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Drug info - St. Johns Wort FAQ - usage, dosage, effects etc

Discussion in 'Antidepressants' started by 0utrider, Aug 13, 2008.

  1. 0utrider

    0utrider Palladium Member

    Reputation Points:
    Jun 6, 2007
    swim found this faq quite good and informative, thoug a little long to read, but information is easy to find if using the searching engine of your browser concerning certain topics. edit: swim created an index now so information is easier to find and edited some stuff.. if anybody has anything to add, please do so..

    please alsoconsider this thread for experience discussions:
    Experiences: St Johns Wort. Effects, Use, Side-effects and Precautions

    [h1]St Johns Wort FAQ[/h1]
    [h2]INTRODUCTION[/h2]: I hope you find this article useful. I have tried to organize this document in such a manner that the less technical information is in body of the document and the more technical notes, such as chemical constituents and pharmacokinetics, are included as appendices. I have also used technical terminology but have provided a translation for non-medical people next to the word. Hopefully, this will allow lay people to obtain information easily while still providing the technical details that a medical or psychological practitioner needs when guiding patient care.
    All of the prescribing information such as dosage and patient precautions have been attached as appendices. Those of you who wish to bypass the long explanations of what St. John's wort does and how it's believed to work can skip directly to the end to see how to use it.

    [SIZE=-1]Note for American readers: The U.S. FDA has not approved St. John's wort for any medical purpose. While other countries have approved and regulated the medicinal use of various herbs, including St. John's wort, their regulatory process is not as strict as the U.S. FDA and sometimes drugs used in other countries are found to have adverse effects that are screened out during the FDA approval process. [/SIZE]
    [SIZE=-1]Because herbs are not regulated in the U.S., there is no regulatory oversight of herbal manufacturing, distribution and labelling. This means that, unlike in many European countries, the contents and potency of any herbal product in the United States cannot be guaranteed. There have been many cases where herbal products were found upon chemical analysis to differ greatly from what is stated on the label; in some cases these products were found to contain dangerous toxic compounds; some were even found not to contain herbs at all but to be composed of standard prescription drugs such as anti-inflammatories and corticosteroids. Imports from China are a particular problem but this applies to imports from other countries and domestically produced products as well. [/SIZE]
    [SIZE=-1]Due to this situation, the author does not and cannot endorse any particular brand or herbal product. [/SIZE]
    [SIZE=-1]It is possible to send individual herbal products to private laboratories to analyze the contents and compare them to the label. Several labs that perform these tests are listed in my FAQ on herbal medicine. However, all testing is at the expense of the user. At this time there is no government agency or consumer advocacy group that routinely monitors the contents of herbal products for purity. [/SIZE]
    [SIZE=-1]Therefore, the use of an unregulated substance is at the patient's own risk. [/SIZE]
    [SIZE=-1]NOTE: The terms "St. John's wort" and "Hypericum" will be used interchangeably in this document. You will also see the word "hypericin". Don't confuse this with Hypericum. Hypericum refers to the whole plant while hypericin is a particular chemical that can be isolated from Hypericum. [/SIZE]

    [h2]1. WHAT IS ST. JOHN'S WORT?[/h2]
    The name St. John's wort refers to the plants Hypericum perforatum and Hypericum augustifolia.[2]
    H. augustifolia is almost never used in commercially available preparations; so, unless otherwise stated, any reference in this article is to H. perforatum.
    The flowering tops are the best source for extracts, but the entire above ground portion of the plant can be used. [2]
    The St. John's wort monograph of the American Herbal Pharmacopoeia (AHP) states that St. John's wort consists of "the whole fresh or dried plant or its components, including not less than 0.04% naphthodianthrones of the hypericin group calculated as hypericin." [26].
    H.perforatum is native to Europe, western Asia, North Africa, Madeira and the Azores. It has been transported and now grows wild in parts of Australia and North America, notably Oregon and the Pacific Northwest, where it is known as Klamath Weed.
    H. perforatum is also known as Qian Ceng Lou in Chinese; St. Jan's Kraut in Dutch; Herba de Millepertuis, Herba de Saint Jean and Toutsaine in French; Johanniskraut, Johannisblut, Blutkraut and Herrgottsblut in German; Perforata, Iperico and Pelatro in Italian; Zwieroboij in Russian; Hipericon in Spanish and Johannesort in Swedish. [26]



    The Hypericum genus contains about 400 separate species.[1] The AHP states that Hypericum is in the family Clusiaceae; some authorities classify it as part of the Guttiferae family; others assign Hypericum it's own genus of Hypericaeae. [26] From what I can tell, the family Clusiaceae appears to supercede and include both the older families of Guttiferae and Hypericaeae.
    Finally, Max Wichtl states in his classic textbook _Herbal Drugs and Phytopharmaceuticals_ that adulteration of St. John's wort is fairly common, most notably with other Hypericum species.
    The most common adulterates of St. John's wort are H.maculatum, H. barbatum, H.hirsutum, H.montanum and H. tetrapterum. [26] In the wild, St. John's wort also can easily be mistaken for Rose of Sharon (H. calycinum). [1]
    See my general article on herbal medicine for information on testing for adulterates and consumer rights re: adulterated herbs. (See top of document for how to get a copy.)
    (See Appendix A for a complete list of regulatory status by country.)
    Since the U.S. FDA does not recognize theraputic use for any herb, we must draw on the existing scientific literature and the regulations of European countries to determine the theraputic value of St. John's wort.
    The most commonly approved indication in European countries is external use in wound healing and bruising.
    The next most often approved use is internally as an antidepressant and sedative.
    Most herb researchers accept the German Commission E monographs as the world's best documented set of herb regulations and believe they provide the most logical basis for product labelling.
    The German E Commission has approved St. John's wort for the following conditions:
    Internal consumption:
    Psychogenic disturbances, depressive states, sleep disorders, anxiety and/or nervous excitement, particularly those associated with menopause.
    Oily Hypericum preparations are approved for stomach and gastrointestinal complaints and have anti-diarrheal activity.

