#613: Supplement Safety & Medication Interactions – Giulia Guerrini, MPharm

0:00Hello and welcome to Sigma Nutrition Radio. This is episode 613 of the podcast. My name is Danny Lennon. You are very welcome to the show. Today we're going to be talking all about supplement safety and potential interactions with various medications and some things that we should all be aware of, whether we are nutrition or health professionals working with people who are going to be taking supplements and or medications, or anyone who really is considering taking a certain supplement, how we weigh up some of these decisions and whether it's actually going to be worth it from a safety perspective.

0:33To go through some of this data, I'm going to be talking with Giulia Guarini, who is a registered pharmacist with a master's degree in chemistry and pharmaceutical technology, currently now working at Examine as a researcher and has headed up a large part of a new project for their Examine Clinician Edition where they've created a really useful tool that we'll mention called their Supplement Navigator, aimed particularly at professionals in nutrition and health. And so with that, we're going to use Julia's expertise to walk through a number of the aspects that could relate to safety generally around supplements, certain types of supplements that maybe we typically think of as safe, and then also the main areas where there could be interactions with medications, what those could be, how we can weigh that up and so on.

1:22As I mentioned this whole topic around supplement safety and their efficacy how that leads to interaction medications and how to check for those was all part of the supplement navigator developed by examine is now available as part of their examine clinician edition service for health professionals it has a number of other tools as well that includes their supplement database in-depth guides study summaries etc and now in addition to this supplement navigator. But if, as you go through this, you think that it might be a tool useful for you and your practice, I'll put some information in the description box where you're currently listening.

1:59You also can get a free trial of that from Examine right now. See if it's something that helps your practice. And so if any of this resonates through the conversation, just know that might be something of value. So that is in the description box where you're listening. Or of course, if you just go to the episode page over on sigmanutrition.com, you'll find more about that. and what examine have more generally. And so without further ado, let's get into this conversation with Giulia Guarini.

2:39A very big welcome to the podcast to Giulia Guarini. Thank you so much for taking the time to come and join me on the podcast.

2:45Giulia Guerrini: No, thank you. Thank you for having me. This is a topic I'm actually really excited to talk about personally because we haven't discussed it as directly as we'll be able to discuss today on this podcast previously. It's something that will, of course, be of great importance to many people listening. And it's, I think, a concern for a lot of practitioners as well as general folks who either take supplements or are interested in their health or are using certain medications. And so I think there's going to be a lot here that will be novel to people that they can be used. But before we get to any of my questions, maybe a good place to get us started is for people listening, can you give them an introduction to your own professional and academic background and anything else that might be relevant for them to know?

3:26Giulia Guerrini: So my name is Giulia Guerrini and I'm originally from Italy. I've been living in the UK for the past 12 years, specifically in London. I graduated with a master's degree in chemistry and pharmaceutical technology and I am now a GPHC, so a general pharmaceutical council registered pharmacist here in the UK. And in my career, I worked as a pharmacist for several community and online pharmacies. But my passion for nutrition and specifically research in supplement and nutrition brought me here at Examine, where I now work as a researcher, writer and safety team lead. And in fact, in the past few years, my work at Examine has been mainly focusing on building a safety information database for supplements.

4:13Giulia Guerrini: So including information on side effects, interactions, precautions for specific population or conditions and safety during pregnancy and breastfeeding. I was really happy to work together with an amazing team of pharmacists and researchers at the Supplement Navigator, which is the latest tool that we launched. that basically allows healthcare professionals to check which supplements have evidence for a specific condition. And at the same time, they can check if this supplement interact with any of their clients or patient medications. And it was really fun to work on this project, definitely challenging at time, but it was really, really interesting.

4:52Giulia Guerrini: I've learned so much, still learning from it. And I think especially as an ex-community pharmacist, I would have loved to have this because it saves you tons of time, but also it helps you making evidence-based recommendations for supplements and at the same time keeping safety in mind. I can only imagine the amount of work that went in and it's been really impressive to see how that's came along. And for people listening, if you are interested in that, I'll put more information in the description box and certainly worth checking out if you are working in the field. But before we get back to that, Julio, if we start from an overview level, many people have a question of, oh, is this safe or could this be problematic and so on.

5:31But of course, that question of is something safe depends on many things. It's very context dependent. From an overview level, could you maybe talk a bit to this about how different contexts that we place that question in will determine whether something can be deemed safe or not in those specific situations?

5:51Giulia Guerrini: Yeah, absolutely. I think context, especially when we talk about supplement plays a crucial role. Of course it's important to know you know if I'm taking a specific supplement if I have any specific condition medical condition or if I take medications that is super important to keep into account but also factors like when I take the supplement or how is the supplement formulated or how am I taking it in the sense of am I taking it orally am I injecting it am I applying it on the skin inhaling it because the different contexts can really change whether a supplement is safe or unsafe for you. If you agree, I can kind of discuss a bit each of these points individually because I think they deserve a bit of time.

6:36Yeah, fantastic. That'd be excellent.

6:38Giulia Guerrini: Well, timing. So when should you take a supplement definitely matters. And I can think of timing in two different ways. So timing during the day, I'm going to use a very basic example here, but melatonin. Melatonin is a supplement that you normally take to normalize sleep patterns and you take it before bed usually. If I take my melatonin supplement at eight in the morning with my breakfast, I might start getting symptoms of drowsiness, dizziness. So something that was a wanted effect suddenly becomes a side effect because I'm taking it at the wrong time. And also I can think of timing relative to other supplements and also to other medications that I'm taking.

