Federica Santoro 0:08

Herbal

Intro

Federica Santoro 0:09

remedies have been used for thousands of years to treat what ails us. Yet why do we know so little about their side effects compared to modern medicines? My name is Federica Santoro, and this is Drug Safety Matters, a podcast by Uppsala Monitoring Center, where we explore current issues in pharmacovigilance and patient safety. This episode is part of the Uppsala Reports Long Reads series, where we select the most topical stories from our news site, Uppsala Reports, and bring them to you in audio format. Today's article is The Color of Signals, written by UMC Pharmacovigilance Scientist Daniele Sartori and published online in August 2023. After the read, I sit down with Daniele to learn more about the safety of herbals. So make sure you stay tuned till the end. But first, let's hear the article read by Daniele himself.

Article read

SPEAKER_01 1:23

The Indians dye the bright yellow with the root of a plant which grows spontaneously in the western woods, and which might, very properly, be called Radix Flava Americana. It was in this manner that in seventeen ninety three Mr Hugh Martin introduced the American Philosophical Society to his experiments dyeing linen, wool and silk using the roots of a plant that he had observed Native Americans use in a similar manner. Mr Martin was referring to the plant that Linnaeus had named Hydrastins in the tenth edition of the Sistema Nature in seventeen fifty nine. It then became known as Hydrastis Canadensis Line, or Golden Seal. Much later, in a tenth issue of the Bulletin of the Lloyd Library of eighteen eighty four, we learn more about this plant's main active ingredient hydrastin, an alkaloid also called berberin in Europe at the time. In fact, the plant and its alkaloids had medicinal properties. The plant was used as a diuretic, stimulant, and escarotic by Native Americans, while Americans praised hydrastin's laxative and tonic properties, and used it to treat nausea, heartburn, aphthros, inflammation, and even mourning sickness. Beyond its many uses, however, a common complaint were its staining properties, as anything it touched would essentially become yellow for quite a while. Notably, one will not be able to find any mentions of any adverse effects of either the alkaloid or the plant in the bulletin. Today, we know more about hydrastin or berberin. For one, these names refer to two distinct alkaloids, which only share their colour. In fact, not only do they have different chemical structures, but they come from different parts of Golden Seal, the first from its roots, and the other from the flower, leaf, and stem. Berberin, however, is the only active ingredient that has seen some use to date. Currently it is all the rage on TikTok, what it's touted as being a natural alternative to Azempic, a type two diabetes medication that has also been trending on social media platforms as potentially being effective for weight loss. Possibly, this idea comes from three studies that have been summarized along with eight others in an umbrella review on berberin. In it, there are indications that berberin might have effects on body composition measures, such as body mass index and waist circumference. Much like in the past, where the focus of such research were the beneficial effects, the included studies neglected to mention potential adverse effects, with only seven of eleven reporting them as part of their findings. Even though these weight loss effects appear to be modest at best, we still focus on the benefits of interventions rather than their harms. For herbals, we tend to underestimate their adverse effects under the assumption that, since they have been used for hundreds, if not thousands of years, they must be harmless. This is not the case. Drug-induced liver injury has been associated with the use of several common herbals, among which rhubarb, senna, green tea, black kohosh, and ephedra. Herbals have also been involved in interactions with medicinal products, the most famous example being unwanted pregnancies brought about by Saint John's Wort, which accelerates the clearance of oral contraceptives. Going back to Golden Seal, it should not be taken during pregnancy, as berberin can induce or worsen kernicteris, a form of brain damage in newborns due to high levels of bilurbin in their blood. Despite these potentially serious risks of harm, there are challenges to collecting data on herbals. For context, Vigibase contains around 142,000 reports on herbals. Some of these remedies have been used at least since the Herbus papyrus from 3,500 years ago, when the pyramids were three digits old. By contrast, medicinal products that have been on the market since 1968, when the Beatles were filling up Piccadilly Circus with the yellow submarine and Vigibase had just started, have several million reports. Part of this lack of data may be explained by patients' tendency to not disclose the use of herbals to their health carers. In turn, health practitioners tend not to ask about the use of herbals or otherwise note information on the use of herbals by their patients. All this complicates signal detection since it ultimately relies on how much data we have. At a conference on the safety of herbals hosted by the Drug Safety Research Unit last April, I gave an oral presentation on part of the results from a scoping review of signals on behalf of its co-authors. The study suggested that the number of signals of herbal medicinal products was strikingly low compared to the total number of signals included in the review, and identified some signals of interaction between medicinal products and herbals. All signals on herbals were based on clinical or statistical analyses of case reports, so the low numbers may have been driven by an overall lack of reports. Among the signals included in the analysis, there was one from 2003 on golden seal and yellow tooth stains in children, which was based on only two case reports. In the original manuscript, one of the reporters, a pharmacist, had indicated that berberin could be the cause. Eventually, in 2004, the German regulatory agency added this adverse effect to the monographs of products containing golden seal. It is rather surprising that this adverse effect had not been noted before the 2000s for two reasons. First, in nineteen ninety seven, golden seal was quite a commercial success to the point where it became an endangered species in North America. Second, it produces a visible, albeit mild effect, the colour yellow. Yellow is one of the most conspicuous colours. It is a colour of warning in nature. It is used in alert signs and to designate school buses. Yellow incites action or reaction to some situation. In pharmacovigilance it does so to evidence. I would not be the first to draw the parallel between signals and the color yellow. As succinctly written by Rafe Edwards in the editorial to the first twenty sixteen issue of the signal document, the analogy works insofar as we consider signals as warning signs and that we do not dwell on them. The more data we have, the brighter the light. In the case of herbals, despite the long established presence in the history of humans, the light is dimmed, even when, in nature, they bring about a bright yellow.

