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Toxicology Reflections

St. John’s Wort

15 Comments

Author –

The belief that a product that is natural is also safe is a common misconception among users of herbal remedies1. In reality, herbal remedies have the same potential to elicit adverse effects as prescription drugs either directly or indirectly through interactions with other herbs and/or synthetic drugs2. In Canada, approximately 71% of people have reported using some type of herbal therapy including homeopathic drugs, herbal remedies, vitamin supplements and minerals5. Of those only about 12% report having experienced adverse effects from herbal remedy use5. However, less than half of all users of herbal remedies in Canada report adverse reactions5. Other risks are associated with the use of herbal remedies including contamination with heavy metals or over concentrating the pill with the active ingredient during manufacturing, false claims which delay consumers from seeking medical treatment and absent warning labels regarding adverse effects and interactions5. The latter risk is especially true for a product sold in Canada which has risen in popularity across North America and Europe in recent years for the treatment of mild to moderate depression1,2. Specifically, in Canada it is among the top ten most popular herbal remedies6. This product is St. John’s Wort, also known as Hypericum perforatum, an antidepressant that interacts with countless prescription drugs. This reflection will introduce and briefly discuss the risks associated with the use of Hypericum perforatum or St. John’s Wort as it is more commonly known.

St. John’s Wort is a plant of the family Hypericaceae whose extract is used in herbal remedies to treat mild to moderate depression1,2. It has also been used in the treatment of anxiety, sleep disorders, obsessive compulsive disorder, seasonal depression, cancer, gastritis, burns, cuts and abrasions, kidney disease, scabies, hemorrhoids and hypothyroidism1,2. The main ingredients are hypericin and pseudohypericin as well as hyperforin and adhyperforin1. All four ingredients are similar in structure and exert the main pharmacological effects of the herbal medicine1.  However, hypericin is thought to be the active ingredient in the treatment of depression1. The effective dose is 900 mg per day taken as three separate doses (ie. 300 mg taken three times daily) with 0.2-0.3% hypericin in the formula1,2. Animal studies and clinical trials have found St. John’s Wort to be highly efficacious in the treatment of mild to moderate depression when used without any other drugs or herbal medicines1,2. This is because it inhibits the reuptake of serotonin, noradrenaline, dompamine, glutamate and gamma-aminobutyric acid which are neurotransmitters that play a role in mood regulation1. A few clinical studies have found it to be as effective at treating mild to moderate depression as tricyclic antidepressants as well as imipramine (both prescription drugs)1,2. In addition, the herbal remedy has few adverse effects, again when used by itself, and in some cases has been found to have less adverse effects than similar prescription antidepressants; a meta-analysis of 23 studies of clinical trials completed by Russo et al. (2013) found 19.8% reported effects in St. John’s Wort users compared to 35.9% reported effects in users of prescribed antidepressants1,2. The adverse effects that it does have are relatively mild and include mild gastrointestinal irritation, lethargy, allergic reactions, dizziness, nausea, rash and restlessness1. The more serious side effects, photosensitivity and manic episodes, are rare and the latter occurs only in predisposed patients1,2.

Despite a lack of direct adverse effects, St. John’s Wort is still an herbal medicine to be concerned about because of its ability to interact with several prescription drugs. Among the prescription drugs St. John’s Wort can interact with are, central nervous system drugs, bronchodilators, cardiovascular drugs, calcium channel blockers, cardiac inotropic drugs, hypocholesterolaemic drugs, gastrointestinal drugs, oral contraceptives, anti-inflammatories, anti-microbials, antineoplastics, immunosuppresants, oral hypoglycaemic and drugs used in the treatment of HIV1,3. Its ability to interact with these drugs is due to alternate mechanisms of action (MOA) which do not play a role in the treatment of depression. First, St. John’s Wort is a potent activator of CYP enzymes that are involved in the metabolism of drugs1,2. Through this mechanism it can decrease the plasma concentration of prescription drugs taken concurrently with St John’s Wort1,2. Second, it also intensifies the activity of P-glycoprotein (P-gp) which is an adenosine triphosphate-dependent drug transporter that is located throughout the body and plays an active role in drug excretion1. Most prescription drugs are metabolized and excreted using CYP enzymes and P-gp transporters, respectively1. Therefore, the joint use of St. John’s Wort with prescriptions drugs that fall under the category listed above can result in the prescription drugs losing their effectiveness via increased metabolism and clearance1,2. Lastly, in the case of CNS drugs, St. John’s Wort may act synergistically resulting in serotonin syndrome which, in worst-case, can result in a coma1.

Subsequently, the concern with St. John’s Wort is its ability to interact with several prescribed drugs. Often, it is not taken alone but is taken in combination with other prescription medicines1. Its use is under-reported to medical professionals both because they do not ask for the information and because the public does not perceive the use of this herbal medicine as a risk to their health1,2. Furthermore, natural health products (NHP) such as St. John’s Wort are not as rigorously regulated as prescription medicines in Canada which can lead to their misuse and the occurrence of adverse effects which go un-reported4,5. Future reflections will explore in greater depth the interaction of St. John’s Wort with clinical drugs in order to characterize the hazard, the estimated exposure of the population to St. John’s Wort, potential at-risk populations, the perception of risk that the Canadian population has towards this drugs, the estimated risk, the current regulations of NHP and their shortfalls and potential solutions to ensure that the risk of NHPs, particularly, St. John’s Wort are being explored, assessed and evaluated, and made public.

