Jeremiah Ridderbos | 12/28/2022
St. John’s Wort (SJW), also known as Hypericum perforatum, is a widely used plant that has a plethora of different uses in the field of human medicine. SJW is used for many diverse health conditions ranging from dermatological conditions to mental illness. Some dermatological uses that St John’s Wort is known for is the treatment of problems such as burns, wounds and contusions. A study on St. John’s wort on patients with atopic dermatitis hypothesized that due to the antibacterial and anti-inflammatory properties of hyperforin (an extract of SJW), the application of topical SJW cream to dermatological conditions (such as eczema) would result in better healing of the affected tissues when compared to placebo. The patients selected had symmetrical atopic dermatitis and were treated with both topical placebo cream and hyperforin cream on opposite sides of their body. The intensity of the skin lesions was based on redness, crust, papulation, excoriation (self-skin picking), lichenification (tough and leathery skin) and scaling. These variables were rated on a scale of 0 -3 with 0 being none and 3 being severe. After 28 days of treatment, the intervention resulted in decreased score of 5.3 points while the placebo only dropped 2.3 points (Schempp et al., 2003).
SJW is known to be useful for other medical conditions. One such area of common use is generally in the treatment of mild to moderate depression and some instances of major depression. In a review article of 29 studies, the conclusion formed was that SJW was more effective than a placebo intervention. Furthermore, studies also showed SJW to be similarly effective as standard antidepressants with significantly fewer side effects. Hyperforin has been shown to inhibit the uptake of chemicals such as dopamine, serotonin, norepinephrine and GABA (Zanoli, 2004). Although the 29 studies were not homogenous, the generalized conclusions clearly pointed toward the efficacy of SJW for the treatment of major depression (Linde et. al., 2008).
Another area of treatment that Hypericum perforatum shows great potential is in the alleviation of neural pain. Diabetic peripheral neuropathy (DPN) is a sometimes painful, common side effect that accompanies a very high proportion of diabetics. In a study on lab rats with DPN, the subjects were given SJW (selected for its anti-inflammatory and analgesic properties) and feverfew (commonly used for aches and pains). The results of the study found that dried SJW extract had a significant analgesic effect and even increased the pain threshold of the rats with DPN (Galeotti et al., 2013). While these findings were from experiments conducted on rats, this treatment should be investigated further in order to fully explore its potential benefits in humans.
While the aforementioned medicinal properties of Hypericum perforatum illustrate clearly how the plant can benefit people, there is another side of the drug that the general population must be aware of when using SJW. When patients who take SJW for issues such as depression are concomitantly using other medications, there can be devastating health consequences. Many drugs such as the immunosuppressant cylcosporin, HIV protease inhibitors and oral contraceptives (just to name a few) are rapidly metabolized when taken with SJW. This is due to hyperforins impact on pregnane X receptors (PXR). When these receptors are activated by SJW, expression of certain enzymes known as monooxygenase cytochromes/ cytochromes P450/ CYP3A4 is upregulated. CYP3A4 is known for its broad substrate specificity as well as its ability to degrade a vast number of pharmaceuticals (Dinis et al., 2019).
With the upregulation of CYP3A4 expression, many pharmaceuticals such as HIV protease inhibitors and immunosuppressants are quickly metabolized before they have a chance to act. This renders the co-administered drugs ineffective when taken in the presence of SJW. One hypothesis is that hyperforin from SJW activates metabolic pathways that play a role in defending the human bodies against the toxicity of other ingested plants by swiftly filtering and metabolizing any harmful chemicals (Moore et al., 2000). In addition to the aforementioned drug categories, products containing SJW are also known to interact with antibiotics, anti-asthmatic medications and anticoagulants, all of which could produce emergent situations. Lastly, the metabolites of SJW provide an additive effect for people who take it with prescription antidepressants, which causes serotonin syndrome, another medical emergency.
While this disposal mechanism could potentially be great if we ingested something harmful, people take drugs that they rely on for survival. Obviously, in the event that a patient is using SJW with other medications, it is problematic if those other medications quickly broken down. Something must be done to end this problem. A couple common solutions have been proposed to this issue. They are to halt SJW treatment or sell it as a BTC (behind the counter) drug with consultation from a pharmacist, or to develop another form of hyperforin with the same anti-depressive properties but without activating the pregnane X receptors.
Discontinuing SJW treatment for certain conditions is one solution to its effect on pharmacokinetics in humans. However, if there is no other option but to stop hyperforin treatment, a review must be done on the individuals management of depression. One effect of SJW withdrawal that individuals should be aware of is the sudden increase in active pharmaceutical blood levels that could potentially be toxic (Medsafe Editorial Team, 2000). Regardless of whether stopping SJW treatment is necessary or not, clear and proper labelling of medication is essential to preventing any negative effects. Another potential solution for this issue is to make SJW strictly a behind the counter medicine. While this alteration would not require your doctor to prescribe St. John’s Wort, it would require that only a pharmacist would have the ability to distribute this drug to you. This is significant because a pharmacist is highly trained in understanding how drugs interact with each other and SJW is no exception. Making SJW a behind the counter would give a pharmacist the opportunity to screen a consumer’s selection of drugs for any negative interactions between the purchased items. Because it is known to affect the functions of many classes of medications, having the supervision of a pharmacist could prevent many unnecessary side effects. This is why Saint John’s Wort may be a strong candidate for becoming a behind the counter drug.
An alternative to halting hyperforin treatment is to develop another form that still retains the anti-depressive properties without causing increased drug metabolism. While little research has been done explicitly on hyperforin bioengineering, there is highly advanced technology that makes this a reasonable solution. Despite there being some concerns with nanoengineering such as toxicity and inconsistent reproducibility, there is a clear use for this method. To this date, technology has allowed researchers to modify target tissues and even distribution within tissues. One example of how well nanoengineering medicines can work is in a case with malignant melanoma. With the construction and use of nanoparticle blocks composed of Dacarbazine, the treatment of malignant melanoma In vivo showed no significant side effects (Zhidong et al., 2022). This example is included to show how effective nanoengineering can be at alleviating side effects of treatments as potentially harmful as cancer therapy. While this option is intriguing, the possibility depends on if any modification could be beneficial and how easy it is to modify the chemical structure. With more research directed to this area, altering the chemical structure of hyperforin could become a viable solution. This medical development could enable patients to take SJW along with other pharmaceuticals causing any negative effects, which would be extremely beneficial for this population.
When considering the two solutions, the obvious ideal path would be to for the subject to manage their depressive symptoms and properly halt SJW treatment. This would be preferable because it requires no research and the depression (if still present) could be managed with an alternative, well-researched drug for the issue. The alternative of changing SJW to a behind-the-counter drug could help prevent negative effects of medication usage due to consumer ignorance. However, if switching medications (or stopping SJW completely) is not possible, the next best path would be to switch to nanoengineering. While copious amounts of research must still be done on the technology as a whole, the potential for obtaining the positive effects of hyperforin without activating the PXR cannot be ignored. A breakthrough in this technology could change the administration of not only Saint John’s wort, but also countless other drugs.
References
Dinis, P., Wandi, B. N., Grocholski, T., & Metsä-Ketelä, M. (2019). Chapter 14 – Chimeragenesis for Biocatalysis. Biomass, Biofuels, Biochemicals, 389–418. https://doi.org/10.1016/B978-0-444-64114-4.00014-5
Galeotti, N., Maidecchi, A., Mattoli, L., Burico, M., & Ghelardini, C. (2014). St. John’s Wort Seed And Feverfew Flower Extracts Relieve Painful Diabetic Neuropathy In A Rat Model Of Diabetes. Fitoterapia, 92, 23–33. https://doi.org/10.1016/j.fitote.2013.10.003
Linde, K., Ramirez, G., Mulrow, C. D., Pauls, A., Weidenhammer, W., & Melchart, D. (1996). St John’s Wort for Depression: An Overview And Meta-Analysis Of Randomised Clinical Trials. BMJ: British Medical Journal, 313(7052), 253–258. https://www.jstor.org/stable/29732456
Medsafe Editorial Team. (2000). “Interactions with St. John’s Wort (Hypericum perforatum) Preparations” New Zealand Medicines and Medical Deavices Safety Authority, 20: 42-48 https://www.medsafe.govt.nz/profs/puarticles/sjw.htm
Moore, L. B., Goodwin, B., Jones, S. A., Wisely, G. B., Serabjit-Singh, C. J., Willson, T. M., Collins, J. L., & Kliewer, S. A. (2000). St. John’s Wort Induces Hepatic Drug Metabolism Through Activation of the Pregnane X Receptor. Proceedings of the National Academy of Sciences of the United States of America, 97(13), 7500–7502.
Schempp, C. M., Windeck, T., Hezel, S., & Simon, J. C. (2003). Topical Treatment of Atopic Dermatitis with St. John’s Wort Cream – A Randomized, Placebo Controlled, Double Blind Half-Side Comparison. Phytomedicine, 10(9), 31–37. https://doi.org/10.1078/1433-187X-00306
Zanoli, P. (2004) “Role of Hyperforin in the Pharmacological Activities of St. John’s Wort”, CNS Drug Reviews, 10 3, p203-p218, 16p.
Zhidong Chen, Xu Chen, Gan Liu, Kai Han, Jingxiao Chen, & Junqing Wang. (2022). Editorial: The Application of Nanoengineering in Advanced Drug Delivery and Translational Research. Frontiers in Bioengineering and Biotechnology, 10. https://doi.org/10.3389/fbioe.2022.886109
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