Welcome, Daniele!

Federica Santoro 9:09

That was Daniele Sartori reading The Color of Signals. And here he is with me once again in the Drug Safety Matters studio. Welcome back. Thanks for having me, Fidder. So last time you were here, we chatted about signal detection and sources of evidence in pharmacovigilance. A topic that really resonates with our audience, judging by how many times the episode was downloaded. And so I'm delighted to have you back. But this time we're talking about herbal medicines and their safety.

Why we don't talk about harms

Federica Santoro 9:43

As you point out in the article, we tend to consider herbal products harmless because they come from nature, and also because they've been used by millions of people for hundreds of years. Are there any other reasons though why we rarely focus on the harms of these products?

SPEAKER_01 10:03

Yes, certainly. I can come at least with two in mind. There probably are others. These are under-reporting and the regulations surrounding herbals. So when it comes to under-reporting, I think we can think back to a study that Joe Bundes and colleague did in 98. Essentially they asked around 500 people who used herbal medicinal products. And they said, well, they asked them would you report a serious ADR to your GP? And would you do the same if this ADR took place when you took an over-the-counter drug? This was all for serious ADRs, according to the ICH criteria. And they said that well, 43% of them said they would not consult their GP for a serious ADR, whether from a herbal or an over-the-counter drug. And 26% said that they would consult their GP for a serious ADR from an over-the-counter drug, but not to a herbal drug. So there is a tendency towards not disclosing your ADRs to your GP. This is, of course, quite dated. And this is maybe not entirely on the patients, it might also be in a sense on the health practitioners, not because they are complacent or because they don't want to report. In a Canadian survey, they found out that healthcare practitioners were not properly trained in academic years to reporting adverse effects to herbal medicinal products. So there might be problems that occur at multiple levels of society and that target multiple strata of society.

Federica Santoro 11:58

You mentioned also a regulatory challenge.

SPEAKER_01 12:00

Yes. So in in Europe we have clear regulations that surround herbal. So we have a definition for a herbal medicinal product. This contains the notation medicinal product. So any herbal medicinal product that is put on the market in Europe needs to have sufficient data that shows the efficacy of these products. As opposed to supplements, for example. This distinction between supplements and herbal medicinal products does not apply to all countries, certainly not outside of the European Union. So in some legislations, herbals are simply regulated as supplements, and this means that not only you might have supplements whose efficacy is not up to the standards of the European Union, but you might have that the safety of these products is not monitored equally as we would do it in Europe. What this entails is also that in countries where the safety of supplements is heavily monitored, the data is collected in separate databases, which would mean that for analysis you'd have to combine multiple sources of data, and this might complicate things a bit.