    External use:
    Oily Hypericum preparations are approved for the treatment and after-treatment of incised and contused wounds, muscle aches and 1st degree burns. [1]

    St. John's wort has recently come to popular attention in the U.S. primarily because of its scientifically documented antidepressant action.
    As a result, many of the less scrupulous herb distributors have started marketing St. John's wort as "nature's Prozac" or even "nutritional support for depression". While St. John's wort does indeed appear effective in the treatment of certain cases of depression, the real situation is considerably more complex. It's not at all clear whether St. John's wort works in the same manner as Prozac, if it works more like dopamine stimulating agents such as bupropion (marketed as Wellbutrin in the U.S.), if it is more similar in action to tricyclic or other heterocyclic antidepressants or if a brand new mechanism of action is present.
    The most striking thing about St. John's wort is the fact that sexual dysfunction from St. John's wort has never been reported in the scientific literature.
    Sexual dysfunction is perhaps the leading reason why people discontinue prescription antidepressants, and the reason behind why St. John's wort is receiving so much attention. Up to 70% of people on Prozac and a lower percentage of people on other antidepressants, both male and female, experience sexual problems including loss of libido, inability to achieve or greatly reduced orgasm and, in men, loss of the ability to have an erection.
    An antidepressant that does not cause sexual dysfunction would be a great boon to many people with depression.
    So, the main question on most people's minds about St. John's wort right now is:
    "How effective is it in treating depression and are there any adverse effects?"
    A. Evidence of efficacy and safety:
    In essence, there are a number of double-blind and placebo-controlled, but short, studies in humans and all demonstrate that St. John's wort has anti-depressant, anti-anxiety and mild sedative effects. While most of these studies are small, one was conducted on over 3200 patients.[6] (However this study was not controlled; its primary value is in collecting reports of adverse reactions).
    Additionally, there is one study that suggests that St. John's wort may be effective in the treatment of Seasonal Affective Disorder [18] and a number of studies in animals demonstrating plausible mechanisms by which St. John's wort could exert antidepressant effects.
    Human studies also consistently report that St. John's wort has far fewer side effects than conventional prescription antidepressants and is tolerated better by patients.
    The most convincing evidence for the efficacy and safety of St. John's wort is a meta analysis published in the August 1996 issue of the British Medical Journal.
    The full reference is:
    Authors: Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D
    Title: St John's wort for depression--an overview and meta-analysis of randomised clinical trials
    British Medical Journal 313(7052), 253-258 (1996)
    This study has caused the scientific and medical communities to sit up and take notice. The main reason for this is because BMJ is world renowned for their strict peer review standards. It's HARD to get published in the BMJ.
    Another reason is the careful analysis and research techniques the authors applied to their review.
    A meta analysis is one way to get around the inaccuracy of small studies. Small studies are less accurate than large ones because there is a greater possibility that the findings are just a statistical fluke: if you have 3 people in your study, and one has a side effect, that's one third of your study group. If you report this, you have may have grossly over-magnified the significance of the finding. On the other hand, maybe you run the same study on 100 people and only one has a bad reaction. In both studies, only one person reacted but the difference is that in one study, 33.3% reported adverse reactions and in the other 1.0% reported it. So, the more people in the study, the lower the probability that a particular finding is due to chance.
    In a meta analysis, the researchers use statistical techniques to average together a group of small studies, making the population sampled larger and the results more like those of a large study.
    The authors of the BMJ article reviewed 23 different controlled studies including a total of 1757 outpatients with mild to moderately severe depression. Twenty of the studies they reviewed were double-blind, one was single-blind, one was open label. They "quasi-randomized" the results by alternation.
    The preparations used in the reviewed studies were all standardized as to hypericin content and all used a particular alcohol extract of Hypericum called LI 160. However, in the reviewed studies, the dose of whole herb varied considerably (from 300mg to 1000 mg daily) as did the dose of hypericin (0.4 to 2.7 mg daily).
    Depressive symptoms were evaluated with generally accepted measurement scales such as the Hamilton Depression Scale (HAM-D).
    The abstract gives the conclusion:
    "Hypericum extracts were significantly superior to placebo... and similarly effective as standard antidepressants... There were two (0.8%) dropouts for side effects with hypericum and seven (3.0%) with standard antidepressant drugs. Side effects occurred in 50 (19.8%) of patients on hypericum and 84 (52.8%) of patients on standard antidepressants".
    "There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders."[7]
    This seems like pretty strong evidence in favor of St. John's wort.
    However, before we jump to conclusions and start telling everyone to take St. John's wort:

    • All of the studies reviewed were of short duration. Most were 4-8 weeks in length. Most antidepressants become effective after a few weeks; but it may take longer than 8 weeks for antidepressants to build up to maximum effectiveness in certain individuals.
    • The doses of antidepressants used in the control groups were relatively low. Thus, we don't know how well St. John's wort works when compared to a high dose of these drugs.
    • Even though the compounds tested were standardized for hypericin content, it now turns out that hypericin may not be among the agents responsible for St. John's wort's antidepressant effects. This creates difficulty in comparing extracts.
    • St. John's wort has never been compared to SSRIs (Prozac or Zoloft), to MAOIs or to any of the newer antidepressants like Effexnor or Paxil. It has only been compared in humans to tricyclic antidepressants (specifically amitriptyline, imipramine, and maprotiline) and in rats and mice to the above antidepressants plus a non-tricyclic called bupropion. It has been found similarly effective to the above antidepressants but there are a large number of people for whom tricyclic antidepressants don't work and animal studies don't necessarily carry over into human effects.
    • St. John's wort has never been tested in severe depression. Anecdotal reports I've received suggest that it's action is not as effective in severe depression.
    • The authors of the BMJ article quoted above also stated that more information is needed before concluding that St. John's wort is as effective as standard antidepressants. They call for more studies comparing differing doses of St. John's wort to standard antidepressants.
    • In a separate commentary accompanying the article, Peter DeSmet (one of the world's leading pharmacognosy researchers and editor of _Adverse Effects of Herbal Drugs_) and researcher Willem Nolen state that the data are promising but that more studies are needed. In particular, they want to find the most effective treatment dose, and want longer studies in order to evaluate the risk of relapse and late-emerging side effects. They also call for trials in severely depressed patients.[27]
    As a result of the BMJ article, it looks like the studies the authors have called for will happen. The U.S. NIMH (National Institute of Mental Health) and the Office of Alternative Medicine are currently planning a large scale, multi-center trial of St. John's wort. [26]
    [h3]B. By what mechanism of action does St. John's wort exert antidepressant effects? [/h3]
    Nobody knows.
    Actually, this situation isn't very different from other antidepressants. Even though we have good theories about the actions of SSRIs, tricyclics and other antidepressants, we don't really know for sure how they work, either. But these drugs ARE much better studied than St. John's wort.
    Two things are clear:
    1. SSRIs such as Prozac (fluoxetine) and Zoloft (sertraline) are well known to have mild stimulant properties. Unlike SSRIs, Hypericum has a significant sedative effect. This may be due to a sedative compound separate from the antidepressant agent or may be a direct effect of the antidepressant chemical(s). If the latter, this suggests that we are NOT dealing with an SSRI, so it's not "nature's Prozac".
    2. Dry mouth has not been reported for Hypericum, suggesting that it does not have the anticholinergic (acetylcholine inhibiting) action that tricyclic antidepressants are famous for.
    The most popular hypothesis is that St. John's wort works like other non-MAOI antidepressants, probably through serotonin and norepinephrine reuptake inhibition. (In other words, by preventing the brain from reabsorbing the neurotransmitters in question and so keeping serotonin and norepinephrine levels in the brain at a higher level.) [14]
    In support of this theory, a 1984 study on 6 women found that St. John's Wort increased the levels of norepinephrine metabolic byproducts in the urine. (This study also found St. John's Wort to have anti-depressive effects).[1]
    A German study in 1995 also found that Hypericum extract caused 50% inhibition of serotonin uptake in in rat brains.[16]
    Another theory is that St. John's wort acts on many levels simultaneously, creating an accumulating effect via serotonin, norepinephrine, and dopamine-reuptake inhibition, a low-level MAOI effect and by action on the hypothalamus inhibiting cortisol secretion.[14]
    One researcher has found evidence that St. John's wort acts on dopamine. St. John's wort effects in animals are antagonized (reduced or stopped) by drugs known to reduce dopamine functional activity. These drugs include haloperidol, sulpiride, a-methyltyrosine and g-butyrolactone.[26] This would suggest a mechanism of action probably similar to that of bupropion.
    It's also now known that hyperforin and some of the biflavones (known to be CNS depressants) are involved in the sedative effects of the plant.[2]
    Crude Hypericum extract has significant receptor affinity for certain chemicals involved in brain neurotransmission, specifically: adenosine, GABA-A, GABA-B, serotonin, benzodiazepine, inositol triphosphate and MAO-A and MAO-B [26]
    Hypericum's high affinity for GABA receptors may be particularly important. GABA stands for gamma-aminobutyric acid. To grossly oversimplify, GABA is one of the main neurotransmitters involved in calming the central nervous system. It has mostly inhibitory effects on neurotransmitter reactions and is found throughout the brain. GABA is also involved in controlling reactions involving dopamine.
    A 1997 study found that flower extracts from three different Hypericum species, including H. perforatum, block GABA and benzodiazepine binding sites in rat brains.
    Benzodiazepines (drugs such as Valium, Xanax and Klonopin) are believed to exert their sedative actions via increasing GABA's effects. That Hypericum enhances the activity of GABA certainly provides a plausible mechanism of action for the sedative and anti-anxiety effects of St. John's wort.[17]
    However, newer research suggests that GABA may also be involved in antidepressant reactions. There is now a significant amount of research on GABA and depression. Certain agents that enhance GABA's activity, notably fengabine, have been reported to have antidepressant effects. Researchers have also found that GABA plasma levels are low in depression of both the unipolar ("regular") and bipolar (formerly called "manic-depressive") type. Interestingly, benzodiazepines have recently been reported to have antidepressant as well as anti-anxiety effects.
    Another very intriguing theory has recently been proposed: an immune stimulating chemical called Interleukin-6 may cause depression in some people. [26] Interleukin-6 is found normally in the human body and is part of the system that stimulates lymphocytes and other white blood cells to defend the body. This theory might explain in part why glucocorticoids such as cortisone (strong immune suppressant agents) improve mood. St. John's wort does inhibit Interleukin-6 production but much more research needs to be done on this theory.
    St.John's wort has been used a lot in the treatment of depression associated with menopause. St. John's wort contains a mild phytoestrogen called beta-sitosterol. The estrogenic effects of beta-sitosterol might account for some of its effectiveness in women during and after menopause. All phytoestrogens are very mild compared to estrogens obtained from animals or the synthesized estrogens used to treat menopause. The estrogenic action of St. John's wort does not appear to cause any problems in men who take it, possibly because of beta-sitosterol's low level of activity; however studies have never been conducted on the effects of phytoestrogens in men.
    [h2]C. THE MAOI CONTROVERSY: [/h2]
    Whole St. John's wort contains an unidentified chemical that inhibits a particular brain enzyme called monoamine oxidase (MAO for short). This enzyme is key to breaking down the neurotransmitters dopamine and norepinephrine, which are "stimulant" neurotransmitters and which are also involved in blood pressure regulation. Agents that inhibit the action of MAO are called MAOIs (monoamine oxidase inhibitors).
    Most MAOIs are antidepressant drugs, with the best known MAOIs being Parnate (tranylcypromine) and Nardil (phenylzine). Some herbs also contain MAOIs. These include yohimbe and large doses of licorice root, among others.
    MAOIs are highly effective in combatting depression, but are used only to treat depression resistant to all other drugs. This is because MAOIs are notorious for dangerous drug and food interactions.
    Most doctors who prescribe MAOIs give their patients long lists of drugs and foods to avoid.
    Thus a controversy has arisen:
    Should people taking St. John's wort follow the same precautions that people taking prescription MAOIs do?
    Opinion is divided.
    When something interferes with the action of MAO, certain compounds that stimulate the sympathetic nervous system have much stronger effects on the body. In particular, the consumption of foods containing large amounts of tyramine (a metabolite of the amino acid tyrosine and a key chemical precursor of the neurotransmitters dopamine and norepinephrine) and/or particular drugs, such as stimulants and most antidepressants, can cause a very dangerous sudden sharp rise in blood pressure when taken by people using MAOIs. This reaction can cause strokes. Even so, these reactions are fairly rare; nonetheless, there ARE fatalities on record from adverse MAOI interactions.
    MAOIs come in two forms: reversible (which inactivates but does not destroy MAO) and irreversible (which does destroy MAO). Irreversible MAOIs are more dangerous than reversible ones and have many more drug and food interactions.
    There are also two types of MAO: MAO-A and MAO-B. MAO inhibitors can inhibit only one of the above, or can inhibit both. MAO-A works on serotonin, norepinephrine and dopamine and is the type of MAO involved in antidepressant effects. MAO-B inhibits other amines found in the brain, notably phenylethylamine. Agents that inhibit only MAO-A have far less potential for causing a hypertensive crisis than agents that inhibit both MAO-A and MAO-B. [24]
    The MAOI in St. John's wort appears to be of the more dangerous, irreversible form and inhibits both MAO-A and MAO-B in living organisms (in vivo). [1,12]