7:22And I think iron is a good fit here

7:25Giulia Guerrini: because iron interacts with so many medications, supplements, and also food, like just to give you a few examples, like grains, seeds, calcium, non-fermented vegetable proteins, polyphenols. So usually we, as an healthcare professional, suggest to take iron supplements either on an empty stomach or two hours before three hours after to avoid any interaction to avoid impacting the absorption of iron and now moving on to formulation I would like to start saying that not every version of the same supplement is the same so when you go to a health food store or you go to a pharmacy you're most likely you're going to find so many different versions of the same supplement but most likely they're not going to be formulated the same so we do need to look into that.

8:15Giulia Guerrini: There are a few aspects that I think should be highlighted. So firstly, the form of the active ingredient. Now, I'm going to be boring and use iron again as an example, but iron you can buy in tablets, capsules, liquids, whatsoever. But when you buy an iron supplement, you're most likely not going to buy elemental iron. You buy an iron salt. And different iron salt provide different amount of elemental iron once they are metabolized. So to give you an example, 300 milligrams of ferrosulfate roughly provides 60 milligram of elemental iron, whereas 300 milligrams of ferrous gluconate roughly provide half of that amount, 35 milligram roughly of elemental iron.

9:00So why does

9:02Giulia Guerrini: this matter in terms of safety? It matters because if I'm trying to correct an iron deficiency anemia and usually ferrosulfate is what they use as a first-line treatment. I noticed a lot when I was working in pharmacy that people struggle to stick to this therapy because ferrosulfate can cause stomach upset, stomach cramps, constipation, a series of side effects. And someone might think, oh, let me just switch to ferrosgluconate. I've heard it's a bit more gentle on the stomach without realizing that actually you're not getting the same amount of iron. So if you're trying to correct a deficiency that is really important obviously.

9:40Giulia Guerrini: If you take iron as a supporting supplement that might not make a huge difference but it can be pretty severe if you are severely deficient. I think another aspect that is worth highlighting is the technology used to make the supplement and the processes that are used. As you know you can find supplements in so many different forms now like tablets and liquids and capsules, aerosols, creams but you can also have supplement formulated with specific technologies that increase the bioavailability of an ingredient and examples include liposomes, macrospheres, micellars and by increasing the bioavailability which is the ability of absorbing the active ingredient you increase the efficacy of a supplement but you also increase the likelihood of side effects and interactions.

10:32Giulia Guerrini: One example is curcumin. Like if you buy curcumin powder from the grocery store you're probably not going to be able to absorb much from it but curcumin supplements are often formulated using these enhancing technologies and by increasing the efficacy and bioavailability of curcumin again you can increase the likelihood of it interacting with medications you're taking or causing more side effects. for a lot of people where there's this gap between the marketing messages they hear and the actual evidence is exactly what you speak to right a company could promote something as this has been shown to be beneficial for x but the actual supplement someone ends up buying could be in a completely different formulation it could have a different dose to what's actually in the study it could have a different route delivery so on and then when it comes to safety there's a number of applications here that if we're determining something is safe or problematic or even going to be efficacious, unless we understand the nuances of all these things, the answer could be very different.

11:34Giulia Guerrini: Absolutely, yeah. It can literally make a difference between a supplement being harmful or beneficial. Another example is immediate release versus slow release or modified release tablets. So immediate release tablets are usually a formulation. They are usually formulation that you take, that metabolize, release the active ingredient right away. Modified release tablets, they usually release the active ingredient within the 24-hour period. So they are quite popular with pharmaceuticals, medication, because usually you need to take fewer tablets in a day. You know, they're more convenient or you might want the active ingredient to be absorbed more gradually.

12:12Giulia Guerrini: But for example, in the case of iron again, modified release tablets are often marketed as more gentle on the stomach or better tolerated. and very often I see people switching from regular tablet to these tablets but is the bioavailability the same? So we have some studies that showed that they are comparable but I found an in vitro study that was quite interesting because it showed that these tablets, some of these tablets, didn't dissolve completely in the 24-hour period. That means that you might not get as much iron as you think you are. So the bottom line is, it's not that these formulation are bad or good is just that if you decide to switch you need to be aware of the fact that you might need to monitor your progresses and you might need to monitor your iron level in this case.

12:59With that in mind so we've mentioned some of that how that context matters when determining the safety specifically for this project that you guys have been working on of determining a safety profile as such for various supplements and how they interact. On one side we could look theoretically at certain mechanisms where there could be an interaction between this particular supplement and some type of biological process in the body, right? On the other end, we could try and look for, well, does consuming or taking a certain supplement have an impact on a specific health outcome that we care about?

13:33And so when we're determining this safety profile, how much do we look at clear actual health outcomes from taking this supplement versus how much do we have to piece together? Theoretically, this could have an impact on this and this within the body.