Federica Santoro 13:21

So it sounds like herbal products basically fall into a grey area, both in terms of awareness and education on their side effects and regulatory practice. We need to sort out these challenges to make sure we do proper pharmacovigilance on them.

SPEAKER_01 13:37

Yes.

Nature's Ozempic

Federica Santoro 13:38

So, as we've said, for many people, natural equals safe. And one example of how strongly people feel about that equation comes from recent social media conversations. And that's the one you cite in your article of berberine being nicknamed nature's Ozempic. Now, for those of us who are not on TikTok, tell us what we missed. Yeah.

SPEAKER_01 14:06

Ozempic is a recently marketed medicinal product that has also become popular on social media because it has weight loss effects. It is approved in a couple of indications, one of which can be weight loss. We still have quite a bit to look into in this product because it was recently launched, so we still have to understand it very well. Regardless, nature's Zempic refers to, of course, berberine, or how social media users have come to perceive and describe berberine as an alternative of Zempic that can be extracted from plants. So to be extremely clear. Now there have been a few studies that have tried to ascertain whether berberine could lead to weight loss, and the conclusion of this studies was yes. However, there is of course some misconception that might have led to berberine exploding as a supplement online, meaning just because a study is published, it doesn't mean that the methods are sound and consequently that the conclusions are sound. So some of that might have contributed to why it became so popular. Of course there are possibly some societal reasons for this. Nowadays we have certain beauty standards and we all enjoy taking care of the way we look, and weight is of course a plays a massive role in how we look. We should also consider that Ozempic is a prescription medicine, and it requires an injection by a healthcare practitioner. So it's not easily accessible. By contrast, berberin is a supplement, it's a pill, and you can buy as much as you want online or at a pharmacy. In some legislation also, prescription medicines and injectable medicines they come with a hefty price tag, whereas supplements do not. So all of these factors might have contributed to this supplement to become very popular online. We should bear in mind that berberin is a laxative, and profound laxation can have serious consequences. In adults you could have hypokalemia, which might lead to rhabdomyolysis if left unchecked. And in children, you could have that profound laxation leads to dehydration, which you don't want to have, particularly in children below two years of age.

Federica Santoro 16:56

So natural does not necessarily mean safe.

Interactions with other medicines

Federica Santoro 17:01

And there's another issue: not only can herbals be harmful per se, they can also interact unfavorably with other medicinal products. Now, what would you say patients should watch out for when they're taking herbals alongside other medicines?

SPEAKER_01 17:20

Recently the WHO posted a document online on key issues that should be tackled when considering herbal drug interactions. And it seems that the best practices on how patients should be educated on the possible interactions between herbals and drugs are more or less what we currently have. So our best tools available remain patient leaflets or drug labels and consultation with healthcare practitioners. So of course we still have the issues that we talked about a bit before, so training should be possibly strengthened on the healthcare side, but I think it's yeah, beyond this. What I think is worth mentioning is that we know that most interactions between herbals and medicinal products tend to be pharmacokinetic. Well this means that if a herbal is administered alongside a medicinal product, the metabolism of the medicinal product might be accelerated or slowed down. In some cases, particularly with medicinal products that require very precise doses and specific concentrations in the blood, this might put the patient at risk for therapeutic failure or even toxic effects. This is it's extremely relevant to patients who, for example, undergo treatment for chronic heart failure or for the prevention of organ transplant rejection. However, I must say that the major interactions between herbals and medicinal products are listed on the product label.

How to encourage reporting

Federica Santoro 19:09

Okay, we've covered the problems. Now let's talk a bit about potential solutions. If herbals are not discussed that often during medical checkups, and it's difficult then to get data on their side effects into pharmacovigilance databases, what can we do about it? So, how do we encourage patients and healthcare professionals to have that conversation in the first place and then to report any issues once they identify them?

