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Stop the Sadness with St. John’s wort

By Paula Jones

1     Introduction

        According the National Institute of Mental Health, depression affects nearly 21 million American adults every year. Depression can affect everything from your mood, to your thoughts, your physical health, and your behavior. Symptoms of depression can include overall sad, anxious, and/or hopelessness, restlessness or irritability, loss of interest in formerly pleasurable activities, fatigue, decreased sex drive, decreased energy, insomnia, overeating, appetite loss, weight loss, thoughts of suicide. For a long time, the flowering herb St. John’s wort has been regarded as an alternative to conventional forms of medication for depression like psychotherapy and antidepressants. It has grown in popularity due to the fact that it is a natural alternative, and because it costs considerably less than the more conventional medications like Zoloft, Paxil, and Prozac. But does it really work, or is it just another old wives’ tale? And if it does work, how does it work? And, even if it is effective, is it safe for you to take? Hopefully, this paper will provide you with some answers to these very important questions (http://nccam.nih.gov/health/stjohnswort/sjw-and-depression.htm).

2     Information from the World Wide Web

2.1    What is St. John’s wort?

        St. John’s wort, or Hypericum perforatum, is a yellow flowering perennial herb indigenous to Europe, but now commonly found in many other temperate parts of the world. It contains many important chemical compounds, including hypericin and hyperforin, both of which are believed to contribute to its medicinal properties. While St. John’s wort has traditionally been used for many medical purposes, including as an abortifacient, a treatment for dermatitis and alcoholism, its primary modern use is as a treatment for depression and dysthymia, a mild form of depression (http://www.allaboutdepression.com/med_15.html).

         

2.2 How does St. John’s wort work for depression?

        The main goal of treatment with St. John’s wort is to reduce the severity of the symptoms associated with depression, or to eliminate them entirely. These symptoms include persistent feelings of sadness, hopelessness, anxiety, guilt, as well as generalized restlessness, irritability, fatigue, difficulty concentrating, and insomnia (http://nccam.nih.gov/health/stjohnswort/sjw-and-depression.htm).

        When used to treat depression, St. John’s wort can be taken in multiple forms. Both the flowers and leaves can be dried for use in teas, capsules, and powders. Otherwise, the flower is crushed, and the reddish-brown extract is obtained for use in extract is obtained for use in capsules or tinctures. The types of John’s wort most frequently found in health food stores in the U.S. contain only certain chemicals, generally the hypericin and the hyperforin, that have been removed from the flower extract (http://nccam.nih.gov/health/stjohnswort/sjw-and-depression.htm).

        The dosage of St. John’s wort when indicated for depression can vary, because the Food and Drug Administration does not have strict regulations on its production or sale, allowing for great variety in the concentration (http://www.nytimes.com/specials/women/warchive/970910_1246.html).

However, the generally agreed about dosage, when using the most

common form, capsules, is between 150 and 1800 milligrams of the 0.3%

hypericin content daily (http://www.mayoclinic.com/health/st-johns-wort/NS_patient-stjohnswort). One can also take 2-4 grams of powdered St. John’s wort three times per day, or make a tea with the dried herb and ingest it twice per day. It is recommended that someone who is new to taking St. John’s wort introduce it to his or her body slowly, starting with a very low dosage (http://www.webmd.com/depression/guide/st-johns-wort?page=2).

        The mechanism of action for how St. John’s wort works to battle depression is unknown, though there are several theories that have been and are currently under investigation. The most prominent is that the herb works by inhibiting the re-absorption of the neurotransmitter serotonin, which is what the class of drugs known as selective serotonin reuptake inhibitors (SSRI’s) are also engineered to do. Also, there is a theory that St. John’s wort works by reducing levels of a certain protein used by the body’s immune systems, although how that would affect depression remains unclear (http://nccam.nih.gov/health/stjohnswort/sjw-and-depression.htm). Finally, some believe that it works by reducing adrenal activity, which is increased during depression (http://health.howstuffworks.com/st-johns-wort1.htm).    

2.3    How effective is St. John’s wort in treating depression?

        There are widely ranging opinions on the Internet about the effectiveness of this herb in treating depression, with as many naysayers as ardent believers. For instance, an article in the New York Times claimed that “there is more to St. John’s wort than hearsay and health-food-store claims” (http://www.nytimes.com/specials/women/warchive/970910_1246.html), and an article on the Mayo Clinic website states, “Overall, the scientific evidence supports the effectiveness of St. John’s wort in mild-to-moderate major depression” (http://www.mayoclinic.com/health/st-johns-wort/NS_patient-stjohnswort). However, if you look at other websites, you can see statements such as, “St. John’s wort is of minimal benefit in treating depression” (http://nccam.nih.gov/health/stjohnswort/sjw-and-depression.htm), and “St. John’s wort is about as effective as standard anti-depressants” (http://health.howstuffworks.com/st-johns-wort1.htm). Suffice to say, there is no consensus about the effectiveness of the herb in treating depression or dysthymia, but there does seem to be agreement that further scientific research could possibly help to illuminate the issue.