13:48Giulia Guerrini: I think this is a super interesting question. I'm really glad you asked it because it's such a huge part of what we did when we worked on interactions, when the mechanism is kind of vague or we don't have the data. When we worked on interaction, we didn't just research this, interact with that, and just you deal with it because that would have been pretty useless. we assigned a level of evidence and severity so the level of evidence is pretty self-explanatory so it depends on the number and type of studies that is available and they support that interaction and the level of severity is a bit more complex and to determine that we had to use different criteria which if you want I can discuss and also the pharmacist and research or clinical knowledge So it's a mix of things that we had to keep into account to then arrive at the final level of severity for each of them.

14:38Giulia Guerrini: So one criteria is the type of medication that interacts with your supplement. So is it medication for headache or for organ transplant rejection? So we need to make a difference between these different uses. And also what is the therapeutic window of this medication? And also we need to take into account the mechanism of action of the supplement. So even if we don't have an interaction study where basically a supplement A is administered with drug B, but we know that the supplement is a strong anticoagulant, then we can predict severity based on that. And also we need to take into account the type of interaction, so pharmacokinetic or pharmacodynamic, and sometimes the worst possible outcome.

15:27Giulia Guerrini: So if you want, I can give you an example. One that comes to mind is curcumin and everolimus, which is that curcumin can theoretically decrease the blood levels of everolimus. Everolimus, just to clarify, is a medication used to prevent organ transplant rejection. So even if this is a theoretical interaction, we can't really mess up with it. You can't just be like, oh, let's just try and give this supplement and see what happens. You can't afford that. So the level of severity here is severe. But to go back to your original question, when you have broader interaction studies like between, for example, supplements and enzymes that metabolize groups of medications, then we can also use other criteria to determine the level of severity.

16:12Giulia Guerrini: So some supplements, actually most supplements, can interact with enzyme classes like the cytochrome P450 family, which is a huge family of enzymes that metabolizes over 50 % of the medications we take. And they can often inhibit these enzymes, meaning that they prevent this enzyme from eliminating the drugs. You can end up with too much drug in the blood and therefore risk of toxicity and side effect. Or they can induce these enzymes and therefore you might lose the efficacy of the drug because you have less drug in the blood. So how do we determine the level of severity here? Well, we were not always lucky enough, but if we are lucky enough to have a pharmacokinetic interaction study that basically look at what happens when a supplement is administered with a specific drug that we know is metabolized by that specific enzyme, and we look at how this drug is metabolized on its own and then we look at what happens when we add the supplement, then we can use what is called the no effect boundary, which is basically the interval within which any change in the concentration of the drug, so in this case caused by an interaction with a supplement, is not clinically significant, so it doesn't warrant any action.

17:33Giulia Guerrini: But any change outside this range can warrant action, can be a moderate or severe interaction, depending on how much the drug ratio has been changed. So there is a lot that goes into determining the level of severity, so the outcome of a specific interaction. And sometimes it's not just always possible to derive it from the study or from the research that you have. You need to use a combination of all these different criteria. I like those distinctions that you made because, of course, in lieu of having a perfect set of data that we would like to have and all the studies we would like to have, people in practice still need to make these types of decisions.

18:12And, of course, it makes complete sense that we might have a different evidential standard if it's something that could have very severe consequences or impact a certain medication that's very important versus the other example you gave. if it slightly changes the efficacy of your paracetamol, it's not going to be that big a deal. And so I think that's really useful for us to keep in mind as we go through this. One of the things that you did allude to is that there are a whole host of supplements or ingredients within certain products that could have potential effects. And I think what might be useful is if we take a few examples, but maybe come from what are seemingly innocuous products or supplements that we use routinely or maybe people aren't aware of.

18:57Are there any good examples of these that are quite widely used supplements that in general are assumed to be safe, but in specific circumstances could have potential safety concerns?

19:08Giulia Guerrini: I'd like to start by saying that I think most supplements have some degree of safety issue, whether for the general population or for specific populations. That's what we've observed while working on interactions and safety data for supplements. but supplements as common as calcium might not be safe for people with some risk factors. So calcium is generally quite well tolerated. If you don't have any medical condition, don't take medication and you take a normal level of calcium. Milk alkali syndrome is basically a condition that is quite rare but is characterized by hypercalcemia, so you have too much calcium in the blood.

19:50Giulia Guerrini: And then you have metabolic alkalosis, so your blood pH is higher than it should be, and kidney injury. Although it's quite rare, the risk of getting this condition can increase for people that take high concentration of calcium, specifically calcium carbonate, because it's calcium paired with an alkali. And they also have other risk factors. So for example, people with chronic kidney disease that don't eliminate calcium as efficiently, or people with osteoporosis, They might take higher concentration of calcium and vitamin D. Or even like pregnant women, because often they get gastric reflux and they might need to take anti-acid like calcium carbonate.

20:28Giulia Guerrini: And also paired with potential morning sickness and other factors, you know, they're more at risk. Or people that take medications like theazide diuretics, anti-hypertensive or calcium binders or anti-acid. So something as simple as calcium might not be safe to everyone. and also calcium might not well i'm generalizing here but it should be supplemented cautiously by people with cancer because people with cancer have a higher risk of developing hypercalcemia so high level of calcium in the blood and we've we've seen that specifically with multiple myeloma and advanced stage cancer but it could apply to any type of cancer another example is like a supplement that is generally safe but if you take above a specific dosage it might become unsafe safe that is vitamin C.

