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St. John's Wort & Vitamin E (Doctors' Edition) PDF Print E-mail
Written by Dr. Edward Zimmer   

I get numerous questions eac week regarding the use of both the herb St. John’s Wort and Vitamin E . The questions themselves relate to issues of safety and the effectiveness of these two supplements. My goal in this issue is to give you the “other side”, empowering you to make more informed recommendations to your patients.

St. John’s Wort (Hypericum perforatum)

  • A number of medical professionals have told me that they do not recommend this herb because studies show that it does not work. In fact, the study most commonly quoted was an April 2001 JAMA study.1 So, let’s evaluate this study and look at other recent studies to see if this basis for not recommending the herb is supported.
  • The JAMA 2001 article concluded that, “St. John’s wort was not effective for treatment of major depression.”
  • So, let’s dissect this JAMA study. The authors of the JAMA study simply dismissed the 30+ previous studies that had been done on SJW. They stated,“...most have significant flaws in design and do not enable meaningful interpretation.” One of those previous studies in severe depression concluded that patients improved significantly on SJW, compared to placebo and the antidepressant drug imipramine.2 This study utilized a dose of 1,800 mg/day of SJW. The JAMA study started with 900 mg/day and only increased the dose to 1,200 mg/day. There was no explanation why they decided to only use 1,200 mg/day instead of 1,800 mg/day. Also, few people knew that this JAMA study was funded by Pfizer.
  • Additionally, in this same JAMA article the researchers noted, “The number reaching remission of illness was significantly higher with St. John’s Wort than with placebo (P=.02)” but they were quick to add, “...but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs. 5/102 [4.9%], respectively.” In other words, SJW did show some significant benefit, but this was immediately downplayed as “very low”. The bottom line is that this is not a study for any clinician to hang their hat on.
  • What other studies are out there that support the use of SJW? Space will not allow me to list all of them. So, I will go over a couple of recent studies that I bet you have not seen.
  • A double blind study published in October 2005 concluded, “SJW was significantly more effective than fluoxetine (Prozac) and showed a trend toward superiority over placebo.” This study was completed on patients with major depression.3 Ending Hamilton Depression scores were 10.2 +/- 6.6 (SJW) and 13.3 +/- 7.3 (fluoxetine). Remission rates were 38% SJW, 30% fluoxetine, and 21% placebo.
  • A double blind study in March 2005 concluded, “The results indicate that hypericum extract STW 3 is not inferior to sertraline (Zoloft) and that it is a well-tolerated drug for the treatment of moderate depression. These favorable effects were achieved with a once-daily dose of 612 mg of hypericum extract given for up to 24 weeks.” 4 Hamilton Depression Total Score decreased from 22.0 +/- 1.1 (SJW) and 22.1 +/- 1.1 (sertraline) to 5.7 +/- 4.8 and 7.1 +/- 6.3 points, respectively.
  • A double blind BMJ study in March 2005 concluded, “In the treatment of moderate to severe major depression, hypericum extract WS 5570 is at least as effective as paroxetine (Paxil) and is better tolerated.” 5 Hamilton depression total score decreased by 56.6% in the SJW group and by 44.8% in the paroxetine group. This same extract was studied in August of 2002 with the conclusion, “H. perforatum extract WS 5570 was found to be safe and more effective than placebo for the treatment of mild to moderate depression.” 6
  • A review study published in January 2005 concluded, “The available studies show that hypericum extract are well tolerated and seem to be effective in routine treatment of mild to moderate depressive disorders.” 7
  • The point to be taken from my examples is that not any one study proves or disproves the benefits of any treatment. The facts, which somehow are very well suppressed, show that SJW is effective and safe when compared to other commonly prescribed antidepressants or placebo in many studies.
  • Now, the consideration to recommend the use of SJW to your patients should not be governed solely by studies showing its effectiveness. SJW is one of the herbs that can interact with a number of other pharmaceuticals. The potential for other drug interactions is a real concern when using SJW.
  • In vitro studies suggest that SJW causes induction of the cytochrome P450 isoenzyme CYP3A4.8,9 Thus, SJW may reduce the serum levels of the following drugs: indinavir, cyclosporine, theophylline, digoxin, warfarin, and oral birth control pills.10-18 Although we view these interactions as potentially harmful, the fact is that up-regulation of cytochrome P450 enzymes may help the body detoxify certain toxins and may be of benefit.
  • Since the true drug interactions of SJW are not known, my recommendation to patients is that SJW absolutely not be utilized if they are taking one of the mentioned prescriptions. This includes any other antidepressants. In fact, I tend to discourage the use of SJW if they are taking any prescription drugs just to stay on the safe side.
  • The clinically important point to be made from the information supplied in this update is that you can suggest the use of this herb to your patients with the confidence that there is published support for SJW in the peer-reviewed literature. My recommendation is that you discourage its use if the patient is taking any number of other prescriptions. We simply do not know with any confidence whether there will be drug-herb interactions. If you decide to suggest the use of SJW, make sure that you direct your patient to buy their SJW from either a health food store or from www.ZimmerNutrition.com. Taking a quality product is of great importance.

Vitamin E

  • Many doctors are now telling their patients to not take vitamin E. This may come as a surprise to you, but I agree with them in the spirit of that recommendation. A number of larger studies have concluded that vitamin E, taken as a supplement, is ineffective at protecting against cardiovascular disease. The conflict and reluctance to accept this negative data amongst some in the health field comes from epidemiological studies that support the opposite conclusion.
  • My goal in this section of this article is to explain why I think that these studies do not support the use of vitamin E as a supplement for the treatment or prevention of cardiovascular disease. Also, I will comment on the recent John’s Hopkins’ study that suggested an increase mortality with the use of vitamin E. Finally, I will give you my take on recommending this vitamin to your patients.
  • To start, I think that it is interesting and important for you to understand how vitamin E came to be. Early studies on vitamin E focused on determining what fraction of the this new substance held the most bioactivity. Studies performed on rats soon revealed that females rats gave no live births when their diet was made deficient in the “alpha” form of what would become vitamin E. Deficiencies in the gamma, beta, and delta fractions did not produce this effect. Thus, it was assumed that the alpha form was the most bioactive form and “alpha-tocopherol (to give life)” became what we now call vitamin E.
  • Until recently, the other fractions of the tocopherol family were ignored. In studying the alpha form, it was soon discovered that this molecule could be made synthetically. The only difference was that it contained an isomeric form that was not found in nature. The natural form exist as a molecule that rotates light to the right (dextro) and is known as d-alpha-tocopherol. The synthetic form also contains the left rotating molecule (levo) and is known as dl-alpha-tocopherol. The synthetic form soon became the dominant form in supplementation due to its lower cost.
  • The question is whether this makes any difference. Who cares if there is synthetic vitamin E if it works the same as the naturally occurring form? The studies show that the natural form is considerably better.19-21
  • As you can imagine, the argument from vitamin E proponents was that the lack of study support was due to the use of the synthetic form of vitamin E. At one time, I was among those who held this view. However, newer studies utilizing natural Vitamin E faired no better.
  • I now believe that a solid explanation for this lack of study report had less to do with the form of alpha-tocopherol and had more to do with the exclusion of the other fractions of tocopherols.
  • I constantly hear health professionals tell patients that the best way to get their nutrients is via diet, not supplementation. I could not agree more. In our food supply, Vitamin E is always found as a mixture of tocopherols. There is no food we eat that contains only high dose of alpha-tocopherol. Thus, I think the lack of support for the use of vitamin E has more to do with the exclusion of the other tocopherols than it does with the natural vs. synthetic debate. This would explain why epidemiological studies looking at the consumption of Vitamin E via diet support its use.
  • Vitamin E supplements containing alpha, gamma, delta, and beta tocopherols are referred to as “Mixed Tocopherol” vitamin E. Recent studies being done on these other fractions support the theory that the benefits to the cardiovascular system come from what I call the “True Natural” form of vitamin E.22-26
  • A recent Johns Hopkins study suggested an increase in mortality due to vitamin E intake?27 The conclusion of this study was, “High-dosage (≥400IU/day) vitamin E supplements may increase all-cause mortality and should be avoided.” I draw your attention to the two most important words in this conclusion: “may” and “all-cause mortality.”
  • All cause mortality as applied in this study included anyone who died of heart disease, stroke, kidney failure, cancer, Alzheimer’s disease, Parkinson’s disease, or any other disease. So, although this study had nothing to do with the risk of cardiovascular death, many just assumed that it did.
  • Quoting from the study, “Overall, vitamin E supplementation DID NOT affect all-cause mortality.” This study’s conclusion was that high-dosage vitamin E was the culprit, not vitamin E in general. So, what are the numbers? The control group had 1022 deaths/10,000 persons while the vitamin E group had only 39 more deaths for a total of 1061 deaths/10,000 persons. 4 of the 11 studies used in this review showed no risk or less death in the vitamin E groups.
  • So, how did they come up with their final conclusion if almost 40% of the studies showed no or less increased death? Here is another quote from the study explaining ONE of the major limitations to their conclusion, “High-dosage trials were often small and were performed in patients with chronic disease.” Although the authors make this statement of major limitation, they then totally ignore it to come to a conclusion that everyone should avoid high-dose vitamin E. Finally, vitamin E in this study showed a BENEFIT at low doses. Why, then did these reviewers not advocate the use of low-dose vitamin E? The observed biases, the poor data, and the pharmaceutical funding should put this study into a better perspective for you.
  • Another study published in July of 2005 in JAMA concluded, “These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention in healthy women.” 28 Amazingly, the data showed a 24% reduction in the risk of dying from cardiovascular disease among healthy women. Although vitamin E did not decrease the amount of heart disease or the mortality for people with heart disease, it substantially decreased by 1/4 the amount of deaths from cardiovascular disease in healthy women. I ask you to honestly try to come up with a reason, other than bias, as to why this result was not highlighted.
  • What, then, do you tell your patients? My recommendation is to tell them that vitamin E has not been shown to be harmful and that they might benefit from taking the mixed tocopherol form of the vitamin. Tell them to stop taking vitamin E as only d or dl-alpha-tocopherol.

 

  • You can contact Dr. Zimmer with any questions or responses via email or at 317-813-1998 / toll free 1-888-813-1998.

REFERENCES

  1. Shelton RC, Keller MB, et al. Effectiveness of St. John’s wort in major depression: a randomized controlled trial. JAMA. 2001 Apr 18(15):1978-86.
  2. Vorback EU, Arnoldt KH, Hubner WD. Efficacy and tolerability of St. John’s wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry 1997:30:S81-S85.
  3. Fava M, Alpert J, Nierenberg AA, et al. A Double-blind, randomized trial of St. John’s wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol. 2005 Oct;25(5):441-7.
  4. Gastpar M, Singer A, Zeller K. Efficacy and tolerability of hypericum extract STW3 in long-term treatment with a once-daily dosage in comparison with sertraline. Pharmacopsychiatry. 2005 Mar;38(2):78-86.
  5. Szegedi A, Kohnen R, Dienel A, Kieser M. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St. John’s wort): a randomized, double-blind, placebo-controlled non-inferiority trial versus paroxetine. BMJ 2005 Mar 5;330(7490):503.
  6. Lecrubier Y, Clerc G, Didi R, Kieser M. Efficacy of St. John’s wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. AM J Psychiatry. 2002 Aug159(8):1361-6.
  7. Linde K, Knuppel L. Large-scale observational studies of hypericum extracts in patients with depressive disorders—a systematic review. Phytomedicine. 2005 Jan;12(1-2):148-57.
  8. Roby CA, Anderson GD, Kantor E,, et al. St. John’s wort: Effect on CYP3A4 activity. Clin Pharmacol Ther. 2000;67:451-457.
  9. Moore LB, Goodwin B, Jones SA, et al. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000 ;97:7500-7502.
  10. Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and St. John’s wort. Lancet 2000;355:547-548.
  11. Ruschitzka R, Meier P, Turina M, et al. Acute transplant rejection due to St. John’s wort. Lancet 2000;355:548-549.
  12. Breidenback T, Hoffmann MW, Becker T, et al. Drug interaction of St. John’s wort with cyclosporine. Lancet 2000:355:1912.
  13. Karilova M, Treichel U, Malago M, et al. Interaction of Hypericum perforatum (St. John’s wort) with cyclosporine A metabolism in a patient after liver transplantation. J Hepatology 2000:33:853-855.
  14. Barone GW, Gurley BJ, Ketel BL, et al. Drug interaction between St. John’s wort and cyclosporine. Ann Pharmacother 2000:34:1013-1016.
  15. Nebel A, Schneider BJ, Baker Rk, Kroll DJ. Potential metabolic interaction between St. John’s wort and threophylline. AnnPharmacother 1999;33:502.
  16. Maurer A, Johne A, Bauer S, et al. Interaction of St. John’s wort extract with phenprocoumon. Eur J Clin Pharmocol 1999;55:A22.
  17. Johne A, Brockmuller J, Bauer S, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s wort (hypericum perforatum). Clin Pharmacol Ther 1999;66:338-345.
  18. Ernst E. Second thoughts about safety of St. John’s wort. Lancet 1999;354:2014-2016.
  19. Lauridsen C, Engel H, et al. Relative bioactivity of dietary RRR- and all-rac-alpha-tocopherol acetates in swine assessed with deuterium-labeled vitamin E. J Anim Sci. 2002 Mar;80(3):702-7.
  20. Burton GW, Traber MG, et al. Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr. 1998 Apr;67(4):669-84.
  21. Traber MG, et al. Discrimination between forms of vitamin E by humans with and without genetic abnormalities of lipoprotein metabolism. J Lipid Res. Aug. 1992;33(8):1171-82.
  22. Liu M, Wallmon A, et al. Mixed tocopherols inhibit platelet aggregation in humans: Potential mechanisms. Amer J of Clinical Nutr 77:700-706, 2003.
  23. Liu M, Wallin R, Wallmon A, et al. Mixed tocopherols have a stronger inhibitory effect on lipid peroxidation than alpha-tocopherol alone. Journal of Cardiovascular Pharm. 39(5):714-721, 2002.
  24. Chen H, Li D, Saldeen T. et al. Mixed tocopherol preparation is superior to alpha-tocopherol alone against hypoxia-reoxygenation injury. Biochemical and Biophysical Research Communications Feb 22;291(2):349-53, 2002.
  25. Li D, Saldeen T, Romeo F, Mehta JL. Different isoforms of tocopherols enhance nitric oxide synthase phosphorylation and inhibit platelet aggregation and lipid peroxidation: implications in therapy with vitamin E. Journal of Cardiovascular Pharmacology and Therapeutics Apr;6(2):155-61, 2001.
  26. Li D, Saldeen Mehta JL. Gamma tocopherol decreases ox-LDL mediated activation of nuclear factor-kappa B and apoptosis in human coronary artery endothelial cells. Biochemical and Biophysical Research Communications. May 27;259(1):157-61, 1999.
  27. Miller E, et al. Meta-Analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2004;142(1)
  28. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005 Jul 6;294(1):56-65.
 
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