controlled, open label observational study of 6141 women in Germany investigated the effectiveness and safety of Actaea alone for neurovegetative symptoms, and in fixed combination with Hypericum for more pronounced mood complaints.³¹⁴ The effectiveness and tolerability profiles of both therapies were supported. For the alleviation of mood symptoms, the fixed combination of Actaea with Hypericum was superior to Actaea alone (p<0.001). The Psych and Hot Flushes subscales showed the greatest improvements for both therapies. Improvement was maintained at 6 and 12 months for both treatments.

A multicentre trial involving 89 symptomatic peri- or postmenopausal women investigated the effect of a combination of Hypericum and Actaea extracts (a 264 mg tablet containing 0.0364 mL extract of Actaea rhizome, equivalent to 1 mg triterpene glycosides, and 84 mg dried extract of Hypericum equivalent to 0.25 mg TH) over 12 weeks.³¹⁵ The herbal combination was shown to be superior to placebo for hot flushes (p=0.021) and overall menopausal symptoms rated on the KI (p<0.001).

Premenstrual syndrome

A pilot study involving 19 women suffering at least 6 consecutive months of premenstrual syndrome (PMS) found that Hypericum significantly reduced the severity of symptoms.³¹⁶ This open, observational study of Hypericum extract (LI 160) found significant reductions in all outcome measures after treatment for two cycles with Hypericum tablets standardised to 900 μg TH per day. The Mood subscale (as opposed to Pain, Physical and Behaviour), however, showed the most improvement. Hypericum was found to be effective and well-tolerated in alleviating symptoms of moderate-to-severe PMS of 6 months or more duration in 170 women in a randomised, double blind, placebo-controlled study.³¹⁷ Hypericum tablets (2.68 mg/day TH, extract not specified) or placebo were administered for 8 weeks (two menstrual cycles). Anxiety (mood swings, anxiety or nervous tension/irritability), hydration (breast tenderness, swelling of extremities or weight gain), depression (depression, crying, forgetfulness or insomnia) and craving (increased appetite, headache or fatigue) were evaluated daily on scale of 1 (not at all) to 6 (extreme). Treatment with Hypericum resulted in significantly lower PMS scores compared with baseline (p<0.001) and compared to placebo (p<0.001). The greatest improvements occurred for symptoms of crying (71%) and depression (52%).

Hypericum (LI 160, 900 mg/day) was found to be superior to placebo for some symptoms of mild PMS in a randomised, double blind, placebo-controlled, crossover study with 36 regularly cycling women aged 18 to 45 years.³¹⁸ Hypericum was statistically superior to placebo in improving physical and behavioural symptoms (p<0.05), but not mood- or pain-related symptoms. There was no difference between groups in terms of plasma hormone (FSH, LH, oestradiol, progesterone, prolactin and testosterone) or cytokine (IL-1beta, IL-6, IL-8, interferon-gamma and TNF-alpha) levels, nor weekly reports of anxiety, depression, aggression and impulsivity measured on the State Anxiety Inventory, Beck Depression Inventory, Aggression Questionnaire and Barratt Impulsiveness Scale.

A double blind, placebo-controlled, randomised trial was conducted with 70 university students with premenstrual syndrome.³¹⁹ Hypericum (extract not specified) (60 drops for 7 days prior to onset of menstruation) was administered for two complete menstrual cycles. Active treatment resulted in a mean reduction in daily symptom ratings of 46.45% compared with 18.1% for placebo. There were significant reductions in all symptoms between the two groups.

However, superiority over placebo was not found for Hypericum in a placebo-controlled trial conducted in 125 normally menstruating women who experienced recurrent PMS.³²⁰ The primary endpoint was anxiety-related symptoms recorded in a menstrual diary based on Abraham’s classification. Although both groups improved significantly in all symptom subgroups (p<0.007 for both groups), there was no difference between treatments (p≥0.57 for all symptom subgroups).

A small study of PMS-like symptoms in late-perimenopausal women investigated the combination of Hypericum (extract equivalent to 5400 mg/day dried herb standardised to contain 2.97 mg TH, 27 mg hyperforin and 54 mg flavonoid glycosides) with Vitex (extract equivalent to dried fruit 1000 mg/day).³²¹ At the end of the 16-week treatment phase, the herbal combination was significantly superior to placebo on Abraham’s Menstrual Symptoms Questionnaire total PMS scores (p=0.02), PMS-D (p=0.006) and PMS-C clusters (p=0.027). The active treatment group also showed significant reductions from baseline in the anxiety (p=0.003) and hydration (p=0.002) clusters.

A case report of premenstrual dysphoric disorder treated with Hypericum extract (900 mg/day) indicated much improvement in symptoms at the 5-month follow-up.³²²

Cognitive activity

In a randomised, double blind trial, the effect of Hypericum extract (2.7 mg/day TH equivalent) was compared with maprotiline on resting EEG and evoked potentials in 24 healthy volunteers. Improved cognitive functions were observed, particularly for Hypericum treatment.¹³⁵

However, no effect on cognitive function was observed in a randomised, double blind, crossover study in 12 healthy male volunteers, administered oral doses of 255 to 285 mg Hypericum extract (900 μg TH content) three times daily for a period of 14 days. No increase was observed in theta power density on qEEG, and Hypericum did not affect heart rate variability.³²³

Hypericum (900 mg or 1800 mg) had no effect on cognitive and psychomotor performance 1, 2 and 4 hours after administration in 13 healthy volunteers in a double blind, placebo-controlled trial in which it was compared with amitriptyline 25 mg. Amitriptyline impaired performance in a battery of psychological tests, while a dose-related impairment was only observed on the digit symbol substitution test with Hypericum.³²⁴

In a double blind, crossover, repeated-measures design, acute administration of standardised Hypericum extract (900 mg and 1800 mg) to 12 healthy young volunteers showed no nootropic effects. At the higher dose, there was even some evidence it caused impairment of numeric working memory and picture recognition.³²⁵

Irritable bowel syndrome

Hypericum extract (900 mg/day) was administered to 30 women with irritable bowel syndrome (IBS) and 20 healthy women. After 8 weeks of treatment, HAM-A and HAM-D scores had significantly reduced in the IBS group compared with pretreatment (p<0.05). Low frequency band/high frequency band ratio (a measure of sympathovagal balance) also showed a significant decrease (p<0.05), and gastrointestinal symptoms of pain and bloating were also significantly relieved (p<0.05). These open label results suggested that Hypericum treatment may be of value in the psychological and autonomic reactivity to stress in patients with IBS.³²⁶

However, these findings were not replicated in a randomised, placebo-controlled trial of Hypericum extract at a dose of 450 mg/day for 12 weeks in 70 participants with an established diagnosis of IBS according to the Rome Criteria II. Both groups reported decreases in overall bowel symptom scores from baseline, with the placebo arm having significantly lower scores at 12 weeks (p=0.03) than Hypericum.³²⁷

Sexual function

A double blind, randomised, placebo-controlled study of Hypericum extract 160 mg tablets in 50 married men (aged 18 to 50 years) with premature ejaculation found the herb to be statistically superior to placebo in intravaginal ejaculatory latency time (IELT) (p<0.001) after 4 weeks.³²⁸ There was a significant increase in intercourse satisfaction and overall satisfaction in the Hypericum group (p<0.001).

A pilot study found that a hyperforin-containing extract of Hypericum increased the duration of sexual intercourse and improved sexual satisfaction in 16 men (average age 35.0±4.6 years) with and without complaints of premature ejaculation.³²⁹ A rapidly dissolving oral tablet formulated with a 20 mg dose of hyperforin was administered at least 15 to 30 minutes before intercourse over a 4-week period. There was a significant increase in mean IELT time from 246±29 to 331±34 seconds (p<0.002) in participants taking the extract. Fourteen of 16 men (87.5%) reported an improvement in IELT, which was seen in men both with and without premature ejaculation. There was also a significant increase in the average male satisfaction score from 3.8±0.27 to 4.25±0.21 (p<0.03). The female satisfaction score also showed a significant increase from 4.9±0.27 to 5.2±0.23 (p<0.04). No systemic or adverse effects on erectile function or orgasm were reported.

Mean time to ejaculation increased with the administration of hyperforin-containing extract to men with premature ejaculation. Ten male volunteers took the above rapid release formulation for 8 weeks.³³⁰ In five men with mean ejaculatory duration at baseline of less than 90 seconds, four reported a benefit (mean time to ejaculation before and after treatment, 58±12 seconds and 131±23 seconds, respectively). In men with ejaculation times greater than 3 minutes at baseline, the mean sexual intercourse duration increased from 266±30 to 391±34 seconds (p=0.02). No adverse effects on sexual function and systemic side effects were reported. Seven of 10 couples reported subjective global sexual satisfaction improvement for both partners after the herbal extract. Five couples reported more frequent female orgasm.

Attention-deficit hyperactivity disorder

In a small, open trial, Hypericum was investigated for attention-deficit hyperactivity disorder (ADHD) in three 14- to 16-year-old male psychiatric outpatients. Hypericum extract 30 mg/day (extract not specified) was administered for 4 weeks, and a placebo for a further 4 weeks.³³¹ Patients’ mean scores improved on the Conner Scale for hyperactivity (which decreased from 13 to 7), inattention (from 14 to 9) and immaturity factors, and the total score (from 27 to 16). Placebo scores were similar to those at baseline. However, Hypericum was not associated with an improvement on the Continuous Performance Test. This study is limited by the sample size, but suggests that Hypericum warrants further investigation for the treatment for ADHD.

