Dosage
There is much confusion in the literature about how to specify the exact dosage of hypericum. The most common way is in mg of total extract. As the strengths of the extracts differ considerably, we have chosen to use mg of total hypericin, which means the dose of all the different hypericins (hypericin, pseudohypericin, protopseudohypericin, etc.) together. One way to get the correct dosage is to multiply the dose in mg times the percentage of total hypericin.
ESCOP recommendation is 0.2-1.0 mg total hypericin daily (1).
This recommendation is a bit low in our opinion, as most of the research shows a trend towards better results with higher doses (70, 105).
The preceding table shows that the mean response rate with Jarsin 300 (= 2.7 mg standard hypericin daily) is 70% and with the other preparations 60%. This is not a very scientific method of finding the proper dose, but better than nothing while we wait for further studies on this subject.
The findings by Perovic et al. of an almost linear dose-response serotonin reuptake inhibitory effect also point in this direction.
Winterhoff et al. (70) have demonstrated in animal experiments that 125 mg hypericum extract LI 160 (= 0.35 mg total hypericin) has an equal effect to 10 mg Imipramine on rats. For good clinical results we therefore recommend 0.9 mg total hypericin three times daily (= equivalent to 75 mg Imipramine).
For those who have very mild symptoms or felt some kind of side-effects on the high-dose treatment, the dose can be lowered to 2-3x 0.25-0.35 mg daily.
For children aged 6-12 we recommend treatment with half the adult dose (1).
It is recommended to take hypericum with food in order to minimize possible gastrointestinal complaints.
No studies have been performed on the effect of hypericum teas. 10-20% of total hypericin gets dissolved into tea at a temperature of 80º C (62). For tea-infusion the ESCOP recommends 2-4 g of dried herb daily. However, if the mean concentration in the plant's upper parts is 0.1%, and 10-20% dissolves into the tea, it means that you have to take 10-20g of fresh leaves to get 2 mg of total hypericin.
As alcohol is a better solvent (approximately 35% gets dissolved at a temperature of 80º C), a schnapps made with 6g of fresh hypericum buds would be enough to get 2 mg of total hypericin (62).
Duration of treatment
The ESCOP does not set any restrictions concerning duration of treatment. The effect of hypericum seems to be very long-term. If the response rate is 60% after four weeks, it is likely to be 70% after six weeks and 80% after eight weeks. (See Figure 2).
Interactions
The ESCOP does not mention any known interactions and there are no known severe interactions reported from millions of treatments. As recent research has demonstrated a SRI effect, we recommend special monitoring and care when combined with other antidepressants, especially MAO-inhibitors, because of the theoretical risk of creating a serotonin syndrome. Some manufacturers also mention possible risk of photosensitivity when hypericum is used together with other photosensitizing drugs such as Chlorpromazine and Tetracyclines. There is no interaction with alcohol (112). The lack of interactions is a great advantage, especially in the treatment of the elderly, who often take many other medications with many possibilities of adverse interactions.
Pregnancy and lactation
No data available. As Winterhoff et al. have demonstrated that hypericum extract inhibits the pituitary secretion of prolactin (70), there might be a theoretical possibility of problems with the production of breast-milk during lactation. If this happens one can simply lower the dose or stop taking hypericum. Besides being a hormone necessary for the production of breast-milk, prolactin also has an inhibiting effect on the menstrual cycle and on the libido (sex drive). A lowering of the prolactin does not pose any risk for the infant.
Effects on ability to drive and use machines
Clinical studies indicate no negative influence on general performance or the ability to drive. On the contrary, healthy volunteers taking hypericum extract performed better in tests simulating car driving than subjects taking placebos (83).
Undesirable effects
None confirmed at dose levels up to 3 mg total hypericin. Photosensitization might occur at much higher dosages (see Overdose). Some manufacturers warn of photosensitization when hypericum is used in high doses by light-skinned persons who stay out in the sun a lot.
In a drug-monitoring study with 3,250 patients on high-dose hypericum treatment (0.9 mg x 3) 0.4% of the patients had allergic reactions (skin rash) (25). About 2% complained of gastrointestinal problems, tiredness and other problems that also could have been secondary to their depression (25). In another drug-monitoring study of 1,040 patients (26) on a lower dose (0.36 mg x 3), there were no complaints whatsoever of adverse skin reactions (26).
