Drug and Herb Interactions — Current Study Findings

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

An enormous amount of effort has gone into the publication and distribution of information concerning negative herb and drug interactions and the dangers presented, yet actual cases of harm have been nearly nonexistent. This cry wolf strategy has led to many physicians wondering what is actually going on here, as clinical problems have not emerged. The widespread publication and distribution of alarming in vitro study evidence has not been supported by in vivo studies or translation into clinical cases of harm. While the potential for negative health effects of concurrent use of pharmaceutical and herbal medicine is real, this subject is well studied in specialized medical colleges that teach herbal medicine, and use of professional herbal prescription from a Licensed Acupuncturist and Herbalist or a Naturopathic Doctor insures the greatest degree of safety.

A 2010 meta-review of all published studies of negative herb-drug interactions at the Hong Kong Baptist University School of Chinese Medicine found 168 articles concerning these theoretical contraindications with cancer therapies alone, but noted that "little direct evidence for such (negative) interaction could be found, whereas there is some indirect evidence for benefit" (PMID: 20832765). A number of reviews of such studies and articles in medical journals in recent years, some from prestigious University Medical Schools in the United States and Europe have noted similar findings. Faced with these facts, the organizations sponsoring these in vivo studies suggest that poor quality of herbal products and poor absorption and bio-availability must be the reason why there are no actual clinical cases of harm from herb-drug interactions. Considering the significant proof that is accumulating of not only clinical anecdotal evidence of herbal success in treatment, but also the evidence in large randomized controlled stage three trials of the effectiveness of herbal therapies, these are amazingly vacant explanations. The potential for professional integration of herbal medicine with standard pharmaceutical care presents the potential for better outcomes, but has been staunchly discouraged in standard medicine, despite the lack of clinical harm. Here is a small amount of scientific data to clarify this situation and help both the M.D. and the herbalist interact with more confidence in Complementary Medicine.

A 2008 joint study of the six most widely reported herbal culprits in potential drug-herb interactions, St. John's Wort, Kava-kava, milk thistle, black cohosh, Echinacea and Goldenseal, by the Colleges of Medicine and Pharmacology at the Universities of Arkansas and Mississippi, found that evidence of inhibition of the P450 pathway of drug catabolism was found only in goldenseal. This study dealt with the CYP2D6 genetic isoform that expresses the enzymes involved in about 30% of all medication metabolism. The study involved three separate studies on humans, each with 18 participants that were randomized to receive standardized botanical extracts for 14 days on two separate occasions, with a 30-day period between the courses of herbal extract. The CYP expression was evaluated using administration of a CYP2D6 substrate, debrisoquine 5mg, and measuring the catabolic rate with urinary analysis. The fact that the other five herbs, which have been widely reported over the years, unfairly, and without substantiation, to alter the circulating levels of key drugs prescribed, have been finally cleared of risk, is significant. Click here to see this study: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2562884

The CYP2D6 pathway is both representative of P450 pathways of catabolism in general, and also the path of catabolism of many antidepressants, antipsychotics, beta-receptor antagonists, analgesics, and antiarrhythmia agents, making it important in the subject of clinical problems with negative interactions. Most studies have dealt with the CYP3A4 substrates, which is a somewhat more widely used path of pharmaceutical biotransformation, but which is more easily inducible and modulated, and concerns pharmaceuticals less widely prescribed and with less danger of clinical problems with temporary changes in circulating levels, except for warfarin (coumadin), which utilizes the biotransformation pathway of CYP3A4 and CYP1A2 primarily, and which we be dealt with in more detail below. Maintaining the right circulating dosage of warfarin is important, since excess "blood thinning" could lead to a bleeding stroke. The CYP3A4 pathway, while associated with a greater number of pharmaceutical catabolisms (biochemical breakdown), is also generally a shared enzymatic pathway with other P450 enzyme expressions, more so than the CYP2D6. One interesting aspect of the plethora of studies concerning drug-herb interaction is the amount of information uncovered that provides the physician with a more complete perspective on pharmaceutical biotransformation and the problems with variance of effective circulating levels and drug-drug interactions. For instance, past exclusion of women in clinical trials of pharmaceuticals, and recent evidence that the female metabolism differs considerably from male metabolism in many cases, has become an issue in drug research only in recent years. The first drug to be affected was Ambien, a sleep hypnotic, as the female metabolism catabolized the drug more slowly, leading to accumulation and adverse effects. Prescribing guidelines were changed for Ambien (Zolpidem), but we can expect more such changes, and perhaps a revelation that women were excluded from drug trials because this fact was known, and hidden. Ultimately, what we are finally seeing is that widespread reporting of potential drug-herb interactions have been widely disseminated in medical journals and the media, yet the subject of actual drug-drug negative interactions is still widely downplayed.

The investigation into the great differences in metabolism of drugs between men and women with the Ambien case highlights the incredible history of pretending that dosage and circulating levels of pharmaceutical drugs are consistent between individuals and groups, and that rates of metabolism of these drugs are set at safe levels consistent with all patients that could be dangerously altered only by taking herbal medicine. While there has been almost no evidence that such altering of the rate of drug metabolism by taking herbal medicines at normal doses has created injury or harm to patients, there is finally an admittance that much harm occurs daily by this pretending that all humans have the same drug metabolic rate, and this rate of drug metabolism is not significantly altered by polypharmacy and negative drug-drug interactions and many other health factors. For instance, a 2014 article in the Scientific American outlines the problem of greatly differing rates of drug metabolism just between men and women, albeit in a surperficial manner. We see that not only Ambien is metabolized at much different rates for men and women, but that pain medication, antidepressants, and many psychotropic drugs, such as atypical antipyschotics, some of which are the biggest selling drugs in the United States at present, and many psyche drugs prescribed to children, are metabolized much differently in men an women, and create harm to the health. To see this article, just click here: http://www.scientificamerican....http://www.scientificamerican.com/article/psychotropic-drugs-affect-men-and-women-differently/ . In a review of the dangers of Ambien, the U.S. FDA admitted that they knew of this great difference in drug metabolism between men and women when they approved the drug decades ago but did not act on this potential harm and risk. We see the same ignoring of risk with failure to acknowledge that patients with liver dysfunction and stress have obviously greatly differing rats of drug metabolism, that taking too many drugs stresses this liver metabolism and alters it, and that various disease states alter this rate of drug metabolism. On the other hand, with no confirmed objective evidence, only "potential' theoretical harm, almost all Medical Doctors have been trained to warn patients about the dangerous drug-herb problems that apparently are insignificant.

In recent years we have finally seen some serious attention to the problem of varying rates of drug metabolism and the deficiencies inherent in the system of analysis in drug trials and FDA approval, as well as safe dosage. In 2010, experts at the Showa Pharmaceutical University, in Tokyo, Japan, showed that 80 percent of drug metabolism concerns not only the P450 enzymes, but the overlooked UDP-glucuronosyltransferases, with glucuronidation a very important and variable pathway. Glucoronidation, or glucuronosylation, is the enzymatic pathway where glucuronic acid is attached to a drug substrate, and is highly involved in the rate of breakdown of pharmaceutical drugs, hormones, bile acids, fatty acid derivatives and Vitamin A retinoids, all of which involve glycosidic bonds. Glucoronic acid is derived from glucose, or sugar, and of course, metabolic dysfunction may have an effect on the glucuronidation pathway, along with age, gender, obesity, liver dysfunction and inflammation, hypothyroidism, and other infectious disease states. Many common medications can inhibit glucuronidation, including benzodiazepines, codeine, ibuprofen, Naproxen, hypertension medcations such as beta-blockers, synthetic hormones such as ethinylestradiol in contraceptives and hormone replacement medications, and anti-depressant medications. Instead of warning all patients about common foods and herbs that they should avoid when taking medications to insure that their circulating effective level of the medication is safe and consistent, Medical Doctors should have been using means to individualize testing and assessment, phenotyping patients to adjust dosage, and providing a method of quickly and efficiently determining the effects of polypharmacy on the effective circulating dosage of their strong medications. We see in this scenario a systematic ignoring of risk and bad behavior on the part of standard medicine. We can only deduce that this behavior is designed to protect current business practices and to discourage use of safe and effective herbal medicine. This has worked, yet we see also a great amount of unnecessary anxiety on the part of patients, sometimes even concerning their eating habits.

As mentioned above, the medical field still generally cites only 6 herbs when talking about potential herb-drug negative interactions, and in the University of Arkansas and Mississippi study, only the standardized extract of Goldenseal was found to negatively affect the circulating dosage of pharmaceutical drugs. It has been easy to incite fear into the patient population with this confusing issue, but these 6 herbs are not generally used in standard TCM herbal practice, and only Black Cohosh is found in the basic TCM Materia Medica. Understanding the details is important to reassure patients who are using herbal medicine, and a large percentage of the population does use herbal medicine. The CYP2D6 pathway of drug catabolism (break down), that is of most concern, is not easily inducible, and so herbal intake would probably either inhibit the enzyme or have no effect at all. This study cited above confirms the potential of a standardized extract of goldenseal to affect the circulating level of debrisoquine by decreasing the rate of catabolism and temporarily increasing circulating levels. Debrisoquine, a derivative of guanidine, is not a pharmaceutical drug, but has been used extensively in studies to investigate variance in biotransformative processes, either due to genetic polymorphisms in the general population, or due to such factors as blood levels of hematocrit, MCHC, plasma proteins, and ponderal index, or body mass. Two key points of interest are seen in this study cited above, the fact that 5 of the 18 study subjects showed clinically insignificant drops in the rates of urinary excretion of the drug, and two, that a standardized extract of the herb was used, rather than the whole herb extract, which has been shown to be less problematic over the years in scientific studies due to the array of modulatory chemicals in the plant. Research in Europe around 2000 discovered that standardized extracts of various herbs were presenting mild to moderate side effects, while the whole, or natural extract index were not presenting these side effects. The theory was presented that the plant had evolved an array of modulating chemicles to protect itself from unwanted metabolic processes. Another parameter that might be considered in the final analysis, is that the 2D6 genetic expression is been shown to be polymorphic in a significant portion of the population, which results in deficiency of the expression of this enzyme. In actual clinical practice, we might ask what would happen if the whole herb extract was used, at the usual low dosage for a short period of time, and why did the standardized extract of considerable dosage not significantly affect the catabolic pathway in all of the subjects.

This brings us to the subject of biotransformative variance in the general population. As stated above, common differences between individuals may have a significant effect on the rate of metabolism of drugs. A 1991 study at the Laboratoire du Centre de Medecine Preventive et Centre du Medicament, in Vandoeuvre-les-Nancy, France, and published in the journal Clinical Chemistry, found that metabolic rates in the random study population varied considerably. Extensive metabolizers excreted an average of 17.4% of debrisoquine in the urine, while poor metabolizers secreted only 0.5%. To review this study, click here: http://www.clinchem.org/cgi/content/abstract/37/3/327. This information on drastic biotransformation variance with debrisoquine was available in 1991, yet was not mentioned in the study on herb-drug interactions cited above. What does this information actually tell us? It tells us that the general health of the individual patient has a lot to do with the effectiveness of the pharmaceutical drugs administered, because a holistic array of health factors can vary the effective circulating dosage considerably, including gender. Prescribing doctors should be asking themselves if their patients could benefit from Complementary and Integrative Medicine in improvement in these general health factors, such as blood quality and quantity, immune health, health of the digestive system, hepatoprotection and decrease in genetic polymorphic expression, etc. Optimal health of the patient apparently has a lot to do with the metabolic variance and effectiveness of the drugs prescribed. A more helpful and positive course of research would be to analyze how integration of acupuncture, diet and herbal medicine could help maintain a healthier metabolism of consistent drug catabolism, as well as safely decrease the adverse effects of medication, or allow lower dosages of problematic pharmaceuticals with many adverse effects.

Current studies of these herbs mentioned above on the CYP3A pathway have also shown that these herbs do not significantly affect the P450 pathway. One 2007 study at the same medical schools cited above shows that clarithromycin and rifampin, frequently prescribed for acute infections, including pneumonia, meningitis, and for the now prevalent TB, significantly modulate the CYP3A catabolism, yet milk thistle and black cohosh have no effect. Click here to see this study: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1865122. This study finds that a search of the medical databases still finds only a handful of herbs with any potential to affect the CYP3A catabolism, and the St. John's Wort (hypericum perforatum) is the most noteworthy, yet chronic ingestion of the active ingredient hyperforin would be necessary to cause up regulation of intestinal CYP3A4, producing reduction in oral bioavailability of medications using this intestinal catabolism. St. John's Wort is not usually prescribed on a chronic basis by a Licensed Acupuncturist and herbalist, but rather to effect changes with short term use that leads to a resolution of health problems. It is also prescribed in small dosage. Here too, is a mistake that many M.D.'s and researchers make, applying paradigms of chronic long term use of herbs in the way pharmaceuticals are generally prescribed.

In the case of reviews of drug-herb interactions, we note that there is seldom mention of very many herbs, and the same herbs continue to be mentioned in every review of the subject, usually St. John's Wort (Hypericum perforatum) is one of two herbs mentioned. Click here to see a typical citing of a medical text on this subject cited in Current Phamacogenomics in 2004: http://www.ingentaconnect.com/content/ben/cpg/2004/00000002/00000002/art00009. The second herb mentioned, evodia fruit (wu zhu yu), is seldom used in standard herbal TCM prescription, and only for short courses if at all, because it is a very spicy, bitter and hot herb with slight toxicity, and is useful only for treatment of hiatal hernia, liver or stomach organ pain, and certain pathologies of vomiting or diarrhea associated with liver and stomach organ pathology. The professional herbalist is aware of the problems of long term use and interactions of this herb from study in medical school and from current herbal clinical texts, and prescribes appropriately. TCM also utilizes knowledge of other herbs which moderate its mild potential adverse effects and utilizes these in formulas with Evodia. This is the standard of practice in Traditional Chinese Medicine (TCM), and the Licensed Acupuncturist and herbalist. The potential for drug-herb interactions is handled with over-caution in TCM medical schools for the most part, and few herbs come up with potential for such interactions, the same as in these current medical reviews.

In 2015, alarm has been raised concerning the increasing percentage of randomized controlled human clinical trials of medicines and procedures that are not accepted and published in standard medical journals. While the U.S. FDA has a rule that such study should be published within a year of completion, many University medical researchers are finding that no one will publish their studies, and to have them published in a journal that accepts all studies is expensive, prohibitively. The same has been true in clinical trials and scientific studies of herbal medicines, and acupuncture, but more so. With the subject of potentially negative herb-drug interactions we see the same generalized and vague warnings of potential problems in the medical literature for decades, with advice to just stop taking all herbal medicine. Finally, we are seeing some publication of human clinical trials that violate this rule in international journals, and finally we are seeing some of these accepted on databases such as the U.S. PubMed. For instance, in 2012, the Jundishapur University of Medical Sciences, School of Medicine, and Department of Pharmacology, in Ahvaz, Iran, conducted a randomized controlled human clinical trial of 40 patients with a diagnosis of Major Depressive Disorder, and compared treatment with a standard dose of a tricyclic antidepressant to treatment with this medication combined with St. John's Wort (Hypericum perforatum), and of course a placebo control. The findings of this stage 1 trial showed that the integration of St. John's Wort did not reveal negative herb-drug interaction, but did achieve better outcomes, and resulted in fewer medication side effects of sexual dysfunction and poor quality sleep. To see this study, click here: http://www.ncbi.nlm.nih.gov/pubmed/24624165 . Future studies will be larger and have improved design, but are expected to open the discussion to consideration of integration of herbal medicine, lowered dosage of problematic drugs, and the ability to provide relief for patients that stop taking the drugs due to problematic adverse side effects.

Drug-drug negative interactions with chronic use, and in patients with varied metabolic rates, is a big concern, that is largely ignored. To see which drugs are using specific P450 catabolic pathways of drug catabolism, and which drugs inhibit these specific pathways, click here to see this table presented by Baylor University Medical Center, in Dallas, Texas: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1312247/table/TU1/ . Such information helps the professional herbalist determine the potential for negative herb-drug interactions and alter the dosage or treatment protocol intelligently. To assume that the field of professional herbology just ignores such data is absurd, and as CIM/TCM increases in acceptance, the professional guidelines will continue to adhere to proven findings to guide therapy and continue to be over-cautious, as the profession has been for centuries, because this field of Complementary and Integrative Medicine strives to offer a safer approach than standard medicine, not as an alternative, but as a complement to standard care.

Besides the lack of reported clinical problems with herb-drug interactions, and the paucity of herbs found with potential for negative interaction despite the large number of herbs used in standard practice, there are considerations of both the modulatory array of chemicals in a plant that reduce negative side effects, and the subject of reactive adaption of our own body's genetic expression and rate of response to increased enzymatic need, that need to be considered when looking beyond research theory into actualities of negative herb-drug interactions. Current research indicates that there is considerable individual variance in P450 expression and enzyme activity level, and that a post-transciptional mechanism is responsible for coregulation of P450 enzyme activity. To confirm these findings, click here to access a 2007 study by the University of Kansas Medical Center: http://dmd.aspetjournals.org/cgi/content/full/35/9/1700. While the material here is highly technical, the content suggests that P450 enzyme activity is affected by a number of variables, including genetic coregulation that may be stimulated by other chemicals in an herb, P450 oxidoreductase, constitutive androstane receptor, and hepatic nuclear factor 4alpha, which also could be affected by various chemicals within a single herb, or by hormonal regulation, and immune cytokines. Deficiency of the hormone leptin in study animals produces about a 20% decrease in P450 levels, and the study cited above shows that levels of hemoglobin and plasma transport proteins have a significant effect on clearance of drugs from circulation.

It seems that applying alarm in the subject of drug-herb interactions may have been premature or an expression of bias when so little evidence has been generated and so many variables not accounted for. Hepatic nuclear factor 4alpha (HNF4alpha) was found to be the most significant post-transcriptional regulator of P450 activity rates, and this genetic factor is known to be influenced both by immunoprecipitation affecting binding to CYP promoters, and by chemicals in common Chinese herbs. A study in 2008 revealed that berberine, from the Chinese herb scutellaria baicalensis (Huang qin) upregulates both mRNA and protein expression of HNFalpha. Click here to confirm this finding published in the World Jounal of Gastroenterology: http://www.wjgnet.com/1007-9327/14/6004.asp. This finding shows how a Chinese herbal formula could modify the P450 effects of specific chemicals in specific herbs in the formula. Chinese doctors that prescribe these formulas have been aware for some time of the chemical effects and have analyzed the modulatory effects of formula variations by both observing symptoms, signs and laboratory reports to reduce any harmful effects on liver metabolism and pharmaceutical clearance. Chinese research on the pharmacodynamics of herbal chemicals has been extensive, and prescription of herbs in China is handled professionally within the hospitals by standard medical doctors and pharmacists with daily clinical experience with concommittant prescription of pharmaceuticals and herbal extracts. Indeed, the majority of teachers in TCM medical schools in the United States are medical doctors and pharmacists with training and experience in China.

In addition to these potential regulators and modulators of the P450 expression rates mentioned above, it has been found that pharmaceuticals themselves significantly affect the P450 expression over time and with dosage. In one study, Nelfinavir, an antiviral drug, increased hepatic CYP3A by 85 percent, and a regulatory intestinal protein Pgp by 83 percent. Study animals had highly variable expression of hepatic CYP3A levels with different dosage, and clearance changed significantly over time, implying a decrease in effectiveness of the drug in the weeks following administration. Increases in CYP3A expression rose as high as 175 percent due to administration of the drug. To see this 2001 study by Glaxo SmithKline, click here: http://dmd.aspetjournals.org/cgi/content/full/29/5/754. Acetominaphen is a drug that has presented severe problems in the clinical setting due to competition in the P450 catabolism. Concommitant use of acetaminophen and ibuprofen may cause severe hepatotoxicity, because the phase one P450 enzyme catabolism of acetaminophen produces toxic n-acetyl-p-benzoquinone-imine that must be conjugated with glutathione before it can be excreted, and ibruprofen interferes with the conjugation. Acetaminophen is not only available over the counter, but is also added to almost all narcotic pain medication, despite the stress it puts on the P450 biotransformative pathway. Surely, short courses of herbs present minor problems with variance in circulating levels of medications compared to these types of problems with drug-drug interactions.

In 2012, the U.S. FDA finally issued a comprehensive guidelines addressing the problems with negative drug-drug interactions, but only as a "draft guidance" for addressing drug interactions and the variety of phenotypes in the population that metabolize pharmaceuticals at significantly differing rates, and the number of metabolic pathways that affect real circulating dosage and effects. Not just the CYP enzymatic pathway in the liver that controls catabolism of toxins, but a host of factors is found to affect the actual dosage effects of pharmaceuticals, especially with multiple drugs prescribed. This study cites the health and function of the liver and kidney, the function of the gastrointestinal tract and membrane, drug transporters in the blood and across cell membranes (e.g. ATP-binding cassette and solute carrier), a variety of liver enzymes, both induction and inhibition of catabolic enzymes, the effects on these factors by multiple drugs, as well as the many metabolites of the drugs, and other factors, such as the genotype variation in humans, and genders, that ultimately affect the actual dosage and effects within the body of each drug. Drug biologics increase the complexity of this evaluation, presenting new metabolic factors that may increase of decrease the actual effective dosage and accumulation of drugs. While these negative drug-drug interactions are included in the standard physician desk reference, the numerous guidelines to avoid such negative effects are largely ignored, until a more drastic health problem prompts evaluation. The U.S. FDA draft guidelines report made certain that the guidelines were "nonbinding", and indeed, if the appropriate measures were to be taken, this would negatively impact the prescription of pharmaceutical medicines greatly. The real question is why there is so much emphasis on negative herb-drug interactions that are still "potential", not seen clinically, and using just a handful of herbs as examples, when the potential for negative drug-drug interactions are measured, real, and increasing yearly as the number and varieties of drugs prescribed increases.

The case of St. John's Wort, almost universally cited in the subject of drug-herb interactions despite little use in professional herbal practice

The study cited above confirms a number of scientific studies that showed that St. John's Wort, or Hypericum perforatum, is not a potent modulator of CYP2D6 catabolism in humans. Other studies have shown that St. John's Wort may modulate the CYP3A4 pathway, but a number of these studies used questionable drugs that produced study bias on the part of the designers. The chief drug used in these studies was dextromethorphan/dextrorphan, and the measurement was of dextromethorphan/dextrorphan urinary ratio, which can be altered by normal changes in urinary pH by twenty-fold. Why these previous researchers did not use a more reliable parameter, such as the studies on St. John's Wort cited above did, has not been explained. We see how study design can have a great affect on the outcome of the research, and how it is possible that research funding and design produced numerous studies that contained inherent bias and misinformation concerning the dangers of St. John's Wort.

Today, the widespread recommendation that St. John's Wort, or Hypericum perforatum, should be avoided when all drugs are used, has finally been tempered to state that there is potential for negative interaction only when using drugs that use the CYP3A4 catabolic pathway of chemical breakdown. This is based on only a few small studies of in vivo effects of chemicals in the herb to act as a CYP3A4 inhibitor, and these studies are shown to use a very high dosage of the standardized herbal extract, something that is almost never seen in professional herbal use. In normal standardized extract, 300 mg is used with hyperforin standardized to 14.8 mg, and studies have shown that increasing the dose to 1800 mg actually decreased the circulating level in blood plasma. Thus, the use of St. John's Wort is relegated largely to small doses with mild effects, and for this reason, Hypericum was used professionally largely in herbal formula, often at even lower dosage. Even at these small doses, though, St. John's Wort was shown in a 2008 Cochrane Meta-Analysis of 29 randomized controlled human clinical trials involving 5489 patients with a diagnosis of Major Depressive Mood Disorder to achieve a significant reduction in symptoms that was compared to SSRI and Tricyclic Antidepressants and found to have equivalent benefits. To see this study, click here: http://www.ncbi.nlm.nih.gov/pubmed/18843608 . Other inhibitors of the CYP3A4 pathway of chemical breakdown include protease inhibitors, macrolide antibiotics, antibiotics such as erythromicin, some azole antifungals, nefazodone antidepressant, anti-hypertensive verapamil and diltiazam, gabapentin, Prozac (fluoxetine), cimetidine, and pregabalin. There is also evidence that St. John's Wort taken for more than 2 weeks will beneficially modulate liver function to improve the P450 CYP3A4 metabolism when it is stressed by multiple drugs that use the pathway. The question of negative herb-drug interaction even with this one herb is unclear and complex, and we have seen no advice in standard medicine to avoid concurrent use of the drugs that use the CYP3A4 pathway and these other drugs that are CYP3A4 inhibitors.

Researchers into St. John's Wort effect on liver enzymes have also noted that this herb, hypericum, has a great number of modulatory effects from the array of chemicals in the whole plant extract. This means that while some chemicals would exert an inhibitory or competing effect on the P450 catabolism, other chemicals in the herb would soon modulate this effect, thus protecting the organism. In these studies, St. John's Wort did exert changes on the P450 catabolism that changed circulating levels somewhat during the first week in vivo, but had the opposite effect during the second week of taking the herb, due to chemicals that aided overall liver metabolism, resulting in an optimum catabolic clearance over time. Now, when we look at our physician's desk reference, we see many drugs that are competitive for various P450 catabolic pathways, and recommendations that these drugs not be prescribed concurrently, or with caution. These recommendations are so prevalent that often they are overlooked in prescription today where the patient is prescribed a number of pharmaceuticals, often by different M.D.'s, and often with prescription of drugs that have been introduced to the market relatively recently. The problem with drug-drug interactions seems to be handled too often with less than optimal scrutiny, yet the published warnings of drug-herb interactions, almost entirely based on a few studies of St. John's Wort are widely distributed.

What is almost always missing from reviews of St. John's Wort on drug-herb interactions is the manner in which the various chemicals in the whole plant extract is modulatory and protective of the patient. Besides having a balance array of chemicals in the herb, some of which protect the organism from excess inhibition of genetic expression, the same way that these chemicals protect the St. John's Wort plant itself, there are chemicals that are proven to help the body modulate potential ill effects in other ways. One way that St. John's Wort protects the organism is by stimulating an increased immune response to modulate unwanted metabolic side effects. The immune system is very responsive and regulatory for much of our common organ function, and St. John's Wort is proven to be immunostimulatory. Click here to see a 2002 in vitro study by the State University of New York, Upstate Medical University, in Syracuse: http://www.liebertonline.com/doi/abs/10.1089/107555302760253667. St. John's Wort also contains a number of chemicals that modulate hormone metabolism, which itself is protective of unwanted metabolic changes in the body. To see the array of chemicals and proven biological acitivities in a herb or food, go to Dr. Duke's Phytochemical and Ethnobotanical Databases, sponsored by the U.S. government. We see at this database that St. John's Wort contains such chemicals as hyperoside, that is antihepatotoxic, cAMP-inhibitor IC50=0.14 mg/ml, hepatoprotective IC80=30 ug/ml, xanthine oxidase inhibitor, antioxidant, and diuretic, all of which could work to optimize drug biotransformation and clearance. A number of other chemicals are found in St. John's Wort that also could be beneficial to liver metabolism and enzyme balance, including quercetin, a potent antioxidant that is a tyrosinase-inhibitor, P450 inducer and P450 inhibitor, allelochemic, anticariogenic, etc. This plant has evolved a metabolism of high levels of protective chemicals to insure its survival, and these chemicals translate into protection of homeostasis in the human organism.

Besides the 2008 in vivo study cited above that found no problems with St. John's Wort in competition at the P450 catabolism, the numerous studies cited are all in vitro studies with flawed study design and inherent bias. One 2008 study at the University of Tokyo Department of Pharmacy tries to correct for study bias and inaccuracy with new methodology, and compares the P450 effects of St. John's Wort to a number of pharmaceuticals in study to see which chemicals have the potential to reduce plasma concentrations of competing pharmaceuticals to levels considered ineffective. Seven chemicals were analyzed statistically from the data collected in 42 DDI studies and only rifampin, phenytoin and carbamazepine reduced the plasma concentrations of other drugs competing in the CYP3A4 pathway to ineffective plasma levels, not St. John's Wort. To see the summary of this study click: http://www.ncbi.nlm.nih.gov/pubmed/18783297?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum. There is no hesitancy to prescribe Tegretol, one of these altering drugs, for an increasing array of problems, such as neuralgia and bipolor disorder.

Similar Attempts to Describe Kava Kava as a Liver Toxic Herb Despite a Complete Lack of Actual Clinical Cases of Harm

Piper methysticum, or Kava, has been used for centuries and emerged as an effective herbal extract to treat anxiety, insomnia and muscle fatigue, using very low dosages, and often, capturing the effective lipid-based lactones in alcohol and glycerite extracts. Like Hypericum perforatum, or St. John's Wort, Kava proved very effective at a low dose and was widely utilized by patients. Consequently, much funding designed to find negative effects of Kava was found, and much subsequent publicity of the supposed liver toxicity of Kava, leading to its removal from many herbal medicines, despite absolutely no evidence of clinical harm in this regard. By 2010, one of these studies, at the Washington University School of Medicine, in St. Louis, Missouri, U.S.A. found that indeed, higher dosages of certain chemicals found in Kava, such as flavokawain B, a chalcone, did induce apoptosis in G2 cells of the liver, mediated by oxidative stress and glutathione deficiency, inhibition of IKK activity blocking nuclear factor kappa beta (NF-kB) and TNF-alpha activation of MAPK pathways of inflammation. To the researchers surprise, though, this hepatotoxic effect was canceled with sufficient replenishment of the glutathione metabolism (PMID: 20696856). From such study, we may surmise that a standardized high-dose extract of Kava could be harmful to the liver if there was sufficient liver inflammation and oxidative stress, that restoration of the cellular detoxifying glutathione metabolism would ameliorate this threat to the liver, and that standard practice of a non-standardized and low-dose Kava extract would seem to do no harm.

Hepatoprotective or inhibiting of liver function?

This brings us to an interesting question. Are the chemicals in total in the herbs studied that effect the P450 catabolism balancing and protective of liver homeostasis, or dangerous and destructive of this homeostasis? We are talking about the whole array of chemistry evolved in the plant, and not a standardized extract that significantly boosts content of one particular chemical. We are also not talking about the pharmaceutical variants of the plant chemistry devised by the current biochemical industry, or products that utilize a patented method of boosting a specific herbal chemical in a plant to unnatural potency.

Numerous phytochemical studies over the decades have demonstrated how herbs and foods contain chemicals that are preserving of optimal homeostasis and are hepatoprotective. One example is the Indian food spice, Trachyspermum ammi, called Carum copticum seed, or Ammi copticum, or simply ajowan. Ayurvedic medicine, like ancient Chinese medicine, has promoted the use of various medicinal herbs in common food preparation for centuries to benefit public health. A study published in the Journal of Ethnopharmacology in 2005 describes the hepatoprotective mechanisms in this food spice. To see the summary, click here: http://www.ncbi.nlm.nih.gov/pubmed/15763373?dopt=Abstract. As we see, this seed extract shifted dose response curves to the right, protecting the patient from excessive dose response, and prevented unhealthy induced rise in liver transanimases that are associated with liver dysfunction. The presence of a calcium channel antagonist also protected against unwanted side effects that could be common in pharmaceutical overdosage.

A number of the herbs that are studied to find evidence of drug-herb interactions are specifically the herbs that became popular because of their dramatic hepatoprotective roles in modern medicine. As more patients in the 1990's took the harmful HIV cocktails with AZT and protease inhibitors, sudden dramatic rises in liver enzymes became common, as did metabolic syndrome, insulin resistance, peripheral neuropathy and a host of serious side effects linked to liver dysfunction. The patients found that taking a small dose of milk thistle for a short course would usually bring the liver enzymes to normal. Similar effects of hepatoprotection with concommittant use of pharmaceuticals was observed with kava-kava and St. John's Wort. Use of goldenseal seemed to prevent gallstones and liver cirrhosis, with content of berberine and chlorogenic acid, an allelochemic, antihepatoxic, cholagogue, choleretic, anti-inflammatory immunostimulant. Rise in popularity and reports of significant clinical benefit seemed to stimulate pharmaceutical investment in research to undermine these herbal therapies. To date, there are almost no cases of actual clinical injury from drug-herb interaction with these herbs, yet there is a vast amount of information distributed to medical doctors, pharmacists and the general public with dire warnings.

The effects of herbal chemicals on the circulating level of Coumadin, or warfarin

Coumadin, or warfarin, is biotransformed by the CYP3A4 and CYPa2 catabolic pathways located in red blood cells that produce NADPH-CYP regulatory enzymes. Warfarin places a dramatic stress on the P450 pathway and problems have been significant in clinical cases with comcommittant use of other drugs, such as quinidine derivatives used for patients with cardiovascular pathologies and atrial fibrillation. The problems resulted in deficiency of prothrombins in erythrocyte production and subsequent hemorrhage or bleeding pathologies, such as purpura. Also, long term use of warfarin has resulted in numerous cases of blood dyscrasia, with deficient or excess production of platelets and prothrombins. These cases are so numerous that many medical doctors and researchers looked for alternatives to warfarin prescription, and finally the FDA advised that low dose aspirin was just as effective in clinical study for chronic use to prevent thromboses. Subsequently, many foods and herbs have been mentioned as potential alterers of warfarin circulating effective levels and warnings issued. These warnings include such common foods as broccoli, pineapple, garlic, avocado, onion, brussel sprout, etc. Herbal warnings have been alarming to physicians, despite a complete lack of clinical evidence, only the potential for negative herb-drug interactions with warfarin. Less alarming to physicians, apparently, are the serious contraindications with an array of common pharmaceuticals proven to cause problems, which include 6 common antibiotics, 5 cardiac drugs, hypertensive agents, cimetidine, piroxicam, phenylbutazone, TB drugs, 3 sedatives and anxiolytic agents, cholestyramine and sucralfate, as well as alcohol. In addition, Harvard Public Health publications have alerted physicians to the proven altering of warfarin levels with corticosteroid medications, and warned that warfarin levels may need to be adjusted when the patient uses a topical antibiotic or antifungal medication for more than a week as well. To confirm these findings, click here: http://www.annals.org/cgi/content/full/121/9/676.

Evidence suggests that there are three definitive problematic interactions, from phylbutazone, sulfinpyrazone, and griseofulvin, and a host of drugs that showed evidence of inhibiting effect, including nafcillin, rifampin, cholestyramine, barbituates, carbamazepine, chlordiaepoxide, sucralfate, and dicloxacillin. There was also a host of drugs that were proven to create potentiating effects of warfarin, including erythromycin, fluconazole, miconazole, metronidazole, cotrimoxazole, and isoniazid, as well as ciprofloxacin, tetracycline, and 6 other antibiotics. Several cardiac drugs showed evidence of potentiating effects, including propranolol, clofibrate, amioodaraone, sulfinpyrazone and clofibrate. Simvastatin, quinidine, and acetylsalicylic acid, or aspirin, also had evidence of harmful potentiation. Now most of these drugs that produce serious drug-drug interactions are routinely prescribed without much apparent consideration concerning drug-drug interactions, yet medical doctors are routinely cautioning patients to avoid herbal remedies at all when taking coumadin, while not discontinuing these pharmaceutical prescriptions. Evidence that foods inhibited warfarin was found only for large amounts of avocado. Now very few people eat large amounts of avocado. The study cited does not confirm evidence clinically of any herb that produced medical problems.

Surely, by now, you have read enough information that at least casts some doubt on all the information given to medical doctors over the last 5-10 years at pharmaceutical luncheons et al, and published prominently in both medical journals and People magazine, concerning the evidence of warfarin and herbal contraindications. There is little Vitamin K in common herbal extractions, and dosage of the few herbs that contain Vitamin K in sufficient quantity are prescribed in much lower dosages than would be dangerous by professional herbalists. As we see from evidence links in this article, the potential for significantly altering the P450 CYP pathway of drug metabolism by common herbs is also negligible.

Where do we proceed from here?

Today, there is still widespread debate concerning the potential of negative herb-drug interactions and the potential toxicity of certain herbs, yet there continues to be a widespread use of herbal medicines with no evidence of clinical harm. Even in the United States studies show that every year at least about a fifth of the adult population used an herbal medicine to treat a disease or symptom, yet almost all of this use is unprofessional and unregulated. Use of professionally prescribed herbal medicines by a physician who graduated from a TCM medical college, or a Naturopathic Doctor, would eliminate any concern, obviously, but there continues instead advice by the M.D. to avoid the use of professional herbalism, where toxicity and negative interactions are well studied. Instead there continues general advice to avoid all herbs, and only 10 herbs are cited when discussing negative herb drug interactions, as though there are only 10 herbs used. In reality, the Materia Medica of professional herbal medicine now documents hundreds of thousands of herbs, and many hundreds are used in simple common practice. This obviously makes no sense, and considering that the patients continue to just buy herbs off the shelf or from the internet, this creates a much greater potential for these negative herb drug interactions. The Licensed Acupuncturist and herbalist, as well as the Naturopath, now has access to a vast array of sound scientific studies to help in this regard. There is a great potential in Complementary and Integrative Medicine (CIM) to actually use these scientific studies to logically address some changes to treatment protocol that would benefit the practice of the medical doctor and the health of the patients. By working with Complementary physicians, instead of against them, the practice of medicine can be adjusted to arrive at the most sensible and least harmful overall treatment strategy. Harmful drug-drug interactions can be decreased, and side effects diminished, by communicating treatment possibilities between the medical doctor and the Licensed Acupuncturist and herbalist. Everyone can benefit if we work together.

Information Resources and Additional Information with Links to Scientific Studies

  1. To easily see the array of chemicals and proven biological activities in a herb or food, click here to access Dr. Duke's Phytochemical and Ethnobotanical Database. A look at these biological acitivities often shows how the herb or food has evolved an array of modulatory effects to minimize potential harm to the organism: http://www.ars-grin.gov/duke/
  2. An example of medication breakdown, or catabolism, in the liver, which produces even more harmful chemicals than the medication itself, is cited in this study of AZT catabolites: http://molpharm.aspetjournals.org/cgi/content/abstract/39/2/258. Often, the patient needs increased stimulation of metabolic pathways and supplementation of potential nutrient deficiencies to optimize the clearance of these harmful metabolites. Herbal medicine, nutrient prescription, and acupuncture can help your patient reduce side effects and preserve general health in these ways.
  3. A 2000 report on the P450 catabolic pathway of drug breakdown in the liver, which determines the effective circulating dosage of our pharmaceuticals, and varies widely from individual to individual, is presented here by experts at Baylor University Medical Center, in Dallas, Texas. This study shows that concurrent use of drugs that utilize, inhibit or induce these enzymatic pathways, such as the CYP3A4, greatly alters the effective circulating level of the drug, and that numerous factors affect drug biotransformation, including genetic polymorphism (type), disease, age, and even gender. While such study has been used to widely discourage any herbal use while taking any drug, and even discouraging various foods in general, there has been little discussion of the dangers of the widespread use of multiple drugs in therapy: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1312247/
  4. A 2010 report on the inadequacies seen in evaluating medication drug metabolism variability, and the failures in systematic evaluation during drug development, was presented by experts at the Showa Pharmaceutical University, in Tokyo, Japan. The recommendation was to expand the evaluation of the variables and pathways of drug breakdown rates, or metabolism, to provide safe guidelines for dosage in the future that takes into consideration the array of factors that greatly vary the effective circulating levels of medications in the body: http://www.ncbi.nlm.nih.gov/pu...http://www.ncbi.nlm.nih.gov/pubmed/20973757
  5. A thorough 2011 report on the subject of variance between individuals in the pathways of drug breakdown by Dr. Alan H.B. Wu PhD, a professor of Laboratory Medicine at the University of California San Francisco, shows that there is proven to be a wide phenotypic and genotypic variance of the rate of drug breakdown, or catabolic rate, in the human organism, but this has been difficult to analyze because it presently needs a liver biopsy to assess in most cases. Patients who have variance in the enzymatic control of breakdown of potent drugs are exposed to toxicity at standard dose or lower effective circulating dose and poor therapeutic effects. When poor therapeutic effects due to slow metabolism of the drug is occurring, there is often a tendency to take more of the drug to achieve relief of symptoms, leading to liver toxicity. Presently, there is almost no effort to effectively genotype or phenotype individual patients to achieve safe and effective dosage of drugs, and an alarming increase in polypharmacy, greatly increasing these negative drug-drug interactions and negative effects of improper individual dosage: http://clinicalproteomicsjournal.biomedcentral.com/articles/10.1186/1559-0275-8-12
  6. A draft guideline for real evaluation of negative drug-drug interactions by the U.S. FDA in 2012 shows that complexity of the problem, and emphasizes that these findings should not be actually implemented. This implementation of an actual patient protection concerning the varying of actual in-body levels of drugs in circulation and tissue accumulations would severely impact the multiple prescription of pharmaceuticals. The fact that functional health of the liver, kidney and gastrointestinal tract is one major factor in these negative effects related to altered drug absorption and metabolism shows that Complementary and Integrative Medicine and a more integrated restorative and preventive approach in health could in fact alleviate many of these concerns. With such a complex and actual problem occurring with multiple drugs affecting real dosages in the body, the question should be posed as to why this is rarely discussed, yet the subject of herb-drug negative interactions that are only "potential" are repeated endlessly: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf
  7. A 2013 assessment by the pharmaceutical associations shows that studies of drug-drug negative interactions are insufficient and avoid in design some very pertinent measures that create potentially harmful alterations in effective circulating levels of the drugs when more than one pharmaceutical is prescribed. The CYP pathway of metabolism is studied, but other affectors such as the levels of transporters etc. are not. The avoidance of study of negative drug-drug interactions creating unhealthy levels of drugs is apparent, yet the number of studies of herb-drug potentially negative interaction are abundant: http://onlinelibrary.wiley.com/doi/10.1177/0091270003252519/abstract
  8. To find the exact mechanisms of harm to the liver that Kava extract could create, research at the University of Washington Medical School, in 2010, discovered that one specific chemical in the herb, flavokawain B, a chalcone, did indeed have dose-related potential to exert an apoptotic effect on liver G2 cells, but only when mediated by oxidative stress and inflammatory mechanisms related to inhibition of IKK activity and nuclear factor kappa beta and TNF-alpha induction of MAPK pathways, and only in the presence of glutathione deficiency, with replenishment of glutathione canceling this liver toxicity: http://www.ncbi.nlm.nih.gov/pubmed/20696856
  9. The findings by experts in pharmacology and herbal medicines at the University of Sydney, in Australia, in 2007, showed that a full meta-review of all published literature on herb-drug interactions revealed that while there is potential for problems, there is very little solid evidence, as the study of many chemicals in the herbs and formulas complicates the assessment, as well as the variance in quality and dosage of the herbal medicine. Only a few herbs are cited in this regard to this problem, and some of this citation, such as the ability of Gingko biloba to affect the the blood thinning coumadin, or warfarin, levels, was shown to be nonexistent, despite many anecdotal warnings. The ability of Siberian ginseng (Eleutherococcus senticosus) to affect digoxin levels was based on a single case study that made no sense, as the levels of digoxin remained high after the digoxin was discontinued, and fell when the Siberian ginseng was discontinued, with these experts noting that perhaps the herb affected the drug assay and not the drug metabolism. We should also note that even with these pharmacological experts they equated Siberian ginseng with actual ginseng, even though the Eleutherococcus is a completely different plant species with completely different chemistry. St. Johns Wort, or Hypericum, was not to only affect a few drugs potentially, not all drugs, and that while a potential harmful interaction could conceivably lead to a serotonin syndrome and even death, there has been no evidence that this ever occurred, and that the common use would not produce significant harm with other drugs. Later studies showed that the Hypericum modulated the CYP liver pathway and normalized the levels beneficially if a large dose was taken for weeks. In effect, professional use of these herbs utilizes short courses and low doses. This review shows that there is no clear evidence of harm from measures and studies of herb-drug interactions and such studies would be hard to design: http://www.researchgate.net/publication/8525519_Herb-drug_interactions_An_evidence_based_approach
  10. A 2010 meta-review of all published studies and articles concerning negative herb-drug interactions in cancer care, by the Hong Kong Baptist University School of Chinese Medicine, found 168 such published articles and almost no direct evidence of the negative interaction, but did find indirect evidence in these studies of positive benefits of the combination of herbal medicine and cancer drugs. The conclusion was that this widely touted negative herb-drug interaction in cancer care was theoretical at best, and that a better study design and more rigorous science was needed to actually present real evidence to guide care. For decades, the denial of positive benefits from professional herbal medicine has relied on anecdotal beliefs, not direct scientific facts, and it is high time that this was resolved: http://www.ncbi.nlm.nih.gov/pubmed/20832765
  11. A 2013 meta-review of all published studies of negative herb-drug interactions in cancer care, by experts at the Utrecht University School of Medicine and the Utrecht Institute for Pharmaceutical Sciences, showed that real evidence of negative herb-drug interactions in cancer care is sparse, with few herbs studied, and evidence accumulated with in vitro studies not duplicated in clinical studies. Such widely denounced herbs as St. Johns Wort (Hypericum perforatum), not even used for cancer care, showed in studies that a dose-dependent inhibition of the CY3A4 pathway occurred in the first week of use, but changed to induction of the pathway with long-term use, and that aged garlic showed no CYP3A4 inhibition or affect drug levels, while milk thistle and ginseng (still referring to Siberian ginseng, which is not actually ginseng, but another species), showed in vitro inhibition but no negative effects in clinical interactions. There should be no doubt after this review that the subject of negative herb-drug interactions have been poorly studied and greatly exaggerated in standard medicine. There also should be no doubt as to the motivations for these gross exaggerations of risk: http://www.ncbi.nlm.nih.gov/pubmed/23394826
  12. A 2015 study of negative potential drug-herb interaction with Echinacea augustifolia and pallida, as well as the commonly used Echinacea purpurea, by experts at the University of Graz Institute of Pharmaceutical Sciences, in Graz, Austria, concluded that "in pharmacokinetic herb-drug studies performed in vivo (in an actual living person), no significant inhibitions of human CYP2D6 and CYP3A4 isoforms have been found after the administration of standardized E. purpurea preparations (the main form and type of the herb used in practice)." These experts stated that the studies contradicting this safety showed that use of standardized E. spp. (other standardized species of Echinacea) showed only mild adverse events and "mostly without causality." The contraindications for autoimmune diseases and with use of immune suppressant drugs "are questionable", especially as beneficial effects of integrating short courses of Echinacea were seen for the immune system function. There was no strong evidence that pregnant women should avoid short courses of Echinacea. These pharmcological experts a the University of Graz saw no reason to advise against use of the herb, even for children: http://www.ncbi.nlm.nih.gov/pubmed/26441065http://www.ncbi.nlm.nih.gov/pubmed/26441065
  13. One example often cited of the potential for negative herbal effects concerns ephedra, called Ma Huang in China, and Mormon Tea in the Western United States. This herb, long used worldwide as a stimulant and a potent bronchodilator to treat acute asthma, is indeed a stimulant, and so very small doses are used in short courses of therapy. There are no records of actual harm from the extensive use of this herb, and until 2004, after metabolites of ephedrine were created and prescribed by Medical Doctors as Fen-Phen, there was no significant concern. Fen-Phen was eventually withdrawn from the market after 50,000 cases of cardiovascular harm and many deaths attributed to this weight-loss drug that had no real equivalency to the herb ephedra. After this event, a meta-review of the use of herbal ephedra was conducted and cited as a reason to ban the use of ephedra in the U.S. in 2004, which occurred, but did not affect the professionally licensed herbalist. Nevertheless, the herb became very difficult to obtain and fell out of use, despite its studied effectiveness as the most potent and dependable bronchodilator known. The chemical ephedrine is widely used, and available in an injectable pen freely provided to parents of children with food allergies that may go into shock and be unable to breath. This and other synthesized metabolites are based on a chemical in the herb ephedra. In this meta-review, though, we see that reviewing over 50 studies that the mild adverse effects occurred in a less than 1 in 1000 subjects, and involved stimulatory effects that could be expected, with anxiety, racing heart and palpitations, gastrointestinal symptoms and unspecified autonomic symptoms. These occurred in 2.3 to 6.6 times the frequency as in the control groups, but this is expected if a strong dose of a stimulant herb is given. No actual harm was recorded, yet this study was the only study cited to ban the use of ephedra after the weight loss drug Fen-Phen was banned or removed. In Chinese Herbal Medicine this herbal extract would never be used for weight loss and a caution to only prescribe short courses of very low dosage due to its stimulatory effects is one of the first thing a student learns: To see this study, click here: http://www.ncbi.nlm.nih.gov/pubmed/12672771
  14. A comprehensive review of the study of Hypericym perforatum, or St. Johns Wort, shows that the potential of the negative herb drug interactions are slight, especially with normal clinical dosage and course. Studies with a standardized extract at a higher level showed very mild adverse effects noted by only 2 percent of subjects, comparable to the placebo. The use of St. Johns Wort for a variety of health problems shows that it is not a potent herbal medicine, but is popular because it contains a number of mildly beneficial chemicals, including antioxidants and anti-inflammatories, and is proven to have some effect on mild mood disorders. In history, it was used as a topical agent to treat neuralgia and skin disorders. We see from this meta-review that it is not a dangerous drug and poses little potential for negative herb drug interactions unless a prolonged higher dosage is administered with other serotonin altering drugs, and even then some studies showed a variety of interactions, some benefiical to the drug effect: http://www.ncbi.nlm.nih.gov/books/NBK92750/
  15. A 2004 study of the effects of the single chemical found in St. John's Wort, or Hypericum perforatum, hyperforin, that was found to induce the P450 liver enzyme metabolism of CYP3A4, and thus potentially able to increase the speed of drug breakdown, or catabollsm, of some drugs, mildly reducing its effective circulating dosage over time, was conducted by pharmaceutical experts at the University of Pittsburgh, in Pttsburgh, Ohio, U.S.A. These experts found that other chemicals in the herb, namely hypericin, had no effect on the enzyme metabolism, and that hyperforin applied directly to liver cells induced increased expression of CY3A4 and CYP2C9, but had no effect on CYP1A2 or CYP2D6 pathways. These experts concluded that "with chronic exposure" to a higher dose of Hypericum, with sufficient hyperforin, that certain drugs could be broken down more quickly, altering the circulating dosages over time. A list of some of the drugs that induce this CYP3A4 pathway includes phenobarbital, phenytoin (Dilantin), rifampicin (antibiotic) and glucocorticoids (prednisone and corticosteroids found in many medications). A list of drugs that inhibit this CYP3A4 pathway include erythromycin, clarithromycin (antibiotics), itroconazol, ketoconazole (antifungals), ritonavir (antiviral), and verapamil (anti-hypertension). : http://www.pubfacts.com/detail/15100173/Induction-and-inhibition-of-cytochromes-P450-by-the-St-Johns-wort-constituent-hyperforin-in-human-he
  16. A Full List of the many drugs that induce and inhibit the CYP3A4 enzyme pathway and drugs and metabolites that use this catabolic pathway are listed here. One should note that these pharmaceuticals, unlike St. John's Wort, are almost all taken chronically in higher dosage, yet there are no common warnings to avoid these drugs: http://www.pharmacytimes.com/publications/issue/2008/2008-09/2008-09-8687