21:15Giulia Guerrini: Like if you take, we've seen diarrhea appearing as a side effect above three grams of vitamin C, but you don't see the side effect usually when you take lower than that amount. So a few anecdotes that unfortunately in some situations have been quite tragic with the use of caffeine as a supplement, which generally in many contexts might be thought of as safe. But in some of these situations where people have used caffeine as a powder, as opposed to a pill or a capsule and then unintentionally have overdosed on that amount of caffeine because they don't measure it properly and end up taking gram amounts instead of milligram amounts.

21:49And again, just speaks to your earlier point about the way we take in a certain supplement also factors into the safety decisions of whether it's always good or not.

21:57Giulia Guerrini: Yeah, absolutely. And another example of a formulation that, for example, might have an increased risk of side effects compared to normal preparation is fish oil, ethyl ester preparation. These are like prescription medication usually. So although fish oil, you know, usually it's pretty safe, but these preparation have been linked to an increased risk of atrial fibrillation for people that have cardiovascular disease or are at risk of. And actually the guidelines say for people that have cardiovascular disease or are at risk of, and they develop any symptoms of atrial fibrillation, if they take this preparation, they should stop them.

22:35Giulia Guerrini: So, you know, some formulation might carry different risks than others. So maybe sticking with that, because that's a useful example where maybe people start taking something like a fish oil because they have a certain risk factor or they're trying to attend to a particular aspect of their health. And there was a few specific types of supplements that I wanted to raise with you that are along similar lines. one being berberine, in the sense that there is data behind its ability to have impacts on glycemic management or lowering of blood lipids. And for that reason is of interest to people who maybe have seen that they have elevated blood glucose or hemoglobin A1c or their cholesterol is high, and maybe they're looking for a natural supplement, so to speak, or what they think is a natural alternative to taking a pharmaceutical.

23:22And again, there could be people who are not currently taking medications that want to decide to take that off the back of hearing about some of this stuff, they do see that, oh, there is actual evidence around this. But again, as with anything, as you alluded to earlier, there's always some type of safety concern. And it can also factor in even more so in a situation where someone is taking a medication for a given risk factor. So in the case of berberine, can you maybe outline some of the things that maybe people should know about this, first of all, in that context of general healthy population, and then specifically in a case where they might be someone who's already on something like metformin or a statin because they have glycemic issues or need to lower third blood cholesterol?

24:05Giulia Guerrini: Well, the safety profile of berberine is definitely different, whether you have any medical condition or take medications, or if you are otherwise healthy. For the general population, berberine is pretty safe we noticed we observed some side effects gastrointestinal specifically like stomach pain diarrhea nausea like bloating but nothing beyond that but one thing to keep in mind even if you don't have medical condition or take medication is that berberine like we said before some supplements are not well absorbed like curcumin and berberine also is not very well absorbed you actually absorb roughly five percent of what the total amount you take so it's often formulated with these advanced technologies that increase bioavailability and like we said before with it increases the efficacy but also the the risk of side effects and toxicity so the risk can increase even for the general population if you switch these formulations and like you said berberine is often taken for its potential blood glucose lowering potential so it's not unheard of that someone takes berberine as well as medication to lower blood glucose.

25:14Giulia Guerrini: And we observed that there is an additive effect, but actually this interaction has been deemed minor in this case, because we haven't observed any cases of hypoglycemia. And in some cases, it might even be a combination that your healthcare provider might want to recommend, or maybe a combination that they just want to avoid. That is not for me to decide, obviously. But also berberine can inhibits several different cytochrome P450 enzymes and CYP3A4 is one of those that metabolizes several medications and to keep this case scenario real atorvastatin and simvastatin are metabolized by CYP3A4 so the combination could possibly increase the levels of these medications in the blood, again risk of toxicity and side effects and I think this risk is probably higher for people that are poor Cp3A4 metabolizer.

26:08Giulia Guerrini: So there is also this aspect to take into account. Some people don't express these enzymes the same as other people. So if you express it less than normal, that means that you might not be able to metabolize those drugs as effectively. And also the risk is higher if you also take medications with a narrow therapeutic window. So carbamazepine or cyclosporine, everolimus, fentanyl and so on. And also berberine can have a blood pressure lowering effect. So if you are also taking medications to lower blood pressure, you know, you might want to monitor blood pressure because we want to avoid a case of hypertension where your blood pressure drops too low.

26:48And also we are talking about what berberine can do to medications, but there are also theoretical interactions where medication can affect the level of berberine.

26:56Giulia Guerrini: These are more theoretical and we couldn't really establish the level of severity. but berberine is metabolized by p-glycoprotein which is basically a transporter that helps drugs medications other substances to exit the cells so to be eliminated and some medication can inhibit this transporter and an example is atrovastatin and sinvastatin so they can increase berberine in the blood just to show that you know how complex interaction can be this is not just a one-way street. Sometimes you can have opposite effects, but both of them existing. Another one that I wanted to bring up, again on a similar note, because many people tend to think of it maybe as, oh, it's a natural supplement we can use.

27:43And again, there's been noted some positive benefits of a general class that tend to be referred to as adaptogens. Within that, maybe right now at least, ashwagandha seems to be having its moment as probably the most popular of those. But within these types of products, are there any patterns of interactions that we note with them that could be important to bear in mind as opposed to thinking, this is just great, we can take this supplement and there's kind of no downside?