    A recent study on rat brains states that an extremely high dose of this herb is needed to actively inhibit MAO-A. The researchers suggest that another compound must therefore be the active agent. This would certainly be consistent with the fact that MAOI type adverse reactions have never been reported from this herb. This paper apparently also found a comparable dose was needed before any inhibition of MAO-B occurred as well. [12]
    The original study that caused people to think that St. John's wort worked by MAO inhibition was conducted by a researcher named Suzuki in 1984. Suzuki reported that hypericin inhibited MAO at doses of 50 mcg/mL. However, 2 other teams of researchers have been unable to duplicate this finding. The solution Suzuki worked with was only 80% pure and these other scientists have suggested that there may have been an MAOI in the other 20% of the solution. Presumably this other 20% contained some of the oil-soluble portions that are normally left behind during extraction with alcohol. This is a strong argument for the use of only alcohol extracts in the treatment of depression.
    Researchers have administered alcohol extracts up to 300 mg/kg to rats without finding any MAO inhibition. However, rats may metabolize St. John's wort differently than humans: it appears that blood levels of St. John's wort in humans are lower than in rats when administered equivalent doses in mg/kg.
    We must also consider the evidence that St. John's wort's effects are reduced by administering agents that decrease dopamine levels. [26]
    This suggests that at least part of St. John's wort's antidepressant effects are from increasing the activity of dopamine. This could be due to MAOI action: however, there are also non-MAOI antidepressants that increase dopamine action by other means, the best known of which is bupropion. Bupropion does not have the same dangerous drug and food interactions that MAOIs do. Thus, St. John's wort does not need to be an MAOI to explain this effect; but on the other hand, this could be indirect evidence of clinically significant MAO inhibition.
    There is also the 1984 study also found increased levels of norepinephrine metabolic byproducts in the urine of women treated with St. John's wort. This would be consistent with increased norepinephrine levels in the body. This could occur either from a mechanism of action similar to Prozac or it could indicate MAOI action. It could also be the result of stimulant action, although no stimulant activity or side effects have ever been reported for St. John's wort. [15]
    St. John's wort *is* in common use in Germany, England and several other European countries and people are not keeling over in the streets from it.
    Since doctors in these countries have been paying close attention to the MAOI effects of this plant, I would think we probably would have heard reports by now if people were having MAOI related problems.
    There are many anecdotes from people who have mixed St. John's wort with foods known to cause bad interactions with MAOIs, and who have had no adverse effects at all. However, MAOI reactions are dose related and normally occur in only about 4% of the people who mix MAOIs with foods or drugs.
    St.John's may well be free of MAOI interactions at normally used doses. However, until a large scale human study on this is done, we won't know for sure. Rat brains are actually a fairly good model to test this stuff, but rats and humans do have some significant differences.
    Also, please remember that in the U.S. there is no regulatory oversight of herbal drug manufacturing. This means that the consumer has no way of knowing for sure if a product claiming to be a pure alcohol extract really is pure or if it contains any oily residue.
    [h3]D. What is the chemical responsible for St. John's Wort's antidepressant effects? [/h3]
    Again, nobody knows. In fact, there may be not one but several agents.
    Until recently, most people thought that the antidepressant agent in St. John's wort was hypericin, and that hypericin worked by MAO inhibition.
    Today, researchers question whether hypericin inhibits MAO.
    These people have proposed certain flavonoids as candidates for the MAO inhibiting agent in St. John's wort because they bear a chemical structural similarity to known MAO inhibitors such as toloxotone and brofaromine [26]
    Of the flavonoids, the strongest current candidate for a single antidepressant agent is amentoflavone.
    However, many researchers also suspect that, since St. John's wort's antidepressant properties are probably NOT due to MAO inhibition, there may well be some other unidentified agent in the plant.
    Additionally, most researchers believe that the effects of St. John's wort are due to a synergistic interaction between several compounds. Thus, the search for a single agent may be the wrong approach.
    Even though all the recently publicity has been over the use of St. John's wort to treat depression, Hypericum has many other effects.
    A. Effects on sleep:
    One study has found that St. John's wort increased deep sleep and slightly decreased REM sleep. [19]
    One particular German St. John's wort product, Hyperforat, has been shown to significantly increase the nighttime production of melatonin in a dose of 90 drops daily over a three week period. [26]
    Many antidepressants prescribed for sleep disorders decrease deep sleep: this suggests that St. John's wort *may* be superior to other antidepressants in the treatment of sleep disorders associated with depression. [19] However, more studies are needed to evaluate St. John's wort's effects in sleep disorders, particularly in sleep disorders not related to depression.
    [h3]B. Anti-viral activity [/h3]
    The American Herbal Pharmacopoeia (AHP) monograph on St. John's wort states that Hypericum is currently undergoing early trials as an antiviral agent in the United States. Unfortunately, I don't have any more details. [26]
    In test tubes ("in vitro"), St. John's wort has been shown to possess anti-viral activity against retroviruses including HIV [3]; herpes simplex 1 and 2; Sindhis virus; murine (mouse) cytomegalovirus; para-influenza 3 virus; vesicular stomatitis virus and equine infectious anemia virus.[26]
    (Please remember that anti-viral activity in test tubes doesn't necessarily mean that the tested agent is going to be effective in humans or animals. Viruses live inside of cells and the major problem of antiviral therapy is getting the agent to the virus without killing or damaging the cell it's hiding in.)
    Hypericin and pseudohypericin, chemicals found in St. John's wort, appear to have an effect against enveloped viruses. These are viruses that rip off a bit of cell membrane when they leave an infected cell and form a little envelope of cellular membrane around themselves. Researchers suggest that hypericin and pseudohypericin work against enveloped viruses by attacking this cellular membrane. All herpes viruses are enveloped as is HIV.
    Hypericin is also a potent protein kinase C inhibitor. Most PKC inhibitors are currently used as cancer chemotherapy agents: the best known example is tamoxifen. Researchers at the University of Southern California are trying to get FDA approval to explore hypericin as a chemotherapy agent in a rare brain cancer called glioma.
    (The possible value of hypericin as a cancer treatment is discussed in more detail in section 9: "Is St. John's wort useful in the treatment of cancer?")
    Some researchers believe that PKC inhibition may explain part of St. John's wort's action against viruses and bacteria. In addition, hypericin and pseudohypericin inhibit the receptor tyrosine kinase activity of epidermal growth factor. This may be involved in both antiviral and anti-cancer activity. [26]
    The anti-viral activity of St. John's wort appears to be partially the result of photoactivation (a light activated reaction). According to one paper, hypericin reacts with O2 in the presence of light to form highly reactive singlet oxygen. The singlet oxygen in turn attacks viruses which are fusing and trying to form structures called syncytia. [26]
    St. John's wort can also convert oxygen to the strong antioxidant enzyme superoxide dismutase in the presence of light. [26]
    The above findings would help to explain why a particular methyl fraction found in St. John's wort appears to have effects against herpes simplex when exposed to UV-A or visible light.[4]
    Unfortunately, I haven't been able to find any studies to suggest that the research above has led to clinical anti-herpes trials in humans. Light activated antiviral agents would not be helpful in most viral infections, since the viral activity takes place in parts of the body that light can't reach. Herpes simplex is an important exception since it manifests externally. It would be very interesting to see a properly controlled study of St. John's wort extracts applied topically to oral or genital herpes simplex sores and then exposed to visible (NOT ultraviolet) light for a given period of time to see if it lessened the pain or duration of symptoms.
    However, this use of St. John's wort against oral and/or genital herpes sores remains speculative on my part.
    St. John's wort's antiviral properties have also been observed in animals and possibly in humans. One group of researchers working on mice found that hypericin can form semiquinone radicals even when no light is present and they suggest that this is partially responsible for its antiviral action in whole animals. [26]
    Finally, Hypericum extracts have been shown to inhibit HIV in test tubes. It does so by inhibiting the action of an enzyme key to HIV reproduction called reverse transcriptase. This is the same mechanism of action by which AZT works.
    This finding led in the late 1980s to human studies of St. John's wort as an AIDS treatment.
    In 1988, an open-pilot study on 18 AIDS patients showed stable or increasing CD4 counts in 16 patients out of the 18. However, CD4 levels are not necessarily the best indicator of drug effectiveness in AIDS. Furthermore, we know from much experience with AZT that HIV eventually mutates and the drug loses any effectiveness it has. There is no reason to believe that this would not also be the case with St. John's wort.
    Today, combined antiviral drug therapy has been shown to be far more effective than the use of a single reverse transcriptase inhibitor. Current AIDS treatments are far superior to any single agent and St. John's wort is not recommended as an AIDS therapy. [26]
    [h3]C. Anti-bacterial and anti-fungal activity [/h3]
    Two Russian St. John's wort preparations have been tested against Staphylococcus aureus in vitro (in test tubes) and in vivo (in living organisms) and found to be more effective than sulfanilamide.[1]
    A resin fraction of an alcohol extract of St. John's wort called LI 160 has been shown to have minor antifungal and "significant" action against gram positive bacteria.[26] Tannins and flavonoids in St. John's wort have been reported to inactivate Escherichia coli at dilutions of 1:400 and 1:200. [26]
    H.perforatum essential oil is anti-fungal. [1]
    [h3]D. Immunologic effects: [/h3]
    A polyphenol compound has been identified that stimulates the activity of certain white blood cells called mononuclear phagocytes and 'cellular and humeral immunity'. [10,11]
    An oil-soluble fraction has been found that exerts mild immune suppressant effects. It suppresses the release of Interleukin-6. [11]
    A freeze dried preparation of St. John's wort has been found to suppress inflammation and white blood cell infiltration in vivo.[1]
    Hypericin inhibits the release of arachidonic acid and leukotriene B. These are precursors of several important chemicals in the body including prostaglandins and cytokines (chemicals that activate lymphocyte and T-cell activity). This has been proposed as a mechanism behind St. John's wort's traditional use as an antiinflammatory.