2.4    What evidence is there that St. John’s wort works?

        One of the reasons that there are such widely ranging opinions on the effectiveness of St. John’s wort in treating depression could be that the evidence itself is extremely inconsistent. For example, The how-stuff-works website cites a 1994 study from the British Medical Journal and claims that it showed that St. John’s wort was better than sugar pill placebos at treating depression (http://health.howstuffworks.com/st-johns-wort1.htm). But, the National Institutes of Health website discusses a study that was co-funded by the National Center for Complementary and Alternative Medicine. It states, “St. John’s wort was no more effective than placebo in treating major depression of moderate severity” (http://nccam.nih.gov/health/stjohnswort/sjw-and-depression.htm). Continued review of the information available on the web yields no more definitive results; there seem to be just as many scientific studies cited in favor of the use of St. John’s wort as there are against it. Fortunately, most websites, do, however, at least cite some scientific study or research. 

2.5    Can St. John’s wort be harmful?

        While there does not appear to be agreement on the effectiveness of using St. John’s wort, most websites do agree on some observed side effects. These side effects can include: increased sensitivity to light, dry mouth, stomach irritation, dizziness, tiredness, and increased blood pressure

(http://www.webmd.com/depression/guide/st-johns-wort?page=2).

        Not only are there potential side effects with use of St. John’s wort, but studies have also shown that there can be serious risks for negative                                     interactions with prescription medications. These medications include (but are not limited to, so check with your doctor) decreased effectiveness of birth control pills, other antidepressant medications, medicines that help the body not reject organs after transplant, medicines used to control HIV infection, some anticancer medications, and some diuretics (http://nccam.nih.gov/health/stjohnswort/sjw- and-depression.htm).

2.6    Who put this information on the web and how trustworthy is it?

        All of the information used in this report came from websites that gave at least a few scientific sources as citations, including well-known and respected names such as the British Journal of Medicine, Journal of the American Medical Association, the National Institutes of Health, and the New England Journal of Medicine (http://nccam.nih.gov/health/stjohnswort/sjw-and-depression.htm), (http://health.howstuffworks.com/st-johns-wort1.htm). However, when looking generally on the Internet, one should always be wary of the information that they find. There were many websites that seemed to be trying to convince you that St. John’s wort was effective as a treatment for depression solely so that they could sell it to you. Always be aware of the motives of the website you are reading; if they are trying to sell you the product or to test it out for them, then they are biased, and you should try to find a more objective source.

3     Information from Scientific Literature

3.1    Summary of the Literature

        In this section, I have chosen five studies to discuss with regards to the effectiveness and the safety of taking St. John’s wort for depression. These studies are from well-known and respected journals, and they all have generally good research designs, although there are specific possible flaws that will be discussed. The first four studies all examine the effectiveness of St. John’s wort and its constituent chemicals in treating depression, and they display varying results. They all agree that, in comparison with a placebo, St. John’s wort does appear to be more effective in the treatment of depression. However, when comparing it to a standard antidepressant, the results are more mixed. The last three studies all work to uncover a mechanism by which St. John’s wort or the chemicals it contains might actually work to reduce the symptoms of depressive disorder. They suggest such things as acting like a selective serotonin reuptake inhibitor (SSRI), a monoamine oxidase inhibitor (MAOI), and even by increasing the presence of sodium ions in the synapse. They all offer convincing arguments for their findings, although they also contain specific flaws, which will be discussed.

 

3.2    What do the studies show about the effectiveness of St. John’s Wort for depression?

        The three studies I have chosen that discuss the effectiveness of St. John’s wort do not all agree in their conclusions. First, let us look at a study conducted by Y. Lecrubier et al. (2002) and published in The American Journal of Psychiatry. It appears to be well constructed, as it was double blind, randomized, and placebo-controlled with a considerable sample size of 375 participants. The participants all had mild to moderate major depression, were drawn from both genders, and met inclusion criteria such as meeting a certain score on the Hamilton depression scale. The effectiveness of treating depression was operationally defined by changes in the Hamilton depression scale score, and the study found significant differences. 52.7% of the group receiving the St. John’s wort showed improvement, while 42.3% of the placebo group showed improvement. So, this study seems to show that, at least when compared to a placebo, taking St. John’s wort could help to reduce or even eliminate the effects of depression (Lecrubier et al., 2002).

Another study, conducted by A. Szegedi et al. (2005) and published in British Medical Journal, compared the use of St. John’s wort to paroxetine (commonly known as Paxil) in the treatment of moderate to severe depression. This appears to be another well-constructed study; it was randomized, double blind, double-dummy, reference controlled, and conducted at multiple centers of research. The only possible problem was that there was no placebo control group, there were only the St. John’s wort group and the paroxetine group. The outcome measure was, again, changes in score on the Hamilton depression scale from baseline to the end of the trial, in this case 42 days. This study showed that the Hamilton depression total score decreased by 56.6% of the baseline value for the St. John’s wort group, while it decreased by 44.8% for the paroxetine group. This shows, much like the study discussed above, that there does seem to be some credence to the claim that St. John’s wort is effective in treating major depression (Szegedi et al., 2005).

        The last two studies that we will look at are meta-analyses. This means that the study is actually an examination of a number of, in this case six, actual scientific studies.  The first of the meta-analyses                                   that we will look at was conducted by Linde et al. (1996) and                                         published in the British Medical Journal.  The goal of the study was to assess the effectiveness of treating depression with St. John’s wort to a placebo and to standard antidepressant medication. This study examined 23 randomized trials with mainly mild or moderately severe depressive disorders. One of the major problems with this study is that the “mild or moderately severe depressive disorders” category is quite large. There are several depressive disorders, of which major depression, which is what the other studies focus on, is only one type. Continuing, this study also did not use the Hamilton Depression scale as its outcome measure, but used several different outcome measures. Also of concern is that the dosage of the hypericin extract from the St. John’s wort varied considerably. Moving on though, this study showed that St John’s wort extracts were significantly superior to placebo and similarly effective as standard antidepressants. These findings are consistent with both of the studies above (Linde et al., 1996).

        The last study that will be discussed was conducted by Kim et al. and published in The Journal of Nervous and Mental Disease. This, appears to well-structured, only including studies that were blinded and controlled, compared St. John’s wort with standard antidepressant treatments or with a placebo, and used the Hamilton Depression Scale as an operational definition of effectiveness. One of the primary goals of this study, in fact, was to correct the errors that had been made in the Linde study. The meta-analysis revealed that when comparing St. John’s wort to Placebo, the scores for the St. John’s wort group showed more dramatic improvement than the studies with the placebo, although they also showed some improvement. It also revealed that, when comparing treatment with St. John’s wort to treatment with tricyclic antidepressants, the improvements were generally similar and sometimes equal (Kim et al., 1999).

         So, overall, the four chosen studies do not agree exactly upon how effective St. John’s wort can be for treating depression, but they do agree that there is evidence that it can be somewhat effective. The Kim et al. meta-analysis, the Linde et al. meta-analysis and the Lecrubier et al. study showed that St. John’s wort is more effective in the treatment of depression than placebos. There is some discrepancy in the findings between the Szegedi et al. study, and the Linde et al. and Kim et al. meta-analyses, as the first found significant difference in the effectiveness of St. John’s wort and the drug Paxil, in favor of St. John’s wort, the second found that there was similar effectiveness as compared to standard antidepressants, and the third did not find any significant difference among the six trials that it analyzed. However, based on the science, it does appear that St. John’s wort is at least moderately effective at the treatment of major depression.

3.3    What does the science say about the mechanism of action for St. John’s wort?

        Another question brought up by the review of the information on the web was how St. John’s wort actually works to alleviate symptoms of depression. Here, we will look at three studies that examined the relationship. First, in a study conducted by W.E. Muller et al. (1997), the possibility of the hypericum extract from St. John’s wort was examined to see if it could work as a monoamine oxidase inhibitor (MAOI) and what its effects on serotonin, dopamine, and norepinephrine, three neurotransmitters very closely associated with depression, were. The study found that the extract seemed to have a significant effect on the inhibition of                                               the re-uptake of the three neurotransmitters, suggesting that it might work in a way very similar to the SSRI’s mentioned earlier in the paper, such as Zoloft. However, the study also showed that the extract was a poor inhibitor of both MAO-A and MAO-B, suggesting that it does not act like an MAOI. The general design of the study was actually quite good, but there is a possible large problem in that it was conducted on rats, and we are trying to generalize it to humans (Muller et al., 1997).