References:

Please note: all references are hyperlinked in-text. However, they are also provided below for your convenience

  1. Russo E., Scicchitano F., Whalley B.J., Mazzitello C., Ciriaco M., Esposito S., PAtane M., Upton R., Pugliese M., Chimirri S., Mammi M., Palleria C. (2013). Hypericum perforatum: Pharmacokinetic, Mechanism of Action, Tolerability, and Clinical Drug-Drug Interactions. Phytother. Res. DOI: 10.1002/ptr. 5050
  2. Ernst E. (2002). The Risk-Benefit Profile of Commonly Used Herbal Therapies: Gingko, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto and Kava. Complementary and Alternative Medicine Series. 136 (1): 42 – 53
  3. University of Maryland Medical Center. (2011). Possible Interactions with: St. John’s Wort. University of Maryland School of Medicine: http://umm.edu/health/medical/altmed/herb-interaction/possible-interactions-with-st-johns-wort
  4. Health Canada. (2012). Drugs and Health Products: A new approach to natural health products. Government of Canada. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/nhp-new-nouvelle-psn-eng.php
  5. Health Canada (2012). Drugs and Health Products: About Natural Health Products. Government of Canada. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/about-apropos/cons-eng.php
  6. World Health Organization. (2002). Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 82
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15 thoughts on “St. John’s Wort

  1. This paper http://rgrobbee.home.xs4all.nl/pdf_files/med_info/stjan_depressie.pdf reviews several studies indicating that St. John’s Wort may be a reliable way to treat mild to moderate depression provided it the correct fit for the patient’s situation and the patient is well-monitored. You have provided quite a bit of info as to why this might be risky. How does this compare to more traditional drugs? Addiction can become a major problem with some synthetic anitdepressants – could SJW provide an alternative?

  2. Author-
    I have yet to find anything in the literature that identifies St. John’s Wort as an addictive drug. However, I am not convinced that other anti-depressants (whether synthetic or not) are addictive. A review of the potential of anti-depressants to result in addiction found that it was unlikely since acute effects, which are also considered as the addictive effects, are not present with anti-depressants1. Another article suggests that antidepressant addiction is limited to patients with previous or family history of substance abuse2. The advantage of using St. John’s Wort is not really associated with addiction. Rather, it is associated with the fact that it produces less adverse effects as similar anti-depressants while maintaining the same efficacy (this is only true for some anti-depressants such as tricyclic antidepressants or imipramine3,4).

    Haddad P. (1999). Do antidepressants have any potential to cause addiction? Pharmacology and Pharmacy. 13: 300 – 307
    Guillen E., Lepine J.P. (2003). Does addiction to antidepressants exist? About a case of one addiction to tianeptine. Encephale. 5: 456 – 459
    Russo E., Scicchitano F., Whalley B.J., Mazzitello C., Ciriaco M., Esposito S., PAtane M., Upton R., Pugliese M., Chimirri S., Mammi M., Palleria C. (2013). Hypericum perforatum: Pharmacokinetic, Mechanism of Action, Tolerability, and Clinical Drug-Drug Interactions. Phytother. Res. DOI: 10.1002/ptr. 5050
    Ernst E. (2002). The Risk-Benefit Profile of Commonly Used Herbal Therapies: Gingko, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto and Kava.Complementary and Alternative Medicine Series. 136 (1): 42 – 53

  3. Author-
    A brief overview of the hazards associated with St. John’s Wort consumption was introduced in the previous reflection. To review, these hazards are mainly associated with the antagonistic or synergistic interactions of the herbal remedy with prescription drugs. However, it is of interest to explore these mechanistic interactions and the subsequent adverse effects more thoroughly in order to outline the hazard assessment for the reader and differentiate between the direct toxicity of St. John’s Wort and its indirect toxicity.

    To begin, it is important to clarify that the hazards associated with using St. John’s Wort alone appear to be negligible relative to the hazards associated with its use concurrent with the use of pharmaceuticals1. Therefore, its indirect toxicity via drug interactions is thought to be of greater concern than the potential adverse effects it may cause on its own (refer to above Sept 11th post for direct effects). This is similar to grapefruit juice and its interactions with pharmaceuticals. The grapefruit juice itself is relatively harmless but when combined with pharmaceutical drug use it indirectly can cause adverse effects5. In other words, the indirect hazards discussed herein are actually caused by the pharmaceutical. Either the pharmaceutical exceeds it therapeutic index and is causing adverse effects because St. John’s Wort is interacting with it in a potentiating relationship or the pharmaceutical never reaches its therapeutic index because St. John’s Wort is acting with it in an antagonistic relationship. In both cases, St. John’s Wort is only affecting the pharmacodynamics of the pharmaceutical not the pharmacokinetics1. In the latter case, the adverse effects that are occurring are already present in the patient and are going untreated. Despite the low hazards associated with St. John’s Wort it remains a concern because it is often used conjointly with other drugs (unbeknownst to the medical practitioner2) and it is through this use that more severe adverse effects may occur1.

    Studies identifying the interactive toxicity of St. John’s Wort are generally greater than 10 days in length1. Therefore, acute effects have not been identified. However, no acute effects associated with the indirect toxicity of St. John’s Wort have been reported in humans1. On this basis, the indirect hazards associated with St. John’s Wort are of a subchronic or chronic nature depending on the length of use of the herbal remedy and of the interacting pharmaceutical.

    Several subclinical and clinical hazards have been identified for St. John’s Wort’s co-use with commonly used pharmaceuticals. I will focus on the interactions of St. John’s Wort with these pharmaceuticals as they are the mostly commonly known to the reader and among the most commonly used drugs. The efficacy of benzodiazepam, a central nervous system drug, is affected when used with St. John’s Wort because of the activation of CYP enzymes by hypericin1. Through its actions hypericin reduces the half-life of benzodiazepam and increases its clearance1. This effect has not been clinically tested1. Warfarin, a commonly used blood-thinner in cardiovascular patients, is also affected by St. John’s Wort. Specifically, the active ingredients in St. John’s Wort reduce the anticoagulant effects of Warfarin by increasing the excretion of both S and R enantiomers (part of the Warfarin racemic that results in its therapeutic effect)1. Approximately 29 case reports have been identified which found reduced time to prothrombin formation or reduced warfarin S and R enantiomer ratios with St. John’s Wort use1. Digoxin, a cardiac inotropic drug that aids in atrial and ventricle contractions, is not absorbed as well in chronic users of St. John’s Wort likely due to the activation of P-gp active transporters that result in an “absorption barrier1”. This interaction has been correlated to hyperforin concentrations in St. John’s Wort in clinical trials1. St. John’s Wort interacts with another commonly used drug, proton pump inhibitors, by increasing its metabolism1. Decreased plasma concentrations of PPIs have been measured in clinical studies1. Similarly, reduced plasma concentrations of oral contraceptives have also been measured in patients using St. John’s Wort likely through a similar MOA1. Lastly, protease inhibitors and non-nucleoside reverse transcriptase inhibitors (used in the treatment of HIV/AIDS), are also thought to have an interactions with St. John’s Wort3. For example, indinavir plasma concentrations were reduced in clinical studies with volunteers and reduced the area under the curve (a measure of total drug absorption) by 57% which is sufficient to reduce the effectiveness of the drug in treating HIV4. The list of drugs listed here are not exhaustive by any means. The previous reflection listed several other classes of drugs that are similarly affected by St. John’s Wort. For more information see Russo et al. In all of these cases the pharmaceuticals may not be effectively treating the ailments in patients who also take St. John’s Wort. Therefore the hazard is the continuation of adverse effects caused by other physiological, biological or chemical factors that are going untreated.

    The hazards listed above allow for a key assumption to be made. That is that there are at-risk groups. Otherwise healthy individuals who use St. John’s Wort and St. John’s Wort alone are unlikely to be adversely affected by the drug2. However, as mentioned many times, this herbal remedy is often used in conjunction with other drugs1. The hazard assessment for the COPC allows for the identification of potential interactions based on the MOA of the active ingredients of St. John’s Wort. The identified interactions can then be used to target specific exposure groups in the risk assessment. Specifically, individuals with mental illness, cardiovascular diseases, CNS syndromes, women of child-bearing age and many others who are on pharmaceuticals whose efficacy is lowered by St. John’s Wort. This results in the continuation of potential hazardous health effects or unintended effects of those exposed. Next week’s reflection will continue to look into the variables to be considered in the hazard assessment including LOAEL and NOAEL derivation and uncertainties associated with clinically adverse effects from St. John’s Wort interaction and individual response variability.

    References:

    Russo E., Scicchitano F., Whalley B.J., Mazzitello C., Ciriaco M., Esposito S., PAtane M., Upton R., Pugliese M., Chimirri S., Mammi M., Palleria C. (2013). Hypericum perforatum: Pharmacokinetic, Mechanism of Action, Tolerability, and Clinical Drug-Drug Interactions. Phytother. Res. DOI: 10.1002/ptr. 5050
    Ernst E. (2002). The Risk-Benefit Profile of Commonly Used Herbal Therapies: Gingko, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto and Kava. Complementary and Alternative Medicine Series. 136 (1): 42 – 53
    University of Maryland Medical Center. (2011). Possible Interactions with: St. John’s Wort. University of Maryland School of Medicine: http://umm.edu/health/medical/altmed/herb-interaction/possible-interactions-with-st-johns-wort
    Piscitelli S.C., Burstein A.H., Chaitt D., Alfaro R.M., Falloon J. (2000). Indinavir concentrations and St. John’s Wort. The Lancet. 355: 547 – 548
    Kane G.C., Lipsky J.J. (2000). Drug-Grapefruit Juice Interactions. Mayo Clinic Proceedings. 75: 933 – 942

  4. Do you know if St John’s Wort is more likely to interact with pharmaceuticals than other drugs? Maybe all antidepressants have the same risk of chemical interaction?

  5. Author-
    The type of drug (prescribed or not) that SJW will interact with is dependent on how the drug is metabolized. SJW interacts with so many pharmaceuticals as well as over the counter drugs because of its unintended MOA which is the activation of CYP enzymes and of P-gp transporters. CYP enzymes are very important in the metabolic break down of a variety of xenobitoitcs that enter the body. In addition P-gp transporters play a key role in the excretion of many drugs. This was all outlined in my first reflection.

    The difference between SJW and precribed anti-depressants is the pre-market regulation process. Pharmaceuticals and non-pharmaceuticals are regulated under the Food and Drug Act and undergo a more vigourous assessment of their safety including interactive effects. Alternately, SJW and other herbal remedies fall under the Natural Health Product Act which doesn’t require the same level of scrutiny. Therefore, the risk associated with anti depressants are much more thoruoughly explored than those associated with SJW.

    Now that is not to say that antidepressants are without adverse effect or similar risks as SJW. They may be more or as risky as SJW. However, these risks are more thoroughly explored during the regulatory process and medical professionals are more aware of the interactive effects of prescirbed pharmaceuticals than they would be about herbal remedies. Stay tuned because I have a reflection that will look into the knowledge that medical professionals have in Canada on herbal remedies.

    Here are some links on the FDA and the NHP Act. It explains which products fall under which categories :

    FDA: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/index-eng.php

    NHP: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/index-eng.php

  6. Author-
    This week’s reflection is focussed on NOAEL and LOAEL derivation for the hazard assessment of St. John’s Wort along with the uncertainty associated with the clinical effects from St. John’s Wort’s interaction with pharmaceuticals and individual variability and susceptibility to St. John’s Wort interactions.

    As mentioned in reflection #1 St. John’s Wort contains several active ingredients including hypericin and pseudohypericin as well as hyperforin and adhyperforin1. Part of deriving a LOAEL and NOAEL is determining which one or combination of these compounds is responsible for the interactive effect of St. John’s Wort. Several studies reviewed by Russo et al. (2013) identify hyperforin as the ingredient responsible for the interactive effects of St. John’s Wort1. Yet, some other studies still found interactions occurring in doses with low or no hyperforin content1. Despite this, the review still recommends limiting the hyperforin content of the pills which would reduce St. John’s Wort interactive potential without reducing its efficacy in the treatment of depression1. LOAELs and NOAELs for hyperforin’s potential to induce CYP enzymes and P-gp transported could be obtained from clinical studies in literature and used to estimate risk in pills with high or low concentrations of this ingredient. For example, studies have found that St. John’s Wort formulations containing less than 1% hyperforin do not result in clinically relevant enzyme induction2. So a potential NOAEL for hyperforin as it relates to St. John’s Wort interaction potential could be < 1%. However, additional research is required to ascertain that the interactive hazards are associated mainly with hyperforin and not with other ingredients such as hypericin. As mentioned in reflection 2, hypericin was thought to be responsible for the reduced efficacy of benzodiazepam1.

    Calculating NOAELs and LOAELs may not be necessary if there is not clinical manifestation of the interactions caused by St. John’s Wort. There is uncertainty surrounding the likelihood that clinically significant adverse effects will occur in individuals who use many of the drugs mentioned in reflection 2 along with St. John’s Wort1. To elaborate, interactions are clearly indicated with many pharmaceutical drugs but reports of adverse effects are few and far between1. Kristin Bielefeld provided a great reference which discusses one such example of indicated interactions without clinical manifestations4. In this article, the interaction of St. John’s Wort with oral contraceptives has not been clinically linked to any unwanted pregnancies4. This may be because the practitioner prescribing the birth control is unaware that the patient is taking the medication and the patient is unaware of the interaction and so they do not link exposure with the effect. As mentioned previously, herbal remedy users often do not disclose to practitioner that they are using herbal remedies3. Another uncertainty not expressly mentioned in the literature includes individual drug metabolism rates and how this affects St. John’s Wort indirect toxicity. For example, an individual who metabolizes a drug more quickly may be more adversely effected by St. John’s because the drug would be metabolized at an even quicker rate and the therapeutic index never attained.

    This reflection attempted to outline factors to consider in the hazard assessment of St. John’s Wort. Last week’s reflection delved more into the effects that result from exposure to specific pharmaceuticals and St. John’s Wort. This week’s reflection attempted to outline the active ingredients that are the main contributors to St. John’s Wort’s interactive potential for which LOAELs and NOAELs should be calculated. Uncertainty surrounding the clinical relevance of the effects and individual sensitivity to these effects was also discussed. The next reflection will attempt to estimate exposure in the population based on the available literature in order to further characterize risk.

    Russo E., Scicchitano F., Whalley B.J., Mazzitello C., Ciriaco M., Esposito S., PAtane M., Upton R., Pugliese M., Chimirri S., Mammi M., Palleria C. (2013). Hypericum perforatum: Pharmacokinetic, Mechanism of Action, Tolerability, and Clinical Drug-Drug Interactions. Phytother. Res. DOI: 10.1002/ptr. 5050
    Hazardous Substance Data Bank. Hyperforin. ToxNet. U.S. National Library of Medicine. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~3lDNsm:1
    Ernst E. (2002). The Risk-Benefit Profile of Commonly Used Herbal Therapies: Gingko, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto and Kava. Complementary and Alternative Medicine Series. 136 (1): 42 – 53
    Gupta R.K., Moller H.J. (2003). St. John’s Wort: An option for the primary care treatment of depressive patients? Eur. Arch. Psych. Clin. Neurosc. 253: 140 – 148

  7. Glad my reference was useful for you! I think you make a really important point about doctors/patients not linking exposure with effect. A couple of studies I found about the increasing prevelance of herbal remedies: Cupp 1999 and Eisenberg et al 1993 had some interesting stats that may be useful in estimating exposure. 25% of Americans who with serious health concerns use herbal remedies but only 70% of those patients inform their doctors. This is pretty startling – usually when I go to the doctor they ask about other medications but they don’t always ask about herbal remedies and supplements. Is there any sort of regulation in Canada that requires doctors or pharmacists to obtain this information? If not, should there be?

  8. Really interesting, and I was thinking along the same lines with Kristin’s comment in terms of a sort of regulation. Do you think it be beneficial that stores that sell herbal supplements maybe at least be required to post a notice indicating that some herbal products may interfere with prescribed pharmaceuticals with the “talk to your doctor” line. I don’t frequent the herbal supplement aisle so not sure if they do this already or not.

  9. The interactions between prescription drugs and SJW are obviously a concern; however, the side effects of SJW seem to be a significantly undesirable outcome. Rapaport et al. (2011) conducted a study attempting to discern the effectiveness of SJW for low level depression. As previous studies indicate, they found SJW to be ineffective in the treatment but associated with adverse effects (Rapaport et al. 2011). I would think that people with mild depression may be more likely to self-medicate given that their symptoms are not extreme enough to warrant alarm from their doctors. If so, it may be even more under reported given that their doctors are not even talking to them about depression or medicating them for it. What do you think?

    I also found the two case studies identified by Andrew et al. (1999) to be an interesting read. Both individuals had manic episodes while taking SJW but interestingly, the male case study was not being treated by doctors for depression at the time. I think these papers illustrate my concern with the use of some over the counter herbal medicines in that the active ingredient you seek is not necessarily at a consistent dose within the product, and there may be other active ingredients with potentially negative side effects. In agreement with other’s posts, communication with your doctor seems to be the best approach; however, I imagine it is difficult to find a doctor that is savvy in both modern and herbal medicine.

    Mark Hyman Rapaport, Andrew A. Nierenberg, Robert Howland, Christina Dording, Pamela J. Schettler, David Mischoulon. 2011. The treatment of minor depression with St. John’s Wort or citalopram: Failure to show benefit over place. Journal of Psychiatric Research, Volume 45, Issue 7, July 2011, Pages 931–941 http://dx.doi.org/10.1016/j.jpsychires.2011.05.001

    Andrew A Nierenberg, Tal Burt, John Matthews, Anthony P Weiss. 1999. Mania associated with St. John’s wort. Biological Psychiatry, Volume 46, Issue 12, 15 December 1999, Pages 1707–1708 http://dx.doi.org/10.1016/S0006-3223(99)00233-4

  10. It was mentioned that it could be “difficult to find a doctor that is savvy in both modern and herbal medicine.” If you were interested in finding this type of health practitioner you could consider a naturopathic doctor. This is a 4-year professional accreditation that includes education in both western science and alternative methods such as herbal medicine. It is not the same as a medical doctor but some natropathic doctors also have an MD (otherwise it would be advisable to also consult with an MD about your health concerns). Note that this is NOT the same as a naturopath, which may involve only a one or two year program with little education in western science. Here is a link to accredited natropathic doctors in Saskatchewan.

  11. Author –
    The comments are great starting points for my next reflection on exposure assessment. The exposure assessment will be discussed more broadly in terms of natural health product use among Canadians and more specifically in terms of herbal remedies/therapies. This is because there is limited to no data on the usage rates of SJW alone especially in Canada. On this basis, this assessment is speculative rather than empirical. However, to start there is information on the dose range of SJW consumed by individual users as well as general rates of use.

    As mentioned in the very first reflection on SJW the recommended daily intake to result in therapeutic effects is 900 mg/day in three separate doses of 300 mg/dose1,2. However, doses can range from 400-900 mg/day depending on the ailment being treated1. The oral route is the main exposure pathway although exposure also occurs through the dermal route via the use of topical creams for the treatment of skin infections1.

    On a population level herbal remedy use is on the rise. A survey reviewed in a World Health Organization’s monograph by Berger (2001) found that out of 2500 people 15 years and older herbal remedy use had increased from 28% in 1999 to 38% in 20014. In addition, analysis of various reports in the same monograph found that SJW was among the top ten most used herbal remedies in Canada (17% among herbal remedy users and 6% use rate in all of Canada)4. Fraser Institute (a Canadian think-tank) published their results of a survey on Complementary and Alternative medicine (CAM) use in Canada. A similar survey was conducted by them in 1997. The survey randomly interviewed 2000 Canadians 18 years or older during the same season in 1997 and 2006 on the use of CAM in the 12 months prior to the survey5. They found that among the most commonly used CAM was herbal remedies at 10% (use highest in British Columbia and Alberta)5. Among those users 70% responded that they used herbal remedies to maintain wellness5. Average age reported for first use of herbal remedies in Canada was 315. However, it was also reported that children used herbal remedies with 15% of households stating that their children used CAM and of that 22% used herbal remedies specifically5. In children, the remedies were more often used to treat illnesses rather than maintain wellness5. Furthermore, expenditure on CAMs including herbal remedies has almost doubled since 19975.

    From the survey data, it appears as if the number of Canadians seeking out CAM and spending money and using herbal remedies is on the rise. However, these numbers could be higher or lower depending on the rate of reported use. As mentioned by Kristin the disclosure of herbal remedy use to health care providers in the U.S. is not 100%. A similar trend is observed with Canadians. In an attempt to focus on SJW I found a condition that SJW is used to treat in the Fraser Survey and the rate of reporting of that condition and CAM use to the medical doctor. Based on the survey results herbal therapy was among the top CAM treatments used for anxiety5. Of the respondents who stated suffering from anxiety, 72% said they sought CAM treatments but only 9% said they reported their condition5. This suggests that herbal remedy and other CAM treatments may be underreported and so exposure rates may be higher than the surveys suggest.

    Similarly, although the presumed individual exposure is based on the recommended dose it may be very well be higher or lower than 900 mg/day. A high level of uncertainty exists in assessing individual exposure to SJW because of the regulations surrounding natural health product use in Canada. Both Melissa and Kristin inquired about the regulations surrounding the use and sale of herbal remedies in Canada and in answer to their questions regulation is lacking in all areas of herbal remedy use and sale. NHPs are regulated separately from drugs by Health Canada and they can be sold prior to full review. However these have to be lower risk products that have some level of safety and efficacy guaranteed9. Those products not yet assessed by Health Canada but for sale in Canada have exemption numbers on them3. All other products that have been assessed and approved should have a NHP or DIN-HM number3. Products are assessed based on brand not extract so several brands of SJW can be assessed or be given an exemption number (without assessment) and sold in Canada at any given time. Recent legislative changes have repealed the use of exemption numbers and created a new system in which the herbal remedy industry is required to self-regulate9. This is an important development that will be discussed in a later reflection. It is important to note that there are no regulations stipulating the disclosure of herbal remedy use between patients and doctors. However, several bottle labels (as mentioned by Melissa) due recommend that consumers seek doctor advice prior to use. A more thorough discussion on the regulations surrounding NHPs and the implications of these regulations in risk assessment will be discussed in a later reflection.

    Lorelei and Melissa both brought up excellent points on the communication of risk between medical professionals and consumers when it comes to herbal remedy use. I want to save this topic for later at it is worthy of its own reflection. But in preview my initial searches have found that pharmacists, medical students and doctors are generally unable to confidently provide correct and accurate information to consumers on the use of herbal remedies6,7.

    Consequently, it is extremely difficult in the current climate to predict the exposure of Canadians to herbal remedies. This is because “book-keeping” on herbal remedy use is obsolete in Canada because of the current regulations. Herbal remedy use is under reported and with the exception of short small-scale surveys no other information is available to determine rate of use and doses because (as I’ve mentioned several times) consumers do not often report their use to medical professionals. In the next reflection I want to explore the concerns associated with medical professional competency on CAM and how this increases the risks associated with herbal remedy use.

    Russo E., Scicchitano F., Whalley B.J., Mazzitello C., Ciriaco M., Esposito S., PAtane M., Upton R., Pugliese M., Chimirri S., Mammi M., Palleria C. (2013). Hypericum perforatum: Pharmacokinetic, Mechanism of Action, Tolerability, and Clinical Drug-Drug Interactions. Phytother. Res. DOI: 10.1002/ptr. 5050
    Ernst E. (2002). The Risk-Benefit Profile of Commonly Used Herbal Therapies: Gingko, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto and Kava. Complementary and Alternative Medicine Series. 136 (1): 42 – 53
    Health Canada (2012). Drugs and Health Products: About Natural Health Products. Government of Canada. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/about-apropos/cons-eng.php
    World Health Organization. (2002). Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 82
    Esmail N. (2007). Complementary and Alternative Medicine in Canada: Trends in Use and Public Attitudes, 1997 – 2006. Public Policy Sources.Fraser Institute. Number 87
    Johnson T., Boon H., Jurgens T., Austin Z., Moineddin R., Eccott L., Heschuk S. (2008). Canadian Pharmacy Students’ Knowledge of Herbal Medicine. Amer. Jour. Of Pharm. Ed. 72: Article 75
    Xu S., Levine M. (2008). Medical Residents’ and Student Attitudes towards Herbal Medicines: A Pilot Study. Can J. Clin. Pharmacol. 15: e1-e4

  12. Author –
    Last week I discussed the exposure assessment for SJW. I identified several limitations in assessing exposure that circulate around two major factors; under-reporting of herbal remedy use by patients to medical professionals and limited regulation. In this reflection, I wanted to wrap up my topic by discussing the knowledge health care professionals possess in relation to herbal remedies and how this affects their communication with patients and also the regulations that Canada has in place to govern herbal remedy use. This discussion will end with some recommendations to improve the exposure assessment and recent regulatory changes to the Natural Health Products Act that may improve the regulation of the industry and allow for a quantitative assessment of risk associated with specific herbal remedy use.

    Lorelei asked last week if medical professionals were “savvy in both modern and herbal medicine.” Well, the two studies I found in the literary databases speak to the lack of knowledge that health care professionals possess when it comes to herbal remedies. The first, by Johnson et al. assessed the herbal remedy knowledge of pharmaceutical students in their final year of study1. The logic behind the study was that pharmacists should be able to provide information to potential consumers on any of the products sold within their pharmacy1. The study was conducted in provinces across Canada including British Columbia, Alberta, Ontario and the Northwest Territories1. The highest scoring students were from B.C. and AB but at both of these universities courses specifically on herbal remedies were offered. Ontario and N.W.T had statistically significant lower test scores1. In both cases, the low test scores were related to no herbal remedy course being offered or a low attendance to the course1. However, it was noted by the authors that the lower test score, although statistically significant, may not result in a significantly greater difference in practice between the two groups1. Some factors which may have affected the results included the time the test was given and the questions on the test1. Alberta students were tested after class while all other exams in other provinces were taken prior to class1. The tests was voluntary in all cases and in Alberta more students may have felt less inclined to take the test if they had limited knowledge on the topic area and could just leave after class1. The test was also a simple exam that if more challenging may have provided results that showed greater differences among province performances1. Overall, the study found pharmacists to be most uncertain in the areas of mechanism of action, adverse effects, drug interactions and dosage1. As I have iterated in several reflections the interactive effect of SJW with other pharmaceuticals is the key hazard associated with its use and is therefore the most important factor to regulate in order to lower risk.

    Another study, by Xu and Levine reviewed the herbal remedy knowledge of 26 medical residents as well as clinical clerks2. The majority of those interviews responded that they felt that they were incompetent in using herbal medicine in practice and that they did not have the necessary formal training on the subject2. Additionally, the majority when asked, did not know where to refer patients seeking additional information on herbal medicine to2. Furthermore, the survey found that the residents and clerks believed that up to 11-30% of their patients used herbal medicines and 80% of respondents felt that 1 in 10 patients was incompetent in the safe use of herbal medicine2. The reasons the doctors gave for not prescribing herbal medicine included a lack of literary sources on the risk-benefit, uncertainty regarding the effects and that they did not believe it would help in treating the ailment2. Based on this survey, patients know little about the safe use of herbal medicine and doctors (in this case future doctors) are unable to provide them with the information necessary to make an informed and safe decision2. This may also tie into the under reporting of herbal medicine use by patients because doctors simply do not ask because they do not know how to evaluate the information they receive when it comes to this subject.

    The second area of concern surrounding herbal remedy use is regulations. Several commenters have posed questions asking about the regulation of natural health products (NHPs). Both Melissa and Kristin asked about regulations stipulating communication of herbal medicine use between patients and doctors. I said in the last reflection that I would explore the regulatory statues surrounding NHP in order to address this question. The Natural Health Products Act (NHPA) was the first act to regulate herbal medicine in Canada3. It came into effect in 2004 and it falls under the Food and Drugs Act3. The Natural Health Products Directorate was then formed to enforce and carry out the NHPA3. Several new regulations were implemented under the NHPA and a few of the key ones for the purpose of this reflection are as follows:

    NHPA main goal is to assess the safety and efficacy of NHP through a research program that included conducting original research within the directorate and using research conducted within the scientific community4.
    Pre-market reviews of products streamline NHPs into low-risk and higher than low risk. Low risk products can enter the market prior to a full assessment with a temporary exemption number. Higher than low risk products had to undergo a full assessment based on efficacy and safety using a number of different sources including accepted traditional references, professional consensus and scientific evidence. Clinical trials are also used to assess safety but are not a requirement in quantifying risk4.
    Good manufacturing protocols (GMP) must be in place in places where NHPs are manufactured, processed and packaged to ensure that NHPs are produced without contamination of unintended products. Within this the manufacturers must also ensure quality of their product4.
    Label requirements to ensure proper use and adverse reaction information4.
    A post-market adverse reaction reporting system was also implemented4.
    Recent developments have also removed the unprocessed products license applications since the NHPD has dealt with the initial product assessment backlog that resulted from the implementation of the NHPA5.

    Based on the above it should be expected that NHPs entering the market do not result in a substantial risk to the consumer. However, SJW may be a special case because of its interactive effects. In my opinion, NHPs such as SJW may be better served as being categorized as drugs and regulated under the Food and Drugs Act. This would mean that they would have to be prescribed by a medical practitioner. Steven mentioned licensed naturopath doctors as another resource that could participate in the prescribing of “special case” NHPs that have hazards that are not directly associated with their use but which fall under an indirect effect. These indirect effects may increase their risk.

    Alternately, if higher-risk NHPs could not be regulated as drugs than another recommendation that could be made to alter the regulations would be a requirement of physicians to enquire about all NHP use by individuals. However, this would be difficult to implement as physicians follow their own set of regulations and amendments would have to occur to those as well. Also, consumers may not seek out medical help if they felt that medical professionals would ask about and deter them from using NHPs. Therefore, it could also be recommended that physicians be provided formal training within school or on the job regarding the potential benefits and risks associated with herbal remedies and other NHPs that are used by a significant portion of the population. Alternately, physicians could inquire about NHP use and then provide the information on the interactive effects of any NHP the individual is on and refer them to a licenced naturopath. Another, important change is recommended is the training of pharmacists on herbal medicine since pharmacies are often where consumers first come into contact with NHPs. Pharmacists should be well versed on the risks and benefits associated with all of the products they are selling. If medical professionals were well versed on the risks and benefits of popular NHPs than they could provide a second level of oversight on the NHP market. Additionally, exposure information would be more easily obtained with this second level of oversight. All of this would help to ensure that the risk remained low for NHPs whose characteristics make them not directly but indirectly hazardous.

    Some think tanks (such as Fraser Institute) have called for the abolishment of the NHPA with claims that it is costly and that the oversight of the NHPD is unnecessary since NHPs do not carry that much risk with their use6. They claim that the lack of adverse reaction reports suggest that most NHPs carry low risk6. However, as mentioned earlier under-reporting is an uncertainty associated in exposure assessment. Since clinical trials are not required in assessing the safety of NHPs it is difficult to be certain of their risk. I agree with the logic behind the NHPA which is that regulation is required because use of NHPs has increased in Canada. Also, although not thoroughly clinically proven (because it is not required) there are hazards associated with the miss-use or over-use of NHPs, such as SJW, and oversight is necessary to protect consumers. The NHPA protects consumers in that it ensures direct safety and efficacy of the NHP, it assures that cross-contamination is not present under GMPs and it ensures all products are sold with labels providing adverse effect information. Additionally, it is in my opinion that the recommendations I mentioned above would provide additional oversight that would reduce the risk associated with indirect effects caused by NHP use. The adverse effects of these NHPs may not be clinically proven but precautionary principle should be applied if literary sources show that unintended consequences of an NHP, such as SJW, could result in adverse effects.

    Johnson T., Boon H., Jurgens T., Austin Z., Moineddin R., Eccott L., Heschuk S. (2008). Canadian Pharmacy Students’ Knowledge of Herbal Medicines. Amer. Jour. Pharmac. Educ. 72: Article 75
    Xu S., Levine M. (2008). Medical residents’ and students’ attitudes towards herbal medicine: a pilot study. Can. J. Clin. Pharmacol. 15: e1 – e4
    Health Canada. (2012). Drugs and Health Products: About Natural Health Products Regulation in Canada. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/about-apropos/index-eng.php (accessed October 8, 2012)
    Health Canada. (2003). Drugs and Health Products: ARCHIVED – Natural Health Products: 53 Recommendations of the Standing Committee on Health. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/about-apropos/53_recommend_nhp-cps_tc-tm-eng.php (accessed October 8, 2012)
    Health Canada. (2013). Drugs and Health Products: Questions and Answers – end of the natural health products unprocessed product license applications regulations. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/faq/uplar-dlmmnt-eng.php (accessed October 8, 2012).
    Ramsay C. (2009). Unnatural Regulation: Complementary and Alternative Medicine Policy in Canada. Fraser Institute Studies in Health Care Policy. September 2009
    As an end note I wish I could have covered the regulatory side of NHPs in more detail. If you want more information Ramsay C. (#6) reference above provides a really detailed overview of the NHPA without bogging you down with the regulatory jargon present in many statutes.

  13. I have found your post to be very interesting and informative.

    Thank you for researching those two studies with respect to physician’s knowledge as it relates to the use of herbal medicines. I was surprised to see pharmacists were the most uncertain with regard to dosing, etc. Perhaps it is because they are more hesitant to make assumptions with regarding to dosing or administration of drugs. I think herbal medicines contain active ingredients that are not often thought to be ‘toxic’ by people that use them frequently so I liked that you chose this topic. SJW is a good example of a herbal drug that can benefit people; however, we should remain cautious if considering its use, especially if taking other medication.

  14. Your posts on this topic were really thorough and informative, thanks for your effort in answering my questions throughout the process! I agree with you that certain NHPs should be regulated under the FDA. If NHPs like St. John’s Wort that can have serious consequences when taken with other drugs, it makes good sense for them to be regulated with the other drugs. Perhaps if they were listed under the FDA doctors and pharmacists would learn more about them and be better prepared on how to instruct patients on their use. Some more examples are provided here – HIV/AIDS patients taking antiretroviral drugs had interactions with a whole host of NHPs (including SJW).

  15. I have often argued with some family members that NHPs should be researched and reported to your doctor when they ask if you are taking anything. I will be passing along a lot of this information in hopes that since it isn’t coming from a family member they may listen better.

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