An audio version of this interview can be found on the Kratom Science Podcast #40
Kratom Science: How did you become involved with studying kratom?
Oliver Grundmann: It’s an interesting way, how I got involved with kratