Saint Johns Wort, Kava & Hormone Base Birth Control.
Here we focus on the P-450 set of metabolizing enzymes. We'll take a look at why you shouldn't combine birth control with St. John's Wort, and why this doesn't apply to the actions seen in kava.
CYP Enzymes are responsible for the metabolization of a vast array of chemicals that occur naturally and in drugs we take. 90% of these drugs are metabolized by CYP enzymes with CYP3A4 and CYP2D6 being the most significant [1]. Many natural compounds interfere with these enzymes. St John's Wort and possibly Kava are two that do, however they do this in specifically different ways.
Inhibition and induction of the CYP enzymes are central mechanisms resulting in clinically significant interactions between drugs and other drugs, and between herbs and other drugs.
Inhibition of CYP enzymes refers to the action of reducing said enzyme’s ability to combine with and break down drugs or chemicals that use that enzyme to be excreted from the body.
Induction of CYP enzymes refers to the action of increasing said enzymes ability to combine with and break down drugs or chemicals that use that enzyme to be excreted from the body [2].
St. John’s Wort (SJW) effect at CYP3A4:
In studies St. John's Wort was shown to be an inducer of the CYP enzyme known as CYP3A4 [3]. CYP3A4 is probably the most important enzyme for human drug metabolism [4]. Ethinylestradiol and gestodene are hormones commonly used in oral contraceptives. Both of these have affinity for the enzyme CYP3A4 to break down [5,6]. When we speak of “induction” that means it causes this specific enzyme to work in “overdrive”. Any drug or chemical that uses that pathway to break down will do so much faster and be eliminated from the body in less time than it would normally take if SJW was not present. In the case of birth control, SJW causes the hormones to be excreted from the body faster which can open the door to effectiveness being lost.
Kava’s effect at CYP3A4:
Kava was shown in the lab to interact with this enzyme location as well, however the crucial difference being that kava, specifically methysticin, was shown to weakly inhibit this enzyme instead of inducing it [7]. The inhibition in this instance would see drugs using this pathway to, in reverse fashion, remain in circulation in the body for longer periods of time. A grain of salt to take with this finding is that this study was run in vitro. Since then, subsequent studies have shown kava NOT having this effect at CYP3A4 in the human body. In 2009 Shord et al found that administration of midazolam, a potent CYP3A4 substrate (uses CYP3A4) was not affected in the presence of kava indicating a lack of inhibition profile at CYP3A4 for kava [8]. What this means is that likely kava has no effect at all at the same location we see problems with the combination of Saint John’s Wort and hormone based birth control pills.
Summary:
The combination and subsequent failure of birth control when combined with Saint John’s Wort is a product of enzyme induction causing birth control to break down and exit the body more quickly than in normal scenarios. Kava, having shown a lack of activity at CYP3A4 in humans or possibly a weak inhibition at this pathway, will not cause these same sorts of metabolization issues with birth control.
[1] Lynch, Tom, and Amy Price. 2007. “The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects.” American Family Physician 76 (3): 391–96. https://www.ncbi.nlm.nih.gov/pubmed/17708140
[2] Roskoski, Robert. 2007. “Modulation of Enzyme Activity.” In xPharm: The Comprehensive Pharmacology Reference, edited by David B. Bylund S. J. Enna, 1–11. https://doi.org/10.1016/B978-008055232-3.60042-X
[3] Markowitz, John S., Jennifer L. Donovan, C. Lindsay DeVane, Robin M. Taylor, Ying Ruan, Jun-Sheng Wang, and Kenneth D. Chavin. 2003. “Effect of St John’s Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme.” JAMA: The Journal of the American Medical Association 290 (11): 1500–1504. https://doi.org/10.1001/jama.290.11.1500
[4] Li, Albert P., and Malle Jurima-Romet. 1997. “Overview: Pharmacokinetic Drug-Drug Interactions.” In Advances in Pharmacology, edited by Albert P. Li, 43:1–6. Academic Press. https://doi.org/10.1016/S1054-3589(08)60199-4
[5] Palovaara, S., K. T. Kivistö, P. Tapanainen, P. Manninen, P. J. Neuvonen, and K. Laine. 2000. “Effect of an Oral Contraceptive Preparation Containing Ethinylestradiol and Gestodene on CYP3A4 Activity as Measured by Midazolam 1’-Hydroxylation.” British Journal of Clinical Pharmacology 50 (4): 333–37. https://doi.org/10.1046/j.1365-2125.2000.00271.x
[6] Murphy, Patricia A., Steven E. Kern, Frank Z. Stanczyk, and Carolyn L. Westhoff. 2005. “Interaction of St. John’s Wort with Oral Contraceptives: Effects on the Pharmacokinetics of Norethindrone and Ethinyl Estradiol, Ovarian Activity and Breakthrough Bleeding.” Contraception 71 (6): 402–8. https://doi.org/10.1016/j.contraception.2004.11.004.
[7] Singh, Yadhu N. 2005. “Potential for Interaction of Kava and St. John’s Wort with Drugs.” Journal of Ethnopharmacology 100 (1-2): 108–13. https://doi.org/10.1016/j.jep.2005.05.014
[8] Shord, Stacy S., Kanan Shah, and Alvina Lukose. 2009. “Drug-Botanical Interactions: A Review of the Laboratory, Animal, and Human Data for 8 Common Botanicals.” Integrative Cancer Therapies 8 (3): 208–27. https://doi.org/10.1177/1534735409340900.
Here we focus on the P-450 set of metabolizing enzymes. We'll take a look at why you shouldn't combine birth control with St. John's Wort, and why this doesn't apply to the actions seen in kava.
CYP Enzymes are responsible for the metabolization of a vast array of chemicals that occur naturally and in drugs we take. 90% of these drugs are metabolized by CYP enzymes with CYP3A4 and CYP2D6 being the most significant [1]. Many natural compounds interfere with these enzymes. St John's Wort and possibly Kava are two that do, however they do this in specifically different ways.
Inhibition and induction of the CYP enzymes are central mechanisms resulting in clinically significant interactions between drugs and other drugs, and between herbs and other drugs.
Inhibition of CYP enzymes refers to the action of reducing said enzyme’s ability to combine with and break down drugs or chemicals that use that enzyme to be excreted from the body.
Induction of CYP enzymes refers to the action of increasing said enzymes ability to combine with and break down drugs or chemicals that use that enzyme to be excreted from the body [2].
St. John’s Wort (SJW) effect at CYP3A4:
In studies St. John's Wort was shown to be an inducer of the CYP enzyme known as CYP3A4 [3]. CYP3A4 is probably the most important enzyme for human drug metabolism [4]. Ethinylestradiol and gestodene are hormones commonly used in oral contraceptives. Both of these have affinity for the enzyme CYP3A4 to break down [5,6]. When we speak of “induction” that means it causes this specific enzyme to work in “overdrive”. Any drug or chemical that uses that pathway to break down will do so much faster and be eliminated from the body in less time than it would normally take if SJW was not present. In the case of birth control, SJW causes the hormones to be excreted from the body faster which can open the door to effectiveness being lost.
Kava’s effect at CYP3A4:
Kava was shown in the lab to interact with this enzyme location as well, however the crucial difference being that kava, specifically methysticin, was shown to weakly inhibit this enzyme instead of inducing it [7]. The inhibition in this instance would see drugs using this pathway to, in reverse fashion, remain in circulation in the body for longer periods of time. A grain of salt to take with this finding is that this study was run in vitro. Since then, subsequent studies have shown kava NOT having this effect at CYP3A4 in the human body. In 2009 Shord et al found that administration of midazolam, a potent CYP3A4 substrate (uses CYP3A4) was not affected in the presence of kava indicating a lack of inhibition profile at CYP3A4 for kava [8]. What this means is that likely kava has no effect at all at the same location we see problems with the combination of Saint John’s Wort and hormone based birth control pills.
Summary:
The combination and subsequent failure of birth control when combined with Saint John’s Wort is a product of enzyme induction causing birth control to break down and exit the body more quickly than in normal scenarios. Kava, having shown a lack of activity at CYP3A4 in humans or possibly a weak inhibition at this pathway, will not cause these same sorts of metabolization issues with birth control.
[1] Lynch, Tom, and Amy Price. 2007. “The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects.” American Family Physician 76 (3): 391–96. https://www.ncbi.nlm.nih.gov/pubmed/17708140
[2] Roskoski, Robert. 2007. “Modulation of Enzyme Activity.” In xPharm: The Comprehensive Pharmacology Reference, edited by David B. Bylund S. J. Enna, 1–11. https://doi.org/10.1016/B978-008055232-3.60042-X
[3] Markowitz, John S., Jennifer L. Donovan, C. Lindsay DeVane, Robin M. Taylor, Ying Ruan, Jun-Sheng Wang, and Kenneth D. Chavin. 2003. “Effect of St John’s Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme.” JAMA: The Journal of the American Medical Association 290 (11): 1500–1504. https://doi.org/10.1001/jama.290.11.1500
[4] Li, Albert P., and Malle Jurima-Romet. 1997. “Overview: Pharmacokinetic Drug-Drug Interactions.” In Advances in Pharmacology, edited by Albert P. Li, 43:1–6. Academic Press. https://doi.org/10.1016/S1054-3589(08)60199-4
[5] Palovaara, S., K. T. Kivistö, P. Tapanainen, P. Manninen, P. J. Neuvonen, and K. Laine. 2000. “Effect of an Oral Contraceptive Preparation Containing Ethinylestradiol and Gestodene on CYP3A4 Activity as Measured by Midazolam 1’-Hydroxylation.” British Journal of Clinical Pharmacology 50 (4): 333–37. https://doi.org/10.1046/j.1365-2125.2000.00271.x
[6] Murphy, Patricia A., Steven E. Kern, Frank Z. Stanczyk, and Carolyn L. Westhoff. 2005. “Interaction of St. John’s Wort with Oral Contraceptives: Effects on the Pharmacokinetics of Norethindrone and Ethinyl Estradiol, Ovarian Activity and Breakthrough Bleeding.” Contraception 71 (6): 402–8. https://doi.org/10.1016/j.contraception.2004.11.004.
[7] Singh, Yadhu N. 2005. “Potential for Interaction of Kava and St. John’s Wort with Drugs.” Journal of Ethnopharmacology 100 (1-2): 108–13. https://doi.org/10.1016/j.jep.2005.05.014
[8] Shord, Stacy S., Kanan Shah, and Alvina Lukose. 2009. “Drug-Botanical Interactions: A Review of the Laboratory, Animal, and Human Data for 8 Common Botanicals.” Integrative Cancer Therapies 8 (3): 208–27. https://doi.org/10.1177/1534735409340900.