In placebo-controlled studies there has never been any difference in amount of side effects between the placebo and trial groups. On the contrary, the placebo group sometimes had more side effects, possibly due to untreated depression (40). In a summary of 15 placebo controlled studies performed on 1008 patients there was no difference concerning amount of side-effects (4.1% on hypericum and 4.8% on placebo), and actually less treatment dropouts because of side effects among patients treated with hypericum (0.4% versus 1,6%) (111).
Overdose
Photosensitization at high dosage is reported during experimental antiviral treatment with synthetic hypericin (35 mg intravenously) in HIV-infected patients. Typical phototoxic symptoms include an itching rash and blisters of the skin 24 hours after exposure to sunlight (58). The symptoms are generally mild and do not create any long-term damage.
Inflammatory reactions in the gastrointestinal tract, pain and vomiting may result from an overdose due to catechine-type tannins (1).
Treatment consists of avoiding light exposure, emptying of the stomach, lavage with protein-containing liquids (gruel, protein broth), milk if need be.
Contraindications
None known.
Pharmacodynamic properties
Numerous clinical studies have shown that hypericum possesses an antidepressant effect of a magnitude similar to synthetic antidepressants, but with a minimum of side effects.
The pharmacological mechanism, though, is still a matter of debate. There are many hypotheses, and it seems likely that hypericum uses many different modes of action simultaneously. Maybe one can see the antidepressant effect of hypericum as an example of the old proverb, "Many small streams together create a great river."
Tissue distribution
One interesting notion is that hypericin is absorbed very slowly, and excreted even more slowly in the brain, skin and stomach of mice. This means there will be a gradual increase of concentration in these tissues over a period of weeks until a steady state is reached (68).
This might explain its slow mode of action, its benign effect-side-effect profile and why its primary sites of action have been in the brain, skin and GI-system. These organs are also the organs considered to be primarily affected by hypericum in traditional medicine (see Figure 3). Hypericin gradually accumulates in these tissues over time, while it passes through other parts of the body rapidly.
Figure 3
Hypericin retention in % after 7 days compared to peak uptake
Serotonin and norepinephrine reuptake inhibitory effect
In a recent study Perovic et al. have demonstrated a serotonin-reuptake-inhibiting effect of hypericum extract in vitro (69). (Low serotonin levels in the synapses between the nerve cells are believed to be one of the primary causes of clinical depression. Inhibiting the reuptake of serotonin in the nerve cells raises the concentration of serotonin.) Müller et al. have demonstrated that hypericum also inhibits norepinephrine uptake (67).
It remains to be established whether this has a clinical effect, as the concentrations of the active ingredients of hypericum in the human brain during antidepressive treatment have not been established.
Effect on cortisol secretion via the immune system
Hypericum inhibits the stress-induced increase of CRH, ACTH and cortisol-secretion by inhibiting the cytokine interleukin-6 and other cytokines excreted by cells of the immune system (monocytes, lymphocytes and other types of white blood cells) (71). This stress-preventing effect on cortisol secretion has also been proven clinically in healthy volunteers (59,70).
(It has been proven that depression causes an increased secretion of the "stress hormones" CRH, ACTH and cortisol. These hormones also have a inhibitory effect on the immune system as well as lots of other effects that could explain some of the physiological changes in depression. The cytokines excreted by white blood cells can also be part of these effects both on their own and by their effect on the cortisol secretion).
MAO-inhibition insufficient
The MAO-inhibitory effect of hypericum demonstrated by Suzuki et al. (108) has not been confirmed in later investigations in an amount sufficient to explain the antidepressant action, although it could still be one of the small streams that create the river (61,62). (MAO, mono-amino-oxidase, is an enzyme that contributes to the breakdown of the neurotransmitters serotonin and norepinephrine. An inhibition of MAO thus results in an inhibition of the breakdown, which results in an increase of neurotransmitters in the synapses).
Effect on melatonin secretion
In a study with 13 healthy volunteers, increased light-induced suppression of melatonin and a significant increase in the nocturnal melatonin plasma concentration was observed after administration of hypericum for three weeks. This effect on the melatonin secretion has also been observed with synthetic antidepressants like Amitryptilin and Desipamin (86).
(Melatonin is a hormone excreted by the pineal gland; it has great importance for the regulation of biological rhythms, sleep and sexual activity. The excretion is inhibited by light and facilitated by darkness. Some disturbances in biological rhythms, sexual activity and sleep during depression could be due to detrimental effects on the melatonin system.)