    [h3]E. Wound healing activity: [/h3]
    A burn ointment made from St. John's wort flowers has been tested in the treatment of 1st, 2nd and 3rd degree burns. According to the AHP monograph "First degree burns healed in 48 hours. Second and third degree burns healed at least three times as rapidly as burns treated with conventional methods and keloid formation was inhibited". [26]
    St. John's wort has also been compared with Calendula, another herb commonly used to heal wounds. St. John's wort applied topically was shown more effective than Calendula. [26]
    Many of St. John's wort effects on wounds and burns are probably due to the anti-bacterial and anti-fungal effects mentioned above. However, the antiinflammatory and other immunologic effects mentioned in the previous section probably also play a role.
    [h3]F. Other properties: [/h3]
    St. John's wort has antioxidant activity. [5]
    St. John's wort appears to have antispasmodic effects on the gastrointestinal tract. [2]
    A water/alcohol extract has been observed to have a protective effect on the livers of animals. Increased bile duct flow has been observed in rats, and this extract also reduced the damage from CCl4 (carbon tetrachloride, extremely toxic to the liver) when given intraperitoneally to mice first treated with barbiturates. [26]
    A procyanidin fraction of Hypericum has been shown to have vasodilating effects on an isolated preparation made from guinea pig heart and also in coronary arteries from pigs. These procyanidins antagonized coronary artery spasms caused by histamine and by prostaglandin F2-delta. These procyanidin fractions acted in much the same manner as procyanidins from hawthorne, an herb long known to possess vasodilating properties.[26]
    It has been shown that St. John's wort may be useful in the treatment of chronic tension headaches, probably due to sedative effects. [26]
    One important note about St. John's wort: at least in the industrialized world, most herbal products are not used by large enough numbers of people to really determine safety and side effects. St. John's wort is a notable exception to this rule: 66 million doses were taken in Germany in 1994 alone (26).
    St. John's wort is now the leading antidepressant agent prescribed by physicians in Germany. Hypericum products account for over 50% of the antidepressant market in Germany and many thousands of people there use St. John's wort every year. [26]
    This means that we have a significant database to work from when drawing reports of adverse effects.
    However, even with large numbers of people using St. John's wort, there is still no one organization charged with collecting adverse reports to herbal drugs. We are still forced to rely on a few studies and on individual practitioners who write up adverse effects and submit the articles to medical journals.
    A. LD50 and toxicity:
    No deaths in humans have ever been reported for St. John's wort.
    I checked the Merck Index to try to track down the LD50 for St. John's wort.
    (The LD50 means the dose that is lethal in 50% of the animals that it is tested on. This is important in determining the safety of an agent: the higher the LD50 is from the therapeutic dose, the safer the drug. Some prescription antidepressants, notably tricyclics, have an LD50 that is only 2 or 3 times that of the therapeutic dose, making fatal overdose from these drugs a realistic possibility.)
    I was unable to find Hypericum as a whole but hypericin is listed in the Merck Index, as are quercetin and quercitrin, other pharmacologically active agents in Hypericum. As far as I can gather from the reference, the LD50 for these compounds has never been tested.[23]
    Doses of Hypericum up to 35 times the standard dose have been given to human volunteers with only minor side effects. This suggests a very high LD50 and concurrent low level of toxicity. [1]
    A formal toxicology study was done giving the LI 160 extract. No adverse effects were noted from a single dose of 5000 mg/kg. [26]
    A 26 week study on rats and dogs at oral doses of 900 and 2700 mg/kg noted only mild toxic effects. According to the AHP monograph, these included:
    "...reduced body weight, slight pathological changes in the liver and kidneys due to the large metabolic load and some histopathologic changes in the adrenals. No effects were seen on fertility or reproduction. No mutagenic potential was evident. Long term (greater than 2 year) carciogenicity studies are just being completed." [26]
    The AHP also mentions a second toxicity study, where rats were given Hypericum as 5% of their diet for 119 days. No adverse effects on the liver, on hepatic drug metabolizing enzymes or significant tissue lesions were found. [26]
    [h3]B. Photosensitivity: [/h3]
    a. Primary photosensitivity in humans:
    St. John's wort can cause photosensitivity (a rash caused or worsened by sunlight) in certain animals and in humans. What happens is that hypericin is absorbed from the intestine and migrates to the skin. Here it is chemically changed by sunlight. The body becomes allergic to the altered compound and an itchy, swollen, red rash develops. This is called "primary photosensitization".
    Photosensitivity from St. John's wort is rare. In all the scientific literature, there is only one individual case report of photosensitivity from St. John's wort. This report involved a photosensitive rash in an elderly woman, which did not lead to further complications and which went away when the herb was discontinued.[13]
    There is also one small study that deliberately tried to induce photosensitive reactions to St. John's wort. In this study, the researchers took fair-skinned persons, gave them the varying doses of the LI 160 extract of St. John's wort and then exposed the subjects to ultraviolet light. There was measurable redness at doses of 1800 mg. daily (600 mg. three times a day) for 15 days. The blood levels of hypericin and pseudohypericin were approximately twice the normal theraputic level for depression. No other adverse effects were noted. [26]
    In a phase-one AIDS trial, four patients were given relatively high doses of IV hypericin. Two were given 0.25mg/kg and two were given 0.50mg/kg. Both patients on the higher dose experienced facial pain, redness and swelling when exposed to direct sunlight for 10-15 minutes after 2-3 doses. One person on the lower dose (who presumably was dark skinned, since the paper mentions that he was of Mediterranean descent) also had pain and redness of his hand after 13 weeks. The effects went away after the hypericin was discontinued. [26]
    I also have two personal anecdotal reports of people developing a photosensitive rash from St.John's wort. Both were in very fair-skinned, blonde-haired, blue-eyed persons.
    b. Secondary photosensitization in animals:
    In sheep and cattle a type of photosensitive reaction has been reported that is occasionally fatal to the animal. (This is the reason why St. John's wort is considered a dangerous weed in some parts of the world.)
    This reaction is related to sunlight and is called "secondary photosensitization". In this case, the altered St. John's wort proteins react with oxygen to destroy red blood cells (called hemolysis).
    This more serious type of photosensitive reaction has never been reported from St. John's wort in humans.
    Cattle appear to be more sensitive to St. John's wort than sheep. [1,12]
    Sheep experimentally poisoned with high doses of H. perforatum have developed anemia and signs of liver damage.
    To quote the study abstract:
    "Sheep given different dosages and frequencies of Hypericum perforatum had decreased hemoglobin, red blood cell count, packed cell volumes, total protein, glucose, cholesterol, triglycerides, and serum alkaline phosphatase activities. Blood urea nitrogen, sodium, potassium, bilirubin (total and direct), and the activities of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and gamma glutamyltransferase increased. Hemato-biochemical assays were useful diagnostic aids to determine the severity of this plant's toxic effects."
    Christopher Hobbs notes in a review article for HerbalGram that the equivalent dosage for a human would be 59 grams (apparently of raw herb, not extracted hypericin) for a 130 lb. individual.[1] This is about 15 times the therapeutic dose. Doses of hypericin up to 35 times the dose used for depression have been given intravenously to people with HIV disease without reports of phototoxic reactions.[1,26] Therefore I'm not particularly concerned about this effect in adult humans as long as people stick to the standard dosage; however, it suggests the potential for a toxic overdose.
    The AHP monograph does warn against the possibility of "auto-intoxication" by both persons with depression and persons with AIDS. They give the treatment for overdose as monitoring for erythema (red, swollen patches on the skin) and keeping the person away from sunlight for up to one week. [26]
    Children would need much less St. John's wort for a toxic reaction than adults and so I think St. John's wort should be kept out of the reach of small children.
    [h3]C. Minor side effects: [/h3]
    Several of the St.John's wort studies note that some people dropped out due to side effects, although at a far lower rate than with standard antidepressants.
    In an uncontrolled study of 3250 people treated for depression with St. John's wort, undesired drug effects were reported in 79 (2.4%) patients and 48 (1.5%) discontinued the therapy. Most frequently noted side effects were:
    * gastrointestinal irritations (0.6%)
    * allergic reactions (0.5%)
    * tiredness (0.4%)
    * restlessness (0.3%).[6]
    Headache and irritability have been reported anecdotally over the Internet by persons using St. John's wort.
    All the side effects reported appear reversible as soon as the herb is discontinued.
    [h2]6. DRUG INTERACTIONS: [/h2]
    It has been shown in animal studies that the effects of St. John's wort are reduced by agents that reduce the activity of dopamine, such as haloperidol. We do not know if this is the case in humans or not. [26]
    In mice, Hypericum extracts have been shown to significantly increase sleep induced by narcotics and to antagonize the effects of reserpine. [26]