In an earlier trial, administration of Hypericum for the treatment of ADHD over the course of 8 weeks did not improve symptoms in a randomised, double blind, placebo-controlled trial involving 54 children aged 6 to 17 years who met the DSM-IV criteria for ADHD.³³² Participants were randomised to receive 300 mg/day of Hypericum extract (standardised to 0.3% TH) or placebo. No significant differences were observed in the change of ADHD Rating Scale-IV score, hyperactivity or the CGI. However, it was reported that post-trial testing of the product used found it contained only 0.13% hypericin and 0.14% hyperforin, raising the question of appropriate quality of manufacture as well as adequate dosing.³³³

Wound healing and skin disorders (topical application)

A randomised, controlled trial with 144 women following caesarean section found that topical application of Hypericum cream (20% oily extract in 80% petroleum jelly, oily extract prepared from one part powder of flowering tops in three parts grape seed oil) facilitated wound healing and minimised scar formation, pain and pruritus.³³⁴ Application of the Hypericum cream was commenced 24 h post-surgery and continued for 16 days, three times daily. Significant differences in wound healing on the 10th day, and scar formation on the 40th day postpartum, were demonstrated for the treatment group compared with placebo (p<0.002) and natural history control groups (p<0.008) using the REEDA scale (redness, oedema, ecchymosis, discharge and approximation), the Vancouver Scar Scale (pigmentation, height, pliability and vascularity) and a visual analogue scale. There was no significant difference between placebo and the natural history control groups (p=0.93).

Oily extracts of Hypericum and Calendula officinalis were evaluated for their tissue regenerating effect on surgical wounds in 24 women who had undergone caesarean section during childbirth.³³⁵ The extracts were made from plants collected during the months of May to July in rural areas in the countryside of Cagliari (Sardinia) by crushing and maceration in wheat germ oil in the proportion of 320:1000 (flowering tops/oil, g/g). Topical application of a mixture of 70% oily extract of Hypericum and 30% oily extract of Calendula reduced the surface perimeter area of the surgical wound by 37.6±9.9% compared with a reduction of 15.83±4.64% in the control group after twice daily administration for 16 consecutive days.

In a randomised, placebo-controlled, double blind, half-side comparison trial in 21 patients, a cream containing 5% of a lipophilic Hypericum extract (standardised to 1.5% hyperforin) showed a significant superiority over placebo (p<0.05) for the topical treatment of subacute mild-to-moderate atopic dermatitis (mean score on the Score of Atopic Dermatitis Index 44.5).³³⁶ Skin colonisation with Staphylococcus aureus was reduced by both verum and placebo, showing a trend to better antibacterial activity for the Hypericum cream (p=0.064).

A phase II, placebo-controlled clinical study found topical hypericin with visible light photodynamic therapy to be an effective and well-tolerated alternative to standard psoralen plus UVA treatment of patch/plaque phase mycosis fungoides and plaque-type psoriasis vulgaris.³³⁷ After 6 weeks of twice-weekly topical applications followed 24 hours later by exposure to visible light at 8 to 20 J/cm², several concentrations of hypericin resulted in a significant improvement of treated skin lesions amongst the majority of patients with cutaneous T cell lymphoma and psoriasis, whereas the placebo vehicle was ineffective.

A prospective study investigated the efficacy of PDT after topical application of an extract of Hypericum in actinic keratosis, basal cell carcinoma (BCC) and morbus Bowen (carcinoma in situ) in 34 patients. Eight patients had actinic keratoses (AKs), 21 had BCC and five had Bowen’s disease.³³⁸ For an average of 6 weeks, the extract of Hypericum (0.07% TH) was applied on the skin lesions and 10 mm surrounding the lesion in a 1 mm thick layer under an occlusive dressing for 2 hours, followed by irradiation with 75 J/cm⁻² of red light. Complete clinical response was observed in 50% of patients with the AKs, 28% with superficial BCC and 40% with Bowen’s disease. There was only a partial remission seen in patients with nodular BCCs. A complete disappearance of tumour cells was found in the histological preparations of 11% of patients with superficial BCCs and 80% with Bowen’s disease. All patients complained of burning and pain sensations during irradiation.

Pain relief

A double blind, randomised, placebo-controlled, single-centre study evaluated the effect of systemic Hypericum extract, 900 mg/day (containing 0.31% TH and 3.0% hyperforin) for 12 weeks in 39 patients with burning mouth syndrome.³³⁹ No significant improvement was noted in pain using a visual analogue scale for either group. However, after 4 weeks of therapy, patients taking the Hypericum extracts reported the burning sensation at significantly fewer oral sites compared with patients on placebo (p=0.036).

A randomised, double blind, placebo-controlled, crossover trial involving 54 patients over 5 weeks reported no significant effect on pain in polyneuropathy, but there was a trend towards a lower total pain score with Hypericum extract (total daily dose of 2.7 mg TH) (p=0.05) compared with placebo. Complete, good or moderate pain relief was experienced by nine patients with Hypericum and two with placebo (p=0.07).³⁴⁰

Sleep disorders

The British Herbal Pharmacopoeia (1983) lists Hypericum perforatum as a herbal sedative.¹

Sleep disorders, as well as anxiety and depressive agitation, were reduced by Hypericum (Ze 117 extract, 500 mg/day) in patients suffering from mild-to-moderate depression with anxiety symptoms in a multicentre prospective, randomised, double blind trial (n=240) conducted over 6 weeks.³⁴¹ There was a marked decrease of depressive agitation (pre/post comparison: 46%), anxiety symptoms (44%) and sleep disorders (43%) during the therapy with Hypericum, suggesting it is particularly effective in depressive patients suffering from anxiety symptoms.