SPEAKER_01 19:39

So when it comes to designing interventions that should elicit a response at multiple levels of society, we are kind of stepping into the realm of complex interventions. So if, for example, you want to introduce a community-based program to achieve a certain health outcome, then you're talking about a complex intervention. One example could be introducing inverticomas healthier meals in schools for children to have a healthy BMI. This is a trivial example. These types of interventions tend to be complex to implement and to evaluate. In this case, we would like to encourage conversation between healthcarers and patients in order to achieve an increase in data. So I think this could qualify in the realm of complex interventions. What I mean by this is that there is no silver bullet or one-dimensional intervention that could help you achieve this goal. We can, however, learn from some of the simple interventions that have been tried to improve reporting. And I think there is an excellent example of a pre-post study conducted in Wales where a group of researchers produced an 83-second video about the yellow card scheme, which is the means through which people in the UK can report adverse drug reactions to the MHRA. Before they showed this video to a random sample of about 1,600 people, they asked these people, Do you know what an ADR is? Do you know what the yellow card scheme is? And do you know how to report an ADR? And in this pre-video questionnaire, most people said they didn't have an answer to these questions. They didn't know. 18.4% of people said they understood what a yellow card system was. And of the people who said, Yes, I know what it is, follow up question were Do you know for? Which medicines this applies. And most of them responded that this applied to prescription medicines. Some of them said that they thought it applied to falsified medicines alone. And 30% of them thought that it also applied to herbals. So we have not a resounding majority of people who know that they can report adverse effects to herbals through the yellow card scheme. After they showed these people the 83-second video, 74% of viewers knew correctly how to report and what they could report and what the yellow card scheme was. What this shows is that a simple intervention can sometimes lead to dramatic improvements into your systems for reporting adverse drug reactions. What this I think also suggests is that our most established systems for reporting adverse drug reactions, which have been around for over half a century, they still require some refreshers in the general population. Of course, this also shows the importance of education and engagement of people. Patient reporting became a thing in the early 2000s in Sweden, and then it spread through Europe. And after patient reporting was introduced, we've had increases in the number of reports, inequivocally. Now, patient reporting, however, is not the status quo in countries outside of the EU, and especially in some countries where the use of traditional medicine or herbal remedies is very prominent. So there might be some opportunities there to extend patient reporting.

Signal detection for herbals

Federica Santoro 23:47

And apart from underreporting, could there be other reasons why you found fewer signals for herbals in your scoping review? Is there something about herbals that makes signal detection on them more challenging, perhaps, than for other medicines?

SPEAKER_01 24:05

Yes. So I think the reason why there were fewer signals of herbals can be explained in two ways. First of all, the study focused on herbal medicinal products, which of course meant that anything that was classified as a dietary supplement was not eligible. Now, after manually reviewing what I excluded for the presentation in London, I concluded that the amount of excluded records from the review was not concerning. Speaking very plainly, assessing reports that concern herbals is quite tricky. To give you an example, in twenty fourteen the Japanese regulatory agency, the PMDA, communicated that Gardenia jasminoidis or cape jasmin was associated with mesenteric phlebosclerosis. So this is a condition that is very rare and leads to calcifications in the veins in your intestines. Specifically, it was the chronic use of cape jasmine that could have caused this. A few years prior, a group of Japanese researchers published a review of twenty five case reports in which they investigated the chronic use of campo medicine and mesenteric phlebosclerosis. Now, a tricky bit about herbals is that sometimes we are dealing with products that contain not just one plant, but multiple plants. And each of these can contain a set of ingredients that can be active or inactive. Sometimes more than one of these ingredients contributes to a clinically relevant effect. And this was precisely the case in this study. So each of the products in campo medicine, which is the traditional Japanese medicine, each of these products could contain between three to fourteen different plants, which is an enormous amount. However, all of them had consistently one plant, which was Cape Jasmine. Based on this, they also proposed a partially plausible mechanism of action of this ADR, and they considered that Cape jasmine contains genipicide, which is metabolizing your intestine to genipine, and it's an active ingredient. And they suggested that the causal agent for mesenteric fibosclerosis was genipine. So clearly they had fairly complete data about several patients taking different herbals, but all sharing the same condition. And I think in the cases where it is tricky is because we don't have all of these dimensions. We don't have complete data, nor these varied number of reports.