Increased secretion of urinary neurotransmitter metabolites after administration of hypericum
A significant increase of urinary neurotransmitter metabolites of serotonin and norepinephrine has been observed after treatment with hypericum (82). This indicates that hypericum, like other antidepressants, might increase the concentration of these neurotransmitters in the brain.
Effect on dopamine and prolactin metabolism
Hypericum inhibits the enzyme dopamine-B-hydroxylase in vitro (64). (Dopamine-B-hydroxylase breaks down the neurotransmitter dopamine, which is involved in the patophysiology of schizophrenic psychosis and Parkinson's disease.) The resulting increase of dopamine increases the production of a prolactin-inhibitory factor, which in turn diminishes the secretion of Prolactin (70). (Prolactin is a hormone necessary for the production of breast-milk. It also has an inhibiting effect on the menstrual cycle and on the libido.)
Effect on benzodiazepine receptors
Hypericin has been shown to potentiate binding to benzodiazepine receptors. This could be one explanation for hypericum's antianxiety effects (65). (Benzodiazepine receptors are involved in the antianxiety and tranquilizing effect of Valium, Rohypnol and other preparations of the benzodiazepine group)
Nice mice
Animal studies in mice treated with hypericum have revealed CNS activities which can be interpreted as an antidepressant effect. Aggressive behavior was significantly reduced and physical activity was enhanced (72).
Typical sedative effects on the ethanol-induced sleeping time in mice have also been demonstrated.
In the so-called forced-swimming or Porsolt test hypericum showed an effect on mice equal to Imipramine (70).
Reserpine antagonism
Oral administration of hypericin in mice resulted in a reserpine antagonism, which is also indicative of antidepressant effects (72).
Effects on EEG, sleep EEG and evoked potentials
The effect of hypericum extract was tested on the electroencephalogram (EEG) of 40 depressive patients after 4 weeks of treatment (34). The results have been interpreted as predominantly relaxing effects (increase in theta activity, decrease in alpha activity and no change in beta activity). Compared to the decrease of alertness after Bromazepam (a sedative of the benzodiazepine group), this particular effect on alpha waves was much smaller after administration of St. John's wort.
In another EEG study a reduction in the alpha and an increase in the theta and beta frequencies as well as a diminished latency in visual and acoustically evoked potentials was shown. Four weeks' treatment resulted in an increase of deep-sleep phases (83).
In a study with 24 healthy volunteers the effects of hypericum on the resting EEG as well as on visually and acoustically evoked potentials were compared with Maprotiline (a synthetic AD). In resting EEG the medications had opposite effects on the theta frequencies (increase with St. John's wort and decrease with Maprotiline) and mainly similar changes in alpha and beta frequencies. The overall results of the study have been interpreted as a tendency of improved of perception and clarity of mind due to treatment with hypericum (85).
(EEG [electroencephalogram] measures the electric activity of the brain by means of electrodes placed in certain positions. The brain waves are described as follows: 13-26 cycles per second (cps) is beta, 8-12 cps is alpha, 6-8 is theta, and 3-5 is delta. The beta waves are most prominent when you are awake and doing focused activities, the alpha waves in relaxation with eyes closed, and the delta waves in deep sleep. The theta waves occur during sleep as well but have also been associated with deep meditation, serene pleasure and heightened creativity. Visually and acoustically evoked poten
tials are a way to measure the alertness and reaction time of the nervous system.)
Pharmacokinetics
In two investigations the bio-availability of hypericin and pseudohypericin was studied in 12 volunteers (89, 90).
Preclinical safety data
Acute administration
No data available.
Subchronic administration
Not relevant.
Note: Photosensitization caused by St. John's wort is mainly known from veterinary studies (91,94). Phototoxic symptoms occurred in a dose-dependent manner in light-colored cattle after substantial feeding on fresh St. John's wort. From this finding it is estimated that a 30-fold therapeutic dose might cause phototoxic symptoms in humans. In a study with the IV application of synthetic hypericin in HIV-infected patients, reversible symptoms of phototoxicity were observed at the highest dosage scheme, which was 35 times higher than the highest oral dosage of total hypericin used in the therapy of depressive disorders (2). In therapeutic relevant concentrations of total hypericin in depressive disorders, i.e., up to l mg daily over 30 days, it was shown in an experimental, double-blind placebo-controlled study with 40 volunteers that no photosensitivity was induced (57).
Mutagenicity
Not relevant.
Copyright © 1996 by Harold H. Bloomfield, M.D. and Peter McWilliams
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