The effects of treatment with Hypericum extract LI 160 at higher doses (900 mg/day, 2.7 mg/day TH equivalent) on sleep quality and well-being were investigated in a randomised, controlled, crossover trial over a 4-week period with 12 older (59.8±4.8 years), healthy volunteers. Analysis of slow-wave EEG activities showed the herb induced an increase of deep sleep during the total sleeping period, although no benefit was found for onset of sleep, sleep duration or intermittent awakenings, which implies it did not exert sedative activity.³⁴² The interference with REM sleep phases typical for tricyclic antidepressants and MAO inhibitors did not occur with Hypericum.⁹⁴

As noted earlier, some evidence of an improvement in sleep was observed in an open, observational study of patients with menopausal symptoms involving 111 women aged between 43 and 65 years.³⁰⁷

Drug-dependency syndromes

One open label clinical trial suggested a benefit for a Hypericum herbal infusion used in combination with rational psychotherapy of depressive manifestations in 57 outpatients with alcoholism and concomitant digestive problems.³⁴³ After one glass four to five times daily over a period of 2 months, it was concluded that the combination was effective for alcoholism in patients with peptic ulcer disease and chronic gastritis.

Results of a one-arm, phase II feasibility study suggested a role for Hypericum in maintaining smoking cessation. The 12-week quit rate was 37.5% (9/24) in 24 evaluable participants with administration of standardised Hypericum extract, (80% methanol extract standardised to 0.3% TH and a minimum of 4% hyperforin) at an oral dose of 900 mg/day in conjunction with cessation counselling messages.³⁴⁴

The effect of Hypericum extract Ze117 (500 mg/day) was compared to a transdermal nicotine patch in an open clinical trial on smoking cessation.³⁴⁵ Participants in both groups decreased the number of cigarettes smoked per day over the study treatment period, and four (of 17) in the herbal group, compared with six (of 14) on the nicotine patches, succeeded in quitting.

Hypericum extract was investigated for its impact on nicotine withdrawal in a clinical study in which 45 adult smokers were randomised to receive an oral spray containing either Hypericum extract or placebo in addition to nicotine replacement therapy.³⁴⁶ After 1 month the abstinence rate was identical in both groups. Craving scores, anxiety, restlessness and sleeplessness were lower in the Hypericum treated group.

However, other more rigorous studies have failed to support the benefits of Hypericum extracts in smoking cessation or withdrawal symptoms. In a factorial design, the effects of Hypericum extract (900 mg/day, LI 160) and chromium, alone or in combination, were compared with placebo for smoking cessation over 14 weeks. No significant effect was observed on absolute quit rates or tobacco withdrawal symptoms.³⁴⁷

Similarly, a three-arm, dose-ranging randomised, controlled trial found no significant differences in abstinence rates at 12 and 24 weeks between verum and placebo, or attenuation of withdrawal symptoms among abstinent participants. A total of 118 previous smokers were randomly allocated to receive 300 or 600 mg of a Hypericum extract (standardised to 0.3% hypericin) or a matching placebo tablet three times a day, combined with a behavioural intervention for 12 weeks.³⁴⁸

In an open, uncontrolled, pilot study, Hypericum extract LI 160 (300 or 600 mg/day for 1 week before and 3 months after a target quit date) plus individual motivational/behavioural support failed to show benefit as an aid to smoking cessation in 28 smokers of 10 or more cigarettes per day.³⁴⁹ At 3 months, the point prevalence and continuous abstinence rates were both 18%, and at 12 months they were zero.

Other conditions

In a preliminary open trial, low dose Hypericum extract was modestly effective in the short-term treatment of irritability in some patients with autistic disorder.³⁵⁰ Three male patients with autistic disorder, diagnosed by ICD-10 criteria, were administered Hypericum (extract not specified) 20 mg/day for 4 weeks. Participants were included in the study if their eye contact and expressive language were inadequate for their developmental level, and if they had not tolerated or responded to other psychopharmacological treatments (methylphenidate, clonidine or desipramine). Parent and mentor ratings on the Aberrant Behaviour Checklist, irritability, stereotypy and inappropriate speech factors improved slightly during treatment with Hypericum. Clinician ratings (Psychiatric Rating Scale Autism, Anger and Speech Deviance factors; Global Assessment Scale; Clinical Global Impressions efficacy) did not improve significantly. Limitations of this study included the small sample size, the low dose of Hypericum used and the short trial duration.

One hundred and sixty patients suffering from depression completed a randomised, double blind, multicentre study investigating the electrocardiographic (ECG) effects of high-dose Hypericum treatment (1800 mg extract, 5.4 mg TH) compared with imipramine. Analysis of conduction intervals and pathological findings indicated that, for the treatment of patients with a pre-existing conductive dysfunction or elderly patients, high-dose Hypericum extract was safer with regard to cardiac function than tricyclic antidepressants.³⁵¹

Metabolic drug interactions

The metabolic interaction of the herb Hypericum with a range of pharmaceutical drugs is both widely known and well documented. The list of interacting drugs is now quite extensive and includes the anticancer drug irinotecan, the antidepressant amitriptyline, the anticoagulants phenprocoumon and warfarin, the antihistamine fexofenadine, the sedatives alprazolam and midazolam, protease inhibitors, cyclosporin, digoxin, statin drugs, methadone and several oral contraceptives (see also Appendix C).³⁶⁹ These clinically documented metabolic or pharmacokinetic interactions appear to rely on the capacity of Hypericum to induce faster metabolism of the drug, resulting in lower blood concentrations and compromised drug efficacy.³⁶⁹ Mechanistic studies suggest that Hypericum is a potent inducer of the cytochrome P450 (CYP) enzyme CYP3A4 (and perhaps other CYPs) and the drug transporter P-glycoprotein (P-gp). This results in increased breakdown and/or reduced intestinal uptake of the drug in question.³⁶⁹