28:10Giulia Guerrini: Yeah, like I said, no downside is pretty rare for any supplements. But we haven't observed any specific patterns specific to adaptogen supplements. supplements but I think the common denominator and this is probably generally for herbal supplement is the lack of safety data so very often the research is simply not there or you know it's poor quality and this is also why often these supplements should not be taken during pregnancy and breastfeeding and also closely related to that but again this is not just specific to adaptogens probably more general to herbal supplement but it's also the presence of quality concerns.

28:47Giulia Guerrini: So I think supplements like, you know, ashwagandha, like you said, Panax ginseng or adiola, they are more vulnerable to risk factors that can impact the final product, like where this plant is grown, what type of soil is used, do they use pesticides, do they not? Or what is the extraction method? What solvent is used? What is the processing method? All these steps, they define the quality of your final product. There is actually one study that specifically looks at the quality of adaptogens and they found that for ashwagandha and shilajit, there is an increased risk of contamination with heavy metals and also increased risk of adulteration.

29:31Giulia Guerrini: So for instance, Panax ginseng or maca, rhodiola, There are several cases of contamination, adulteration, and also licorice. Licorice is an adaptogen, and the content of glycerin in licorice can change so much, can vary so much between products. So this variability, I think, is definitely something that they have in common. And finally, like I said before, many supplements interact with Cytoclon P450 enzymes, so they can alter the concentration of drugs if you take them with drugs. and adaptogens as well. They can, they can, they interact by inhibiting or inducing several C450 enzyme. One of the next ones I wanted to mention has some people sometimes worry about this and that's around melatonin.

30:22We have quite a significant amount of data on it generally and its use even over longer timeframes as well. But some of the concern some people have is that, well, melatonin is a hormone, therefore they tend to have more concern around taking that versus another supplement that's simply maybe a vitamin, a nutrient. And so when it comes to melatonin, do we know much about the safety profile in a general sense, but even more so in situations where maybe someone is going to be taking a medication?

30:50Giulia Guerrini: Yeah. So melatonin is an interesting one, I think, because, but firstly, it's not equally regulated in all countries. So in the UK, for example, you need a prescription. And in most other countries, even in Italy, where I'm from, you can just buy it over the counter. You don't even need the pharmacist approval and I think the concern with melatonin comes from the fact that it is a naturally produced hormone by the pineal gland so it's a gland that regulates the sleep-wake cycle but obviously supplementation with melatonin means that you take higher dosages compared to what your body normally produce.

31:25Giulia Guerrini: So in terms of side effects you know interaction there is a risk of increased sedation if you take it with medications that increase potentially you know increased sedation drowsiness and dizziness but i think the main concern with melatonin that i hear over and over again is the that people worry that it can disrupt the endocrine system so it might disrupt hormone production and the good news is that currently the clinical evidence for the general population say says that melatonin is fairly safe for the general population so this concern really don't have any evidence packing them up at the moment But there are definitely some populations that should be careful when supplementing with melatonin.

32:08Giulia Guerrini: I'm happy to discuss each of these individually, but people trying to conceive or pregnant women, lactating women, children, they definitely need to be more careful or be monitored or in some cases avoid supplementation. So more than like interaction with other medication, I think these are worth highlighting. One thing I wanted to ask before we do move on, and it relates to something you said a bit earlier, that really there is no supplement as such that has zero risk in all particular contexts. So in addition to some of the ones that we've already discussed, are there any other maybe ingredients that we haven't mentioned so far that come to mind as example of one that people maybe commonly think is simply risk-free because it is naturally occurring or is found in a certain food or plant or so on?

32:56And because of that, it has to be risk-free by nature. Are there any good examples of that come to mind?

33:01Giulia Guerrini: Where do I start? So CBD is one that comes to mind. CBD is still quite popular. It's been definitely a very popular supplement in the past few years. People just think, you know, it's a herbal, it's safe, doesn't have THC inside. So what harm can it do? It just drops. I've heard all of this. But actually CBD can interact with drugs and drug classes. for example it can interact it is an inhibitor of cip3a4 so again it can increase toxicity and side effects of medication metabolized by this enzyme and in some cases it might be something that a combination that you want to have like globazim and anti-epileptic sometimes is given with cbd to treat very rare type of epilepsy but sometimes you know in other cases it might be an unwanted interaction.

33:50Giulia Guerrini: And it can also inhibit CYP2C19. So example of medications here, proton pump inhibitors to regulate some acidity or an antidepressant like citalopram. I'm just trying to give you a real life example of what someone that takes CBD oil is likely to be taken as well. And also it can inhibit CYP1A2, medications like olanzapine or even like theophylline is something for asthma metabolized by this enzyme. I can give you other example like one is garlic. Usually the amount found in food is pretty safe but garlic can still interact with medications especially if you take it as supplements to increase dosages.

34:29Giulia Guerrini: For example it can interact with sequinovur is a medication for is an antiretroviral so it can reduce the blood levels of sequinovur. You can imagine this is pretty serious if that happens. Or is a CIT2E1 inhibitor and these enzymes metabolizes, for example, ethanol, so alcohol. So you might be taking, you know, high concentration garlic supplements and then alcohol without realizing you're slowing down the metabolism of alcohol or even in inhaled anesthetics. So if you take it before surgery and it might cause issues. And related to this, although we don't have many, we don't have interaction studies, there are case reports of garlic taken in really high concentration, so 2 ,400 milligram a day or someone crushing four garlic cloves a day and then they went into surgery and experienced bleeding.