Federica Santoro 27:14

Yeah, I can see why it can get trickier in those cases. So then again, we need more data to come in.

Pressing concerns in the field

Federica Santoro 27:22

Right. Uh time for my last question then. You attended a conference on herbal pharmacovigilance in London a few months ago. Based on the discussions there, what would you say are the most pressing concerns in the field today?

SPEAKER_01 27:39

I think we could uh talk about three points primarily, namely nomenclature of plants, adulteration of plants, and again regulation. So the nomenclature of plants is vitally important when it comes to clarity of scientific communications. Just consider Golden Seal. This is a common name, but Golden Seal could also be called orange root in other English speaking countries. Linnaeus named it Hydrastus, Hugh Martin named it Radix Flava Americana, and Philip Miller, who was the chief gardener of the Chelsea Physic Garden in Scotland, named it Warneria, and he wrote to Linnaeus, I named this Warneria, and you named it something else. So clearly if we want to avoid ambiguities, we ought to refer to scientifically accepted names, and for this the Q Garden has made an extensive work on finding out which are the scientifically accepted names, and they have introduced the participants to the conference at the DSRU to the medicinal plant name services that is freely available and where one can learn what are the scientifically accepted names of even a common plant. Just put in the common plant name and you will get the scientific name. Secondly, I think adulteration. So by adulteration we mean in some legislation illicit, but certainly fraudulent addition of materials can be organic or inorganic to plant matter, and this is done to increase its volume or change its organoleptic properties. Anybody could add something black to a pile of pepper to increase the volume or the weight of that pile of pepper powder, and this is usually translated in monetary gains for whoever is performing this adulteration because they could pass falsified pepper for real pepper. Of course, this can be done for spices, but can also be done for herbal medicinal products. So addition of matter to plant powder or plant matter is one way that one could adulterate plants. However, there are more sophisticated methods through which you could add substances to plant extracts, and ensure that upon inspection via UV spectrometry or high liquid pressure comatography, a sample that one is analyzing could look like it's pure plant extract, where in fact it's not. Again for golden seal, you could add Coptus extract, or you could add Oregon grape or barberry extracts to make it look like based on a UV spectrometry, it looks like pure golden seal. Now, in a presentation, Mark Blumenthal from the American Botanical Council warned against these practices and took the opportunity to introduce one of the recent works he published on the methods that people use to adulterate plant materials and on the ways that these can be spotted and we can be safeguarded against people who mean ill for our health. Finally, we touched upon regulation, and this is as we've chatted a bit about before, focused around the lack of harmonization around the regulation of herbal medicinal products. Whereas in some countries, what we would call a herbal medicinal products are called supplements. So the monitoring of their efficacy and safety, as well as the marketing of these medicinal products, can be done radically differently from how we know it's done.

Federica Santoro 31:54

Plenty of food for thought and plenty of action points for the pharmacovigilance community. And I'm glad you cited the issue of nomenclature because we uh dedicated a whole episode in the first year of this podcast to that topic. So I encourage everyone who wants to know more about how medicinal plants are named to revisit that episode. It was an interview with Bob Alkin from Kew Gardens. That was all I had for you today. So thank you very much for taking the time to talk to me. And thanks again for writing the article.

SPEAKER_01 32:29

Yeah, no worries. Thank you for having me.

Outro

Federica Santoro 32:40

That's all for now. But we'll be back soon with more long reads as well as our usual in-depth conversations with medicine safety experts. If you'd like to know more about herbal pharmacovigilance, check out the episode's show notes for useful links. For more stories like this one delivered straight to your inbox every month. Sign up for our free newsletter at upsalareports.org. If you like our podcast, subscribe to it in your favorite player so you won't miss an episode. And spread the word on social media so other listeners can find us. Uppsala Monitoring Center is on Facebook, LinkedIn, and Twitter. And we'd love to hear from you. Send us comments or suggestions for the show, or send in questions for our guests next time we open up for that. For Drug Safety Matters, I'm Federica Santoro. I'd like to thank Daniele Sartori for his time, Matthew Barwick for production support, and of course you for tuning in. Till next time!