It was not long after the first documented cases of the metabolic drug interactions for Hypericum that the evidence emerged that one phytochemical constituent could be largely responsible for this effect. This constituent is hyperforin, a notoriously unstable compound that is only found in some Hypericum subspecies, such as Hypericum perforatum subsp.perforatum.³⁷⁰ For example, in 2001 a letter by Kroll and co-workers to the journal Alternative Therapies already highlighted the importance of hyperforin in causing the drug interactions.³⁷¹

The most compelling case for the culpability of hyperforin came from receptor studies, where it was shown that hyperforin is a potent activator of the pregnane or steroid X receptor. This significant discovery was made in 2000 by two independent research teams.^372,373 The human steroid X receptor (SXR) is activated by a wide range of endogenous and synthetic steroids, and its counterpart in mice is the pregnane X receptor (PXR).³⁷³ However, it is now recognised that the SXR is also activated by other drugs and results in potent induction of CYP3A enzymes, including CYP3A4.³⁷³ In fact PXR and SXR function to protect the body against foreign chemicals or xenobiotics. In an article in the prestigious journal Science, the CYP3A system was described as the ‘garbage disposal’ system of the liver and small intestine.³⁷⁴ This is cutting edge research and hyperforin has actually helped scientists further understand this newly discovered mechanism. Unlike other nuclear receptors, which are characterised by their high degree of specificity, PXR has apparently evolved to be a broad-specificity xenobiotic sensor.³⁷⁵

Hypericum, and specifically hyperforin, also stimulate a second ‘garbage disposal’ mechanism, namely P-gp, probably again by activating PXR and SXR. P-gp is one of several multidrug resistance (MDR) pumps that are found in many living organisms and act to pump out chemicals from cells. For example, MDRs are one mechanism that bacteria use to become resistant to antibiotics. In fact, another name for P-gp is MDR1. P-gp is said to be ‘promiscuous’ in that it can recognise and export a diverse range of structurally unrelated compounds from cells. Since the activation of PXR is also known to increase the transcription of the gene MDR1 that encodes P-gp, it is likely that hyperforin is also the key constituent in Hypericum that induces P-gp.³⁷⁶ Experimentally, it has been verified that it is indeed hyperforin, and not hypericin, that increases the expression of P-gp in vitro.³⁷⁶

The natural conclusion to draw from these findings is that the metabolic drug interactions can be avoided by using a Hypericum preparation that is devoid of hyperforin. However, the prudent clinician would also require verification from clinical studies that this is indeed the case. Fortunately such studies are available.

A clinical study was designed to evaluate the effect on CYP3A function of Hypericum preparations with hyperforin contents ranging from very low to high.³⁷⁷ The test probe drug midazolam was used to indirectly assess induction of these phase I enzymes after all the herbal products were first administered for 14 days. All Hypericum extracts tested decreased the bioavailability of midazolam. The product containing the highest dose of hyperforin (41 mg/day) did this by 79%, whereas that with the lowest dose (0.13 mg/day) reduced bioavailability by only 21%, which is probably not clinically significant. Overall, a dose-response effect for hyperforin was clearly demonstrated.

Perhaps more significantly, several clinical trials have demonstrated that low-hyperforin Hypericum extracts do not interact with key drugs such as cyclosporin, digoxin and the oral contraceptive pill. In the case of cyclosporin, the effect of two Hypericum preparations on the pharmacokinetics of cyclosporin was investigated in 10 renal transplant patients using a crossover design.³⁷⁸ The decrease in cyclosporin bioavailability was 52% for the high-hyperforin preparation, but was only a clinically insignificant 7% for the low-hyperforin product. For each preparation, the doses of Hypericum herb were identical, only the hyperforin contents differed.

The pharmacokinetic interactions between a low hyperforin Hypericum extract and alprazolam, caffeine, tolbutamide and digoxin were evaluated in two randomised, placebo-controlled studies with 28 healthy volunteers. The participants received Hypericum extract (240 mg/day containing 3.5 mg hyperforin) or placebo on days 2 to 11. The test drugs were administered on days 1 and 11. No significant differences in bioavailability were found for all the test drugs between the placebo group and the Hypericum group at the end of the study.³⁷⁹

In an unpublished study, the effect of a hyperforin-free extract of Hypericum was investigated in 16 women aged between 18 and 43 years taking a low dose oral contraceptive pill.³⁸⁰ No significant effect on the serum levels of the pill components, namely ethinyloestradiol and 3-keto-desogestrel (the active metabolite of desogestrel) were observed. In addition, intracyclic bleedings were not reported.