35:23Giulia Guerrini: These are case reports, but still, something as natural as garlic can still have its downsides or licorice or garcinia or even psyllium. Like licorice is such a common supplement, but also it comes in candies or lozenges. And it's not unheard of that someone crushes like one bag a night of licorice and they develop pseudo-hyperaldosteronism, which is basically hyperaldosteronism characterized by high blood pressure, low potassium levels and metabolic alkalosis but your level of aldosterone are actually fine or or low and this is due to the fact that glycerin the active component in licorice can prevent cortisol from being activated so it can cause a mineral corticoid excess so yes something as common as licorice that you can find so really probably a better question that i should have asked is does there exist anything that doesn't have potential implications as opposed to the whole list of things that we could outline here.

36:29Giulia Guerrini: Not that we found out at the moment. One other aspect here is, of course, there's some cases where people may take a specific supplement for a specific indication, but then there's other situations that are relatively common where people are taking multiple supplements at the same time, whether that's an athlete who has multiple supplements that tend to maybe relate to their performance as maybe, as well as some related to their health, or then this whole optimization culture that people are kind of trapped in now where they have this huge list of supplements of all types of things that even potentially could have some benefit.

37:01So if they're in a situation where we're talking about people stacking multiple different products or ingredients together, do we get to a point there where even if nominally we could say for this person in a normal situation, multiple of these ingredients or products are nominally safe? As we start to increase that number that someone is taking, does that kind of change that equation a bit that there could be an accumulation of risk, so to speak?

37:28Giulia Guerrini: That definitely depends on the type of supplements you're taking, obviously. But there is definitely an increased risk of side effects when you start stacking things together. And the consequence of this is not always as obvious as I'm getting more side effects, you know, cumulative side effects, but also sometimes you might reduce the absorption of something that you're taking. like if you're taking iron and calcium they they bind in the gastrointestinal tract you might not realize that you're not absorbing as much iron as you think you are and if you're trying to correct the deficiency not good but also like you said something that i definitely notice also in clinical practice is ingredients overlap so i see people taking so many different supplements one for i don't know multivitamin or a supplement to boost your energy you want to boost your immune system and they don't realize that although some of them of course all of them have some unique ingredients they might contain the same ingredients so they might all have some iron inside so individually they're safe but you might experience you know let's say if you take too much iron from it then you might experience stomach cramps or side effects like constipation because you went beyond the threshold and I think this is where the assumption that supplements are all fine is is wrong because you can go beyond the threshold when you accumulate all the supplements especially let's think about you know fat soluble vitamins they can accumulate so much easier than water soluble and interesting that you ask this question because there were actually and there was actually a BBC article released recently about people stuck in supplements and being surprised that develop all these side effects and toxicity.

39:09Giulia Guerrini: And it was quite interesting to see that it came up on BBC. Because also, I think, stuck in supplements like, I don't know, for example, we talked about an athlete, the risk is not necessarily just taking them together at the same time. Sometimes it's also like cumulative effect throughout the day. So if you think of an athlete or someone taking caffeine as a pre-workout or, and plus at a different point in the day, you take guarana, energy drink and then you might take green tea as a fat burner supplement you might not realize that all these supplements have a similar simulant effect which can you know load up and can add up at the end of the day and i've noticed this so many times with sleeping supplements supplements supplements to promote sleep people don't realize that taking all of these cocktails of supplements together, they can increase the risk of sedation.

40:02Giulia Guerrini: And also the fact that if one supplement has an effect, like a blood pressure lowering effect, and it might not interact with your blood pressure lowering medication because the effect is quite minimal, it can be the case that if you take 10 supplements that have blood pressure lowering effect, then the interaction will become possible and you might experience hypotension like low blood pressure. Or it's also the case that the supplements you're taking interact together. An example is horse chestnuts and ginkgo biloba. They can interact, they compete for the same enzyme. And there was one case report that we observed that we looked into where basically someone experienced kidney injury from this combination.

40:47Giulia Guerrini: And also another point I'd like to make is that some people are more vulnerable than others like people that have chronic conditions or the elderlies children pregnant women their metabolism and physiology may handle ingredients load differently from someone else so I think a message I would like to send is when you choose to stack supplements or to take supplements definitely taking like look if any of these supplements compete for absorption you know if there is an overlapping ingredient so read the label carefully also look at the effects am I taking lots of supplements with the same effect but also practically speaking always mention everything you take to your doctor because there is never someone like one person that oversees all the supplements that people take and even as a pharmacist I noticed that it takes a few tries for people to actually tell you what like the full list of things they take sometimes they don't even mention it because they think, oh, the supplement is fine.

41:48Giulia Guerrini: Let's keep it a secret. With that, one of the big distinctions, I think, that is obvious when we're looking at something like medications versus supplements. And of course, this will depend on the country and the jurisdiction. But in general, the big gap there is in terms of regulation between pharmaceutical products and medicines versus what we see in the supplement industry. And as you mentioned in some cases, it's even much looser in certain countries around regulation. And so because of this, when we're talking about the potential safety of a supplement, as you outlined right at the start, this depends on things like the formulation, the route of delivery, the specific ingredients in that product.