    Conversely, other animal studies show that it decreases sleep induced by barbiturates.[26] There is no good explanation for these seemingly contradictory results. The AHP suggests that it might be due to pharmacokinetic alterations of the drug.
    There are NO studies where St. John's wort has been administered concurrently with other antidepressants. I personally know of some psychiatrists who are prescribing St. John's wort in conjunction with SSRIs and some patients who have combined them on their own. So far, no adverse effects have been reported to me. I also have not seen case reports of adverse drug interactions between St. John's wort and other antidepressants on the phytopharmacognosy or psychopharmacology Internet mailing lists or published in the scientific literature.
    However, when combining agents that act on serotonin, there exists the risk of serotonin syndrome, a rare but potentially fatal disorder. This is usually a problem when combining drugs that preferentially affect a few particular serotonin receptors, notably 5-HT1a and 5-HT2 (serotonin is 5-hydroxytryptamine or 5-HT for short), and especially when combining serotonin increasing agents with MAOIs. Serotonin syndrome has also been reported in people combining the amino acid supplement L-tryptophan (a key chemical precursor of serotonin) with SSRIs such as Prozac. Tryptophan absorbed as part of a normal diet does not appear to increase the risk of serotonin syndrome.
    There are more than 40 serotonin receptors and more are being identified each day. Since we don't know exactly which serotonin receptors St. John's wort affects, we can't accurately judge the risk of this disorder when combining it with other serotonergic agents.
    Therefore: people should NOT combine St. John's wort with other antidepressants without close medical supervision. People combining St. John's wort with other antidepressants should be alert for signs of serotonin syndrome and immediately report them to a physician.
    Signs of serotonin syndrome include confusion, fever, chills, hyperactive reflexes, sweating and difficulty with speech. Myoclonus, a shock-like contraction of a muscle or group of muscles is another sign. In the mouth, myoclonus can feel like a rapid fluttering of the soft palate, tongue or throat, often only on one side.
    There is also the small possibility that St. John's wort may have MAOI interactions. See section 3C: "The MAOI Controversy" for more information.
    St. John's wort should NOT be used while pregnant or if breast feeding.
    First, hypericum extract has been shown to cause contraction of uterine muscles of rabbits and guinea pigs in test tubes.[21] Interestingly, Hypericum species were used by Native Americans as abortifacients.[1]
    This is not a great indicator of what it does in the human body, but why take any agent that could cause uterine contractions and so risk miscarriage?
    Second, there is the possibility that certain chemicals in St. John's wort may cause birth defects.
    There is a lot of scientific debate about this. One study found that mutations occurred when Hypericum oil, tinctures and extracts were applied to cell cultures. Mutations in cell cultures suggest that a compound may alter DNA and lead to birth defects by chromosome damage or to cancer in living organisms. It has been suggested that quercetin was the mutagenic agent.[26] (Agents that cause birth defects are called teratogens.)
    However, other studies both in test tubes and in animals did not confirm this finding. [26]
    A 1:4 water/alcohol extract has been tested for mutagenicity (the ability to change or alter DNA) against salmonella bacteria. This is called the Ames test and is the standard method used to determine how likely it is that an agent can cause cancer or birth defects. St. John's wort has been found to have anti-mutagenic properties, which means it not only does not increase the rate of mutations, but it decreases them below normal.[2]
    It's also been tested in test tubes (in vitro) against rat embryo cells with negative results.[22]
    The extract used yielded 0.2 to 0.3% hypericin and 0.35mg/g of quercetin. This suggests that neither of these compounds are the agents that cause birth defects. If a mutagenic agent is present, the most likely place to look for it would be in the oily fraction. (This is what is most likely to be left behind after water/alcohol extraction, since oils do not mix well with water or alcohols.)
    Even if it turns out that Hypericum doesn't cause cell mutations, there are are many mechanisms other than chromosomal damage by which birth defects can occur. Thalidomide, for example, probably causes birth defects by blocking the formation of new blood vessels between the 6th and 9th week of pregnancy. Thus, it's conceivable that an agent that passes the Ames test could still be teratogenic.
    Of particular concern to me is the effect of an anti-depressant agent on the developing nervous system and brain of a fetus or newborn. This might actually be MORE of a risk in the last trimester of pregnancy or shortly after birth (when the infant brain is undergoing subtle but critical formation) so just avoiding the first 12 week "window of vulnerability" isn't sufficient.
    A note of caution is also due regarding the estrogenic agents in St. John's wort. To my knowledge, beta-sitosterol has never been tested for teratogenic effects. We do know that certain estrogens, notably D.E.S. (diethylstilbesterol) cause deformities and cancers of the reproductive system and reduce fertility in people exposed to them in utero (while still in the womb). It can take many years for such problems to become evident: DES daughters did not develop vaginal cancers until well into adulthood.
    I think we would do well to remember the effects of DES on both males and females, as well as the possible role of estrogenic organohalides in breast cancers and reduced male fertility. In other words, I personally wouldn't take any estrogenic agent during pregnancy if I could avoid it.
    If an anti-depressant is still needed during pregnancy, I'd use a standard prescription antidepressant that's had a long history of use and that we've got some data about in pregnant women. I'd use such a drug only if I couldn't get by without it (i.e. suicide or psychosis is an immediate danger) and for as short a period of time as possible.
    The idea that St. John's wort might contain a useful anti-cancer agent is not off the wall: several important cancer chemotherapy agents were originally derived from plant sources. The most recent example is Taxol, made from the Pacific Yew. Vincristine and vinblastine are other common cancer chemo agents originally derived from a plant (marigold).
    Neurosurgery (a highly respected medical journal) has published two articles by researchers at the University of Southern California in Los Angeles on the use of hypericin as an anti-glioma agent. Glioma is a rare type of brain cancer that is almost always fatal. One article demonstrated that hypericin inhibits the growth of glioma cells in test tubes in a dose dependent manner and suggested that the mechanism was inhibition of a chemical key to tumor cell reproduction called PKC (protein kinase C.) [3]
    The second article was a case report on the use of hypericin on a person who had an inoperable glioma who was receiving radiation and tamoxifen. The patient went into remission for 22 months (pretty good, considering that the average survival time after diagnosis for glioma is under 12 months) and then had a recurrence of the tumor. When cells from the tumor were tested in a lab, they had lost sensitivity to tamoxifen. Because tamoxifen works by inhibition of protein kinase C, the researchers tested the cell culture against hypericin and found that the cells were killed by the hypericin. They also found that hypericin is a stronger inhibitor of protein kinase C than tamoxifen. [20]
    Because it is not approved by the FDA, the authors never actually gave hypericin to this person. However, they suggest that it is a viable alternative to tamoxifen and that it may be useful both as a primary chemotherapy agent in this cancer and also as a second line drug to be used when tamoxifen fails. They urge that it be studied further and at the end of their article indicate that they were trying to get FDA approval for a full clinical study in humans. I don't know the result of their petition or whether further research is being conducted.
    Hypericin has also been tested as an adjunct to laser surgery for skin cancer. Because hypericin is a photoactive agent, it may increase the efficacy of laser in destroying skin cancers. (The light from the lasers may turn hypericin into an even stronger PKC inhibitor.)
    However MUCH more research is needed. At this point in time, it should NOT be promoted as a cancer cure or preventive. I personally would *not* use it in place of standard glioma treatments. However, it appears to be pretty safe, and I might take it as an adjunct to standard therapy. Certainly, a person whose tumor does not respond to standard treatments has nothing to lose by trying it.
    NOTE: If you want to try hypericin for this purpose, you MUST let your doctor know about it. Seriously ill people should never take herbs or any over the counter drugs without informing their physician. Plant derived drugs can and do have interactions with standard pharmaceuticals, foods and other herbs. Also, it may be necessary to administer the drug intravenously. Don't assume that you can just go to the health food store and buy an orally consumed hypericin product and have it work for this purpose.
    [h2]12. TECHNICAL APPENDICES [/h2]
    A. PRECAUTIONS: (Health providers may duplicate and pass out this section without violation of copyright)
    Don't self-treat serious depression! SEEK IMMEDIATE HELP IF YOU ARE HAVING SUICIDAL THOUGHTS.
    Depression is a very serious illness and the suicide rate in untreated depression is at least 15% over the long term. An occasional case of the blues is one thing; a depression that lasts for weeks or months or where you have frequent thoughts of killing yourself is a whole different matter. Because depression so strongly affects a person's view of reality, it's very important for folks with depression to have someone else to check in with who can tell if things are to the point where suicide is a real risk.
    Most cases of depression ARE treatable and if people need more information, I suggest that they check in on alt.support.depression and/or consult a physician or therapist. Call the local suicide prevention hotline (listed in the front of most phone books) if you have thoughts of killing yourself.
    Even though no serious adverse effects in humans have ever been reported for St. John's wort, some precautions are in order. The precautions below are based on the standard precautions for SSRI antidepressants plus additional theoretical information about this plant:
    a. Do not use St. John's wort if you have previously developed a rash from it or if you are allergic to it.
    b. Wear a sunscreen while using it, particularly if you are fair skinned.
    c. Use care if you have a history of photosensitive rash or if you are taking certain medications that can cause photosensitive reactions such as tetracyclines, Thorazine (chlorpromazine) or Tegretol (carbamazepine).
    d. Avoid theraputic ultraviolet therapy and/or tanning salons while using St. John's wort.
    e. Don't take St. John's wort with other antidepressants including SSRIs and tricyclic antidepressants unless you are under a doctor's close supervision.
    f. Do not take St. John's wort with MAOIs (monoamine oxidase inhibitors). If you are discontinuing or beginning an MAOI, allow a minimum of 2-4 weeks between use of St. John's wort and the MAOI.
    Note: Most MAOIs are prescription antidepressants. If you are taking a prescription antidepressant and are not sure if you are taking an MAOI, ask your physician. However, this precaution also applies to certain herbs that contain MAOIs, particularly yohimbe and doses of licorice root in excess of 5 grams per day.
    g. Do not take St. John's wort with haloperidol or other drugs known to decrease dopaminergic activity because they may reduce the efficacy of St. John's wort.

    h. Stick to the standard dosage or the dose on%

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  2. seaturtle

    seaturtle Titanium Member

    Reputation Points:
    Nov 27, 2010
    I'm bumping this thread since it contains a wealth of information on St. John's Wort, moreso than anywhere else in the forum from what I can tell. I've been using St. John's Wort for the first time today, in the form of 450 mg of extract (equivalent to 2.25 grams dry vegetation) stuffed into a pill. Effects came on within the first hour, a noticeable lifting of mood, and most of all my typical daily anxiety vanished, especially in social situations. I often use Opioids and stimulants to maintain a positive mood, but with St. John's Wort I feel perfectly at ease sober. St. John's Wort also seems to counteract anxiety induced by smoking Cannabis.

    A true miracle plant based on this first day, I wish more people knew about this. I'll continue using it and post more info as I do, I'm sure I have much to learn about this plant.
    Last edited: Apr 11, 2013
  3. AlexaN

    AlexaN Silver Member

    Reputation Points:
    Jul 8, 2010
    It is a good alternative to SSRI's....I was on it for mild depression and my father was prescribed 500mg (2xdaily) after a light depression he had post surgery.
    He also mentioned it made him feel more calm and less insomniac on the long run (he was very worried about a personal crisis and could not sleep since he was anxious and was thinking about that matter nonstop which made him uneasy and nervous).
    It has no withdrawal effects when quitting it as much as i know (Can testify for myself and dad and a friend who was on it), however, when taken with other prescription meds, such as ADHD meds or other psychotropic meds one must be careful since possible unpleasant symptoms may occur.
    I read a research mentioning the plant increases serotonin levels in the brain much more than people think...
    Take about 3-4 weeks to kick in and about 6 weeks to reach full effect.

    In our local leaflet there is a also a warning combining it with strong benzos.

    In my land of residence one cannot buy it without a prescription.

    I am very surprised you mention it affecting you so strongly after one day only !
    Never heard of it before.
  4. Calyspical

    Calyspical Silver Member

    Reputation Points:
    Apr 12, 2013
    Could you elaborate on this ?
    Did it say to avoid the combination entirely ?
    Or just not at high doses of one, or both of them ?

    And what is the logic ?

    SJW and Benzos work in completely different ways.
    If Benzos don't interact with SSRI's, I wouldn't expect them to interact with SJW, either