If avoiding the use of Hypericum preparations high in hyperforin will alleviate the pharmacokinetic drug interactions, a key question is whether this will compromise the antidepressant activity. An important issue in this regard was highlighted in a review of hyperforin in Hypericum–drug interactions.⁵⁵ The issue raised was that the extraction process used to make the most clinically tested extract of Hypericum, namely LI 160, was modified in 1998 to target better levels of hyperforin. This was instituted when research became available suggesting that hyperforin was important for the herb’s antidepressant activity. As the review points out, there were no reports of drug interactions with Hypericum prior to 1998, but there were many positive clinical trials for the treatment of depression.⁵⁵

There is still considerable debate concerning the relevance of hyperforin to the antidepressant effects. There are clinical studies that show that low-hyperforin extracts are superior to placebo or equivalent to fluoxetine in the treatment of mild-to-moderate depression. Equally there are clinical studies that demonstrate a low-hyperforin extract was ineffective, compared to a high-hyperforin extract (see earlier). Is it an excess of modern technology, and hence not natural, to be targeting hyperforin during the extraction process? Probably not, since the dry powdered Hypericum herb and the tea, which are both traditional preparations, can deliver clinically significant doses of this phytochemical.³⁷⁷ (The tea must of course be freshly brewed as hyperforin is quite unstable in solution.)

As just mentioned, hyperforin is unstable in extracts of Hypericum, even in the dry extracts found in tablets and capsules. It is most unstable in solution and rapidly decomposes at an acidic pH.²³ Tinctures and fluid extracts (galenicals) of Hypericum older than a few months contain no hyperforin at all.³⁸¹ The most sure and obvious way to avoid the metabolic drug interactions with Hypericum is to use the traditional liquid dosage forms.

As well as the hyperforin content, the actual dose of Hypericum also comes into consideration. A randomised, placebo-controlled, parallel-group study investigated the pharmacokinetic interaction of various Hypericum formulations and doses with digoxin in 96 healthy volunteers.³⁸² Like the other studies already quoted, this study also found that the interaction with digoxin varied with the hyperforin content in the administered dose. But what the study also highlighted was that the hyperforin dose is a function of two variables, namely the hyperforin percentage in the preparation and the action actual dose of that preparation. When using the same preparation (powdered dried herb in capsules) a clear dose-response relationship was demonstrated for the drug interaction. No effect on digoxin bioavailability compared with placebo was observed for herb doses of 0.5 and 1 g/day, containing daily doses of hyperforin of 2.6 and 5.3 mg, respectively. Significant effects were seen at doses of 2 and 4 g/day of herb (containing 10.6 and 21.1 mg/day hyperforin, respectively), although the authors noted that the effect from 2 g/day was borderline and potentially not clinically relevant.

Pharmacodynamic drug in teractions

The published works on this topic are fewer than the pharmacokinetic interactions. Hence it is rather extraordinary that many writers regard the potential for Hypericum to interact with antidepressant drugs as an accepted truth. The very fact that antidepressant drugs as a broad class are often referred to, rather than the individual classes of drugs, implies that a less than rigorous perspective has been taken.

Monoamine oxidase (MAO) is involved in the metabolism and inactivation of synaptically released neurotransmitters. It inactivates neurotransmitters inside the neuron that have either been synthesised or have resulted from reuptake and it exists in two isoforms, A and B: MAO-A preferentially breaks down adrenaline (epinephrine), noradrenaline (norepinephrine) and serotonin; MAO-B prefers phenylethylamine and benzylamine as substrates. Dopamine, tyramine and tryptamine are metabolised equally well by both forms. Most MAO inhibitors (e.g. phenelzine) inhibit both forms, but some newer drugs, such as moclobemide, inhibit only MAO-A and are considered safer. They cause increased intraneuronal levels of neurotransmitters, which does not necessarily lead to increased levels at receptors. Non-selective MAO inhibitors are not as popular now because of their side effects and well-known interaction with tyramine in foods (e.g. cheeses, red wine, etc).³⁸³ Like tricyclics, the clinical effects of SSRIs in depression probably result more from the delayed postsynaptic adaptive responses than from the acute inhibition of the reuptake of serotonin. These drugs include fluoxetine and sertraline.

Serotonin syndrome is defined as an adverse drug interaction characterised by altered mental status, autonomic dysfunction and neuromuscular abnormalities. It is most frequently caused by the use of SSRIs and MAO inhibitors, leading to excess serotonin availability in the CNS at the serotonin 1A receptor. At least one of these drug classes is always involved. It can also occur with single drug therapy and overdose. Elderly patients are more vulnerable and it is often seen now with SSRI over-medication. The clinical picture is nonspecific and there is no confirmatory test. It can be mistaken for viral illness, anxiety or a neurological disorder.³⁸⁴

Is there an inherent issue in prescribing Hypericum with antidepressants? Antidepressant drugs of different classes are often combined, especially by psychiatrists, in patients who are resistant to treatment. This is sometimes called ‘augmentation therapy’. The risk of serotonin syndrome from doing this with drugs is infrequent, and so is likely to be even lower (if at all) when Hypericum is combined with antidepressants (given that the mode of action of Hypericum is unlike conventional drugs; see elsewhere in this monograph and below).

Animal or human studies are most relevant for understanding the mode of action of Hypericum. One study in rats has suggested that the mode of action of Hypericum is more like that of tricyclics than SSRIs.⁷³ But a human study has shown that amitriptyline (a tricyclic) is quite different in its pharmacological effects compared to Hypericum.³⁸⁵ Another human study found that effects of Hypericum were quite different to imipramine (another tricyclic). The authors of this study concluded that its effects could be quite novel and possibly linked to dopamine metabolism.⁹⁶

One article in a prestigious pharmaceutical journal described Hypericum as ‘nature’s Prozac’.³⁸⁶ However, this was countered by other scientists in a subsequent letter, who stated that there is a paucity of in vivo evidence supporting the proposition that Hypericum impairs any form of monoamine reuptake.³⁸⁷ In their response the original authors agreed and stated that:³⁸⁸

An experimental in vivo model found that two different Hypericum extracts (with different hyperforin levels) had no effect on the neuronal activity of the dorsal raphe nucleus of the brain.³⁸⁹ This contrasted sharply with fluoxetine and sertraline (SSRIs), which markedly depressed such neuronal activity by increasing the synaptic availability of serotonin.

There is currently a paucity of evidence from either in vivo models or from controlled clinical trials that Hypericum interacts pharmacodynamically with any class of antidepressant drugs. However, there are a number of case reports in the literature. These are reviewed below for the major classes of antidepressant drugs.

There are no published adverse reports of pharmacodynamic interactions for Hypericum and tricyclics: neither case reports nor trials. There is a credible clinical study for amitriptyline that showed reduced plasma levels (and hence a pharmacokinetic interaction).³⁹⁰ Since nortriptyline is basically a metabolite of amitriptyline, this would probably apply for this drug as well. However, all the issues governing the pharmacokinetic interactions with Hypericum will apply (as discussed previously).

The first case report of an alleged interaction between a Hypericum product (unspecified) and an SSRI (paroxetine) was published in 1998.³⁹¹ The patient exhibited symptoms of grogginess, incoherence and slow movements, which could hardly be described as serotonin syndrome. The authors incorrectly described Hypericum as a MAO inhibitor. Four case reports of serotonin syndrome in elderly people were described in one published report, as due to an alleged interaction between Hypericum and sertraline.³⁹² An alleged interaction between Hypericum and paroxetine resembling serotonin syndrome was published in 2000.³⁹³ A manic episode (possibly serotonin syndrome) attributed to an interaction between Hypericum and sertraline was also published in 2000.³⁹⁴ The quality of all such reports is low.

There are a few case reports in the published literature of adverse pharmacodynamic interactions between Hypericum and novel antidepressant drugs. For example, reports exist of serotonin syndrome attributed to the interaction of Hypericum and the modified cyclics trazodone³⁹⁵ and nefazodone respectively.³⁹² An adverse reaction between the selective noradrenaline reuptake inhibitor venlafaxine and Hypericum has also been published.³⁹⁶ Again the quality of these reports is low.

In conclusion, the research has shown that pharmacokinetic drug interactions should not be an issue for doses of Hypericum less than 2 g/day herb (or its equivalent) or any doses of a Hypericum preparation low in hyperforin (such as a tincture or fluid extract). These preparation and dosage guidelines should be followed whenever there is a requirement to recommend Hypericum to patients taking any of the drug medications known to interact with this herb. In particular, the guidelines should be strictly observed in all patients taking any form of the oral contraceptive pill. However, for depressed patients not taking any of the problem drugs it is best to recommend preparations that deliver a reasonable dose of hyperforin (in the range 15 to 30 mg/day). These will, by necessity, be tablets or capsules containing a dried extract.

In terms of potential pharmacodynamic interactions, the exact mode of action of Hypericum on monoamine neurotransmitters is not fully understood. Results from comparative in vivo studies suggest that its pharmacological profile is quite different to SSRIs and tricyclics. There is currently little convincing evidence from either in vivo studies or controlled clinical trials to support the contention that Hypericum interacts with any class of antidepressant drugs.

On current evidence, the risk of an adverse pharmacodynamic interaction between Hypericum and conventional antidepressant drugs must be rated as quite low. Suggestions of a strong likelihood of such interactions in the literature are tainted by medical politics, since antidepressant drugs are often combined in modern therapy, yet the risk of serotonin syndrome from such practice is regarded as low. If clinically appropriate, it is suggested that Hypericum can be combined with antidepressant drugs under professional supervision. A low dose should be recommended at first both as a caution and to reassure the patient. Due to media attention, and in some cases warnings on labels, many patients are concerned about the drug interaction issues with Hypericum. Sometimes they have also received advice from their medical doctor or psychiatrist on this matter. Hence, all the above recommendations need to take into consideration the fully informed consent of the patient.

General

Adverse events associated with Hypericum tend to be mild and occur rarely. In clinical trials, side effects are often reported no more frequently with Hypericum extracts than in the placebo arm. Data from a meta-analysis of 35 double blind randomised trials showed that dropout and adverse effects rates in patients receiving Hypericum extracts were similar to placebo, lower than for older antidepressants, and slightly lower than for selective serotonin reuptake inhibitors.⁴¹⁴ No serious adverse effects were reported in any study. Hypericum extracts appear to be free of the cardiac or anticholinergic side effects normally associated with antidepressant medications.²⁵⁷ In a review of large-scale observational studies with at least 100 patients suffering from depressive disorders, comprising a total of 34 804 patients, the percentage of patients reporting side effects ranged between 0% and 5.9%.²⁵¹ Hypericum extracts were associated with only mild side effects, the most frequent being gastrointestinal symptoms, followed by increased photosensitivity and skin symptoms. Headaches, palpitations,²⁶⁶ fatigue and restlessness²⁴⁷ have also been reported. Anxiety was reported by a small number of participants in trials (5 patients of 2404 patients²⁹⁴ and 8 of 3250 patients⁴¹⁵). One clinical trial reported the side effects of muscle and joint stiffness, tremor, sweating, muscle spasms and pain.²⁷⁸ Frequent urination was reported in 27% of participants taking 900 to 1500 mg Hypericum extract daily for 8 weeks, compared with 11% placebo participants.²⁶² The most common adverse event (one per 300 000 treated cases) among the spontaneous reports in the official German register to year 2000 relate to reactions of the skin exposed to light.⁴¹⁶

Adverse events from individual case reports often involve concomitant medication or other pathologies, making it difficult to establish a causal connection with the administration of Hypericum extracts. Cases where the link is considered possible are included below.

Photosensitivity

Pharmacokinetic studies suggest that the phototoxic threshold level of hypericin is not reached with the normal doses of Hypericum used for the oral treatment of depression.⁴¹⁴ However, cases of reversible photosensitivity to Hypericum have been reported, including one case of a burning, erythematous eruption that occurred after 4 days of treatment with 33 mg Hypericum extract.⁴¹⁷ Photosensitivity developed in a 61-year-old woman after taking a Hypericum extract for 3 years, which resulted in elevated, itching red lesions in light-exposed areas.⁴¹⁸ The reaction was reversible and confirmed by provocation test. A patient consuming Hypericum at the time of laser treatment developed a severe phototoxic reaction to laser light.⁴¹⁹ In a clinical study, volunteers consuming a threshold dose of Hypericum extract containing 5 to 10 mg hypericin experienced a mild increase in photosensitisation.⁴¹⁶ Mild-to-moderate, reversible photosensitivity developed in participants in two clinical studies of HIV and hepatitis C with oral hypericin in doses from 0.05 to 0.5 mg/kg/day.^{43,44,233,236} For example, one of these was a phase I study of intravenous and oral hypericin in HIV-infected adults, in which five of 12 participants receiving the 0.05 mg/kg/day dosing schedule and six of seven receiving the 0.10 mg/kg/day dosing schedule developed phototoxic reactions.⁴³ However, intravenous hypericin, 0.25 or 0.5 mg/kg twice weekly or 0.25 mg/kg three times weekly, or oral hypericin 0.5 mg/kg daily, caused severe cutaneous phototoxicity in 11 of 23 evaluable HIV-infected patients with CD4 counts less than 350 cells/mm³.⁴⁴

In contrast to these findings, no evidence was found for a phototoxic potential of the Hypericum extract LI 160 in humans when it was administered orally at typical clinical doses up to 1800 mg daily.⁴²⁰ A prospective randomised study in 72 volunteers of skin types II and III investigated the effect of the Hypericum extract LI 160 on skin sensitivity to ultraviolet B (UVB), ultraviolet A (UVA), visible light and solar-simulated radiation. No significant influence on the erythema index or melanin index was detected in the single-dose (5.4 or 10.8 mg hypericin) or the steady-state studies (5.4 mg hypericin, and subsequently 2.7 mg hypericin, per day for 7 days), with the exception of a marginal influence on UVB-induced pigmentation (p=0.0471) in the single-dose study. These findings were in accordance with previous pharmacokinetic studies that found hypericin serum and skin levels after oral ingestion of Hypericum extract were always lower than the assumed phototoxic hypericin threshold level of 1000 ng/mL.⁴²⁰

Other studies supporting this finding found no significant changes of erythema threshold levels following exposure to UV radiation, visible light and solar-simulated radiation with oral LI 160;⁴²¹ and no significant change in UVB photosensitivity and a UV light sensitivity that was not, or only marginally increased, with oral intake of Hypericum extract (4.5 to 5.4 mg/day TH equivalent for 7 to 15 days).⁴²² There was an increased UVA photosensitivity in the subgroup of light sensitive skin types.

Three cases of topical use of Hypericum creams or oil with or without oral administration (dosage unspecified) resulted in phototoxic reaction upon exposure to sunlight or, in one case, after phototherapy commenced.⁴²³ These include erythematobullous dermatosis and facial bullae related to sun exposure, UVB phototherapy-related follicular erythema and urticarial oedema. However, one patient had lupus and another had psoriasis.

In cell cultures, it was found that phototoxic effects with Hypericum extracts in conjunction with visible light and UVA only occurred at high concentrations.⁴²⁴ Peak hypericin levels in skin blister fluid following administration of an oral dose of 1800 mg or steady-state administration (900 mg daily for 7 days) was at least 20 times below the estimated phototoxic concentration of 100 μg/mL.¹⁶⁵ It has been suggested that the risk of significant photogenotoxic damage incurred by the combination of Hypericum extracts and UVA phototherapy may be low in the majority of individuals.⁴²⁵