        A second study, conducted by Franklin et al. (1999), suggests support for the theory that St. John’s wort might work by increasing the amount of dopamine in the brain. The study was constructed well, using a double blind, placebo-controlled, balanced-order, and crossover design. However, problems might arise from the small sample of twelve volunteers, as well as the fact that they were all male. Yet another problem with the study is that the participants are healthy males, not ones suffering from depression; the results might be different for those suffering from depression because altered brain chemistry is a known factor of depressive disorders. Continuing, the results of the study did, in fact, show some evidence for the possibility that St. John’s wort works, at least in part, by enhancing certain aspects of dopamine neurotransmission. This study does also refer to previous research stating that the extract from herb has the property of blocking dopamine reuptake in rodents, so that the same mechanism might possibly occur in humans (Franklin et al., 1999).

        The final study that will be discussed was conducted by Trieber et al. (2005). It suggests an even more specific mechanism for blocking the reuptake of neurotransmitters, further suggesting a more specific mechanism for how St. John’s wort might work. This study examines a possible mechanism by which the chemical found in St. John’s wort, hyperforin, might be able to inhibit neurotransmitter reuptake. The study was designed to study the effect of hyperforin on both human platelets and rat cells. Blood was gathered from healthy, unmedicated volunteers and rats, and then studied using a measure of fluorescence. The study seems to be well set up, particularly since both human and rat cells were studied. The results of the study show that hyperforin might inhibit the re-uptake of serotonin (increasing the amount in the brain), by raising the amount of sodium ions in the synapse, the area between nerves (Trieber et al., 2005).

        All three of these studies shed possible light on the mechanism for St. John’s wort with regards to how it might alleviate symptoms of depression. The first suggests that St. John’s wort works by inhibiting the reuptake of certain neurotransmitters such as dopamine, norepinephrine, and serotonin, thereby increasing the amount of each in the brain. This is of particular interest because SSRI’s, like Prozac, Paxil, and Zoloft, have the same effect on serotonin, which is how they are successful in treating depression. The first study is also important because it shows that St. John’s wort is a poor inhibitor of monoamine oxidase, which eliminates that mechanism of action (Muller et al., 1997). The second study is important because it suggests that St. John’s wort might also work by increasing the amount of dopamine in the brain, dopamine concentration being a very important factor in the biochemistry of depression (Franklin et al., 1999). Finally, the last study is important because it suggests a specific chemical found in St. John’s wort that might be responsible for the inhibition of the reuptake of serotonin, and a specific mechanism by which this is possible (Trieber et al., 2005).

4     Conclusion

        In conclusion, I would like to say that St. John’s wort has the potential to be an effective treatment for major depressive disorder. The information on the web has been generally well researched, and the scientific studies certainly seem to suggest a certain amount of efficacy in its usage. However, one should always exercise caution when taking information off the web. There are many websites out there whose main goal is to sell St. John’s wort, or any other product, and so the information on those sites should always be taken with a grain of salt. Also, if you do decide to use St. John’s wort to treat any malady, you should discuss this with your doctor first, and remember the side effects listed above: they can be serious! I am confident that more research will be done on this topic, and that the research will not only further illustrate the effectiveness of the herb in treating depression, but will also allow a specific mechanism or mechanisms of action to be uncovered.

References

 

Franklin, M., Chi, J., McGavin, C., Hockney, R., Reed, A., Campling, G., Whale, R.W.R., & Cowen,      P.J. (1999). Neuroendocrine evidence for dopaminergic actions of hypericum extract (LI 160) in healthy volunteers. Biological Psychiatry, 46 (4), 581-584.

Kim, H.L., Streltzer, J., & Goebert, D. (1999).  St. John’s wort for depression: a meta-analysis of well-  defined clinical trials. Journal of Nervous and Mental Disease, 187, 532-538.

Lecrubier, Y., Clerc, G., Didi, R., & Kieser, M. (2002). Efficacy of St. John’s wort extract WS 5570 in major depression: A double-blind, placebo-controlled trial. The American Journal of Psychiatry, 159 (8), 1361-1367.

Linde, K., Ramirez, G., Mulrow, C.D., Pauls, A, et al. (1996). St. John’s wort for depression—an    overview and meta-analysis of randomized clinical trials. British Medical Journal, 313(7052),     253-259.

Muller, W.E., Rolli, M., Schafer, C., & Hafner, U. Effects of hypericum extract (LI 160) in         biochemical models of antidepressant activity. (1997). Pharmacopsychiatry, 30 (2), 102-107.

Szegedi, A., Kohnen, R., Kienel, A., & Kieser, M. (2005). Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St. John’s wort): Randomised, controlled double blind non-infereiority trial versus paroxetine. British Medical Journal, 330 (7490), 503.

Treiber, K., Singer, A., Henke, B., & Muller, W.E. (2005). Hyperforin activates non-selective cation   channels (NSCCs). British Journal of Pharmacology, 145 (1), 75-83.

 

 

 

 

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