42:29But again, then we have this extra layer of when it comes to someone taking a supplement, we're going on the basis of assuming that what they're actually taking is what it's supposed to be as well. And so then another factor for someone to consider in that decision around safety to take a supplement or not for them is the specific quality of the product that they're buying, the sourcing of it, the reputation of that said product versus other alternatives. What are some of the things that you would like people to know around that when they are taking that step of deciding on a supplement for themselves or whether they should take it, how to factor in things like quality sourcing and how that affects their overall risk.

43:10Giulia Guerrini: Yeah, absolutely. I mean, don't get me started on this. I think we normalize so much the fact that supplements have not regulated that we forget about what that means. And I think the first point you made is that we need to raise awareness that this is an issue. So if you don't mind, I'll give you an example. To put it into context is if you go to a pharmacy and you buy a pack of paracetamol. One tablet has 500 milligram and you can take up to four grams before you get any liver toxicity. But then you find out that one of the tablets actually had three grams and you took five. Like how will that resonate?

43:44That would be crazy, right?

43:46Giulia Guerrini: But that doesn't happen with medications because they need to undergo several safety testing, clinical trials before they're even released into the market, sometimes even a fourth trial phase post-marketing where you basically measure the side effects and you monitor safety but supplements don't and it's completely at the discretion of the manufacturer whether these tests are done or not and I don't want to scare anyone I don't want to say all supplements are bad absolutely not there are many manufacturers that are good they perform their due diligence they even use third-party companies to test their supplements and put your mind at ease but it shouldn't be a Russian roulette you shouldn't just be guessing.

44:28Giulia Guerrini: I think one thing also to remember is the fact that sometimes quality of a supplement is not necessarily affected intentionally. There are several cases of cross-contamination. So contamination from the production site or where you source your ingredient. There is a case of a magnesium supplement manufacturer where they found that some of the supplements were contaminated with anabolic steroids. Imagine an athlete taking magnesium thinking, I'm fine, and actually they don't pass their antidoping test. There are several other cases of adulteration and contamination. So the problem is, here you asked me, like, what should I look at?

45:05Giulia Guerrini: I think you should definitely look at purchasing your supplements from reputable sources and check if your supplement manufacturer has performed any third, any quality testing, has used third party companies. That means that, you know, it's less likely, the result, the outcome is less likely to be biased because these cases are not unheard of and if we have time I can give you several examples of supplements being adulterated with pharmaceuticals and medications that can carry significant health risks. And again this is not to scare people off it's just to highlight the fact that supplements are not regulated and we should definitely push for that.

45:46Giulia Guerrini: Like maca ginseng and yohimbin supplements some of them have been found to be adulterated with medications for erectile dysfunction like Viagra, Sildenafil and Bitter Orange. Some supplements, I'm talking about case studies, were found to be contaminated with synthetic stimulants. Imagine the cardiovascular risk associated with this or even whey protein contaminated with anabolic steroids. There are cases. This doesn't normally, I say normally because it's not impossible, but it doesn't normally happen with pharmaceutical because there is quite a strict protocol before they can enter the market.

46:22Giulia Guerrini: And other cases include, like I mentioned, is St. John's Watch, where they swap plants. Sometimes we read of supplements where they used cheaper species of plants, but obviously these plants, they have different chemical composition, different effects, different safety profile, or sometimes they contain food dyes that basically trick these food dyes. sometimes they're used to trick quality tests into reading higher concentrations of the active ingredients when you actually didn't add as much. It's crazy. Or CBD supplements containing traces of THC. But one that stuck with me is definitely melatonin because there is one study, a Canadian study, where out of 31 supplements, only nine contained within 10 % of the amount stated on the label and the others contain from 83 % less to 478 % more.

47:19Giulia Guerrini: Now imagine the difference in the risk profile and also efficacy of a supplement. It's crazy to me that this can happen and people are really unaware of it, that there is no way for the consumer to be 100 % sure. It really does show how we've normalized this lack of regulation and it's just kind of thing, well, that's the way it is and we can try and do things to navigate around it but in many cases it's very difficult so julia before we finish one final thing if we have time that i'd love to ask you about is in your perspective based on the data you've reviewed and going through these potential interactions and looking at all these different types of ingredients and supplement classes and so on was there any that stick with you as a good example where you would like to see maybe a bit more awareness or even regulatory scrutiny around that you think would be something people should pay more attention to?

48:16Giulia Guerrini: Well, I think there are definitely some supplements that maybe deserve a better regulatory scrutiny. I can think of proprietary blends, for example, pre-workout supplements that more often than not they contain, well, we don't really know what they contain and the amount of ingredients or very popular supplements like sexually enhancing supplements or supplements for weight loss. In general, I don't want to disappoint, but I don't have any specific exclusive example of something that I think should be regulated more than others. One example though of a supplement that has some safety concern, I think, but we don't have human data, enough human data that looked into it is curcumin.

49:00Giulia Guerrini: Curcumin has been associated with several liver toxicity cases and randomized control trial that found that it can alter like vary the levels of some enzymatic like some enzymes but we don't have a lot of research on this which is quite shocking considering how popular curcumin is as a supplement and I think I hope I'm not deviating from your question too much but I think this brings me to my next point which is the lack of safety data around supplements I know we talked about quality but the fact that also something that people don't often don't think of but we definitely observed in our work on interaction is that studies on safety or studies that include safety information are not always powered to look into safety so safety is not always the main outcome so safety is sometimes you know mentioned in passing like side effects and that means that the methodology used might not be rigorous enough to you know detect severe even rare but potentially severe side effects and and there are a series of issues that that comes with like blinding can be inadequate or randomization might not be good enough small sample sizes or baseline data often missing so it's also the case that you know we might if the if the study is not powered for safety then we might detect side effects that are not actually related to the supplements it's not only the opposite and or follow-up period that are not long enough so we might not be able to detect long-term effect of a supplement and also the thing that probably annoyed me the most the fact that sometimes safety for lots of these supplements, like side effects, is mentioned in a table as a list of side effects.

50:51Giulia Guerrini: But what is depression for you might not be depression for me. So, you know, if the study is not powerful, that is hard to standardize all these side effects and actually make a reliable conclusion. That's such a great point that oftentimes people might even do this, that they point to certain studies and say, well, look, there isn't really much concern around this supplement for those reasons. But what they're pointing out is literally just a list of noted side effects in some of those participants, which, as you outlined, has no comparison to actually doing a trial to specifically detect safety data around the supplement.

51:26It's not powered for that. It's not set up to in its design to actually determine that. And really, it's just noting we observe these certain side effects in these people, but doesn't really give us anything in terms of an actual safety profile. So lots to be done and hopefully that can be improved going forward, but we will see with that before I get to the very final question, Julia, maybe to go back to what we started at the very start of the podcast for people listening who are really interested in this stuff. Maybe they are working as practitioners in this space or are generally just interested in this topic around these interactions.

52:01Can you maybe mention again, what you guys at examine have been doing, what exactly that you've put together that may be useful for those and anything else that you might want to mention to them that might be worth checking out?

52:14Giulia Guerrini: Yeah, absolutely. I think the idea of building a supplement navigator came from the fact that healthcare professional, everyone is super busy. And when you have a patient or a client in front of you, you really don't have time to read a thousand articles or to spend the hours that we spend in researching and all these interactions and safety issues. And the Supplement Navigator is the latest tool that we launched at Examine that basically allows you as a healthcare professional or an individual, of course, anyone can use it, to search which supplement can be used for a specific condition. So which supplements have good evidence for a specific condition.

52:55Giulia Guerrini: And since we want you to save time we wanted everything to be in the same tool so while you check that in the same tool you can also check for interactions with your client's medication so you can like even copy paste the entire list of medication add them in bulk and even add some more supplements like maybe your client or patient is already taking and check for interactions and see if there is any issue with your current patient's regimen or if a supplement that you thought I might recommend these supplements but actually it does interact with that medication so I might recommend a different option.

53:32Giulia Guerrini: So we built this tool to make essentially to make healthcare professionals life easier and to allow them to make evidence-based recommendation but also like I said at the beginning to keep safety into account always because that is absolutely crucial. Fantastic and for anyone interested in learning a bit more about that, I'll put some information in the description box where you're currently listening or over on the episode page so you can go and learn more about that if that's of interest. With that, Julia, we get to the very final question that I always end the podcast on, and this can be to do with anything completely outside of what we've even discussed today.

54:07So if you could advise people to do one thing each day that might have a positive impact on any area of their life, what might that one thing be?

54:17Giulia Guerrini: Oh, that's a really tough question. Maybe I should think about it and answer that for myself. Do you know what? Because I personally, this is my personal preference, I don't take supplements, which is a big disclosure considering my work. I would say for me, the biggest thing is keep a healthy and balanced diet every day and exercise. like that that for me is what keeps me sane keeps me going and hopefully keeps me healthy fantastic julia thank you so much for taking the time out to come and talk about this stuff with me for all the excellent information that you've given here it's been a real pleasure and i think people are going to learn a lot from the work you put out so thank you so much for doing this no thank you it was really really fun to be on this podcast i really hope people can take something home from this and I hope I help people in general understand why they should keep safety into account.

55:10Giulia Guerrini: And like we said before regarding the supplement navigator, if you want to try it, there is a free trial. Just give it a go. If you like it, good. If you don't like it, please send some feedback. We love feedback.

55:34Thanks for listening into this episode of Sigmund Nutrition Radio. If you're interested in some of the things that we talked about today, and in particular when Julia mentioned the examines Supplement Navigator that's now available on their clinician edition service for health and nutrition professionals, then more of the information is linked up in the description box where you're currently listening. there's also a free trial that you can get to see if it's something that's of utility to you and basically as you'll see at that link you can put in a certain health condition a health goal or supplement and then cross-reference that with certain medications or other supplements that someone might be taking and from there you get a list of not only the safety and the interactions between those but the level of evidence for each of those as well and you can use that to make decisions around that for a particular individual.

56:24So you can put in everything they're potentially taking and it will cross-reference all those. It'll also highlight anything that could be of a safety concern. It also allows you to then generate PDF documents or potential protocols directly for those, etc. So all of that is explained at the links in the description box there. So if you are a professional working with clients or patients where there could be potential issues around use of supplements and or medications, this might be a useful tool. So give that a check. That's linked in the description box where you are currently listening right now.

56:57Or if you go over to sigmanutrition.com and you just navigate to the episode page for this episode, episode 613, then you will be able to find more information there and it might be of utility. So that is it. Thank you so much for listening into the episode. Hopefully you join me again for next week's episode. And in the meantime, take care.