With the warm days of summer approaching, I begin to look for the sunny beauty of the humble little flowering plant, St. John’s wort(Hypericum perforatum). Called St. John’s wort because it blooms around the feast day of John the Baptist (June 24th), the plant grows prolifically in southern Oregon, particularly along roadsides and in meadows. The bright yellow five-petaled flower resembles a halo; when pressed, the flowers release a crimson liquid that symbolized to early Christians the spilled blood of their beloved St. John.
St. John’s wort has been used in herbal healing for centuries, and continues to play a prominent role in botanical medicine. I often refer to the herb as a “neurological adaptogen” stress-reliever and mood balancer. I also use it based on traditional usages, which include nerve tissue regeneration, protection, and pain relief. As a neurological restorative plant, St. John’s wort is among the best-suited agents for treating nerve damage. Today, St. John’s wort extract (SJWE) is commonly used to treat depression—in energetic terms, it restores and uplifts the “Vital Spirit,” while clearing liver heat and toxins. Topically, St. John’s wort has been used as a vulnerary, and I frequently employ hypericum oil mixed with other herbs and essential oils for numerous applications such as neuropathy.
The subject of St. John’s wort extract (SJWE) herb-drug interactions is an ongoing saga, and the issue arose again at the “Integrative Medicine: Cancer Strategies” conference where I lectured last weekend in Scottsdale, Arizona. I felt I needed to speak up for the plant medicines that I love, and which I have seen bring so much healing to people. Unfortunately, there are many people who speak about herbs who know little about botanical medicine, other than what they read or hear (and their sources also know little or nothing about plant medicines).
Botanical medicines are complex, and often work in very different ways from pharmaceutical drugs. I’m going to get technical here, for those of you who are interested in the science behind the plant. Recent reports and research seek to clarify SJWE’s drug interaction profile. A more thorough understanding of the plant’s pharmocokinetics has revealed its profound effect on all three phases of hepatic detoxification. The primary Phase I detoxification pathways influenced by SJWE are CYP450 enzyme pathways, most notably a specific pathway called 3A4, but also CYP2D6, 2C9, and a pathway called PXR, or Pregnane receptor X, which activates many other pathways. Many commonly prescribed drugs utilize these pathways for metabolism, in some cases for excretion of the drug, and in others for conversion of a drug into an active metabolite.
The difficult aspect of the SJWE conundrum is that when you look at all of the combined data, there is little actually known about the interaction induced effects of SJWE on drug metabolism. More importantly, does the net effect cause the drug to be less effective at treating the condition for which it was prescribed? There have been many theoretical assumptions made with regard to SJWE’s interaction profile, and all failed to prove the latter to be true.
Most of the interaction research on SJWE and various drugs, including the chemotherapeutic drug CPT-11 (Irinotecan), have demonstrated that SJWE extract (600-900 mgs daily) can reduce blood levels between 20-40%. It’s important to note that 50% of all drugs are metabolized by CYP3A4. Most of the research on SJWE has either utilized 900 mg. of SJWE, an amount that is not typical within an ETMS setting (for example, 3 capsules of our proprietary blend for mood enhancement provide 300 mg.), or they are in vitro studies which are very difficult to interpret and apply to clinical practice.
However SJWE up-regulates, it increases the detoxification of all drugs that are broken down and excreted by the body. In the case of CPT-11, SJWE also reduces SN-38, so it may decrease the amount of the active drug—but things are just not that simple when it comes to the complexity of botanical medicine and understanding the multitude of ways that plant compounds affect the body and interact with drugs. Let’s take a closer look at other ways that SJWE interacts. SJWE has demonstrated the ability to inhibit multiple cancer-related amplified pathways including PTK (protein tyrosine kinase) inhibitor (Eur J Pharm Biopharm. 2003 Jul;56(1):121-32, Clin Cancer Res. 1996 May;2(5):843-6) and the modulation of cytokines including TNF-alpha, inhibition of viral induced cell transformation and through mitochondrial-related pathways (Oncol Res. 2000;12(9-10):409-18, Hostanska, K., Reichling, J., Bommer, S., Weber, M., Saller, R., 2003). The pro-oxidant photodynamic properties of hypericin have also been exploited for the photodynamic therapy of cancer (PDT) as hypericin, in combination with light, effectively induces apoptosis and/or necrosis of cancer cells (Int J Mol Sci. 2010 Feb 4;11(2):562-94, Curr Drug Targets. 2002 Feb;3(1):55-84, J Photochem Photobiol B. 2008 May 29;91(2-3):67-76. Epub 2008 Feb 7, Lasers Med Sci. 2001;16(4):276-83.Neurosurg Focus. 2006 Apr 15;20(4):E20).
SJWE has been shown to significantly inhibit tumor growth in tumor-bearing animals (Chemico-Biological Interactions (2010), doi:10.1016/j.cbi.2011.02.026). In one animal study involving prostate cancer treatment with SJWE, tumor growth was inhibited by 70%. Regional lymph node metastasis was observed in 100% of the control mice compared to 30% of mice treated with SJWE (Cancer Letters 210 (2004) 27–33). SJWE may also be a potent radiosensitizer as well (Clin Cancer Res. 1996 May;2(5):843-6).
SJWE has demonstrated profound anti-cancer effects including selective anti-angiogenic capacity (PLoS One. 2010 Mar 9;5(3):e9558, Int J Cancer. 2009 Jul 1;125(1):34-42). According to an article in the International Journal of Cancer:
“Our data indicates that hyperforin is a compound that interferes with key events in angiogenesis, confirming the recent and growing evidence about a potential role of this compound in cancer and metastasis inhibition and making it a promising drug for further evaluation in the treatment of angiogenesis-related pathologies,” (Int J Cancer. 2005 Dec 10;117(5):775-80).
In a balanced review of the data, it becomes apparent that although SJWE may decrease blood levels of pharmaceutical drugs, this action does not reduce their effectiveness. In addition, SJWE decreases side effects, improves tolerability, and may even improve response rate because of its pleotrophic anti-cancer effects. For example, many cancer chemotherapy drugs have a dose-limiting toxicity; diarrhea is a common side effect and limits the amount of drug that can be administered. This is true for many frequently used drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. Studies have shown that SJWE can alleviate irinotecan-induced diarrhea, most likely the result of the anti-inflammatory effects of the herb. The researchers concluded, “Further studies are warranted to explore the potential for (SJWE) as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities,”(Toxicol Appl Pharmacol. 2007 Apr 1;220(1):108; author reply 109-10).
Some studies are investigating the beneficial effects of combining botanical medicines with pharmaceutical drugs. For example, one study showed that a combination of CPT-11 or SN-38 with a PKC inhibitor (such as hypericin) resulted in the decrease in proliferation and an increase in apoptosis in malignant glioma cells (Cancer. 2003 May 1;97(9 Suppl):2363-73). Because SJWE is a potent PKC inhibitor, we could theorize and suggest that combining SJWE with CPT-11 could increase the anti-cancer effects. Another study, involving SJWE with the chemotherapeutic drug temador, also suggested a positive synergistic effect (Neurosurg Focus. 2006 Apr 15;20(4):E20).
In light of all of this, it appears that SJWE decreases patient morbidity and mortality when combined with CPT-11. I am not suggesting taking large doses of the two together, I am only helping to defend SJWE and to clarify the larger picture. I certainly believe that more research is called for.
With the huge increase in prescription and nonprescription drugs, along with indigenous hormones (estrogens), xenoestrogens, dietary factors, and emotional stressors, SJWE may be a lifesaver for many. The CYP detoxification pathways, in particular CYP 3A4, are under enormous strain and SJWE specifically assists in helping us detoxify carcinogens.
I do believe that we should be more concerned with drug-to-drug interactions. For example, for more than a decade women with ER+ breast cancer have been given the drug tamoxifen, an ER antagonist, to prevent reoccurrence of breast cancer, or to manage existing breast cancer. Many of these woman developed depression and were prescribed antidepressants—specifically, selective serotonin reuptake inhibitors (SSRI’s). Until recently, no one questioned this practice, until it was discovered that SSRI’s are notoriously potent CYP2D6 inhibitors of 2D6, another CYP enzyme that is essential for converting tamoxifen, a pro-drug, into its active metabolite, and that woman taking these drugs together suffered a significant increase in mortality (BMJ. 2010 Feb 8;340:c783. doi: 10.1136/bmj.c783, BMJ. 2010 Feb 8;340:c693. doi: 10.1136/bmj.c693). In addition, the hot flashes that are a common side effect of tamoxifen are typically treated with SSRI’s. This is a serious issue, and yet poly-drug prescribing by one or multiple physicians is common. What I find most ironic is that if these women were also taking SJWE, they might have been able to convert tamoxifen into its active metabolite, because SJWE also activates CYP 2D6 (Mol Nutr Food Res. 2008 Jul;52(7):755-63). Even more interesting is that women who carried the CYP3A4*1B allele had a 3-fold increase in the risk of developing endometrial cancer following tamoxifen treatment (Carcinogenesis vol.28 no.10 pp.2139–2142, 2007). Prescribing SJWE could have saved them—this is theoretical of course, but interesting and worthy of study.
My take-away message: Don’t always believe that herb and drug interactions are bad. In my clinical practice of more than twenty-five years, I have used botanical medicines, including SJWE and other complimentary botanicals and nutrients, in a formula specifically designed to help people enhance their “Vital Spirit.” I believe we should exercise caution, not fear, and employ the six thematic elements of the ETMS, which include logic, common sense, science, tradition or classical wisdom, intelligent intuition, and prayer to help create the most effective formulation for an individual.
Lastly, SJWE is a safe and effective anti-depressant in mild to moderate depression, with many more added benefits, including other positive neurological effects, effects on reducing inflammation, and antibacterial, antiviral, antitumoral and antiangiogenic effects (Life Sci. 2006 Jun 6;79(2):105-11. Epub 2006 Jan 24.) Multiple comparative trials of SJWE and other antidepressants, including SSRIs, provide support for SJWE extract efficacy (Eur Neuropsychopharmacol. 2010 Nov;20(11):747-65. Epub 2010 Aug 14).
Two large meta-analyses have concluded that SJWE is more effective than placebo for the treatment of mild-to-moderate depression and less likely to cause side effects than commonly prescribed antidepressants (Bmj 313 (7052), 253–258. 1996; Pharmacopsychiatry, (Suppl 1), S51–S55. 2001). According the 2008 Cochrane report, for more major depression, the available evidence suggests that SJWE: a) is superior to placebo in patients with major depression; b) is similarly effective as standard antidepressants; and c) has much fewer side effects than standard antidepressants (Cochrane Database Syst Rev. 2008 Oct 8;(4):CD000448). St. John’s wort is clearly an herbal ally, with numerous beneficial health promoting and healing benefits. This humble plant deserves our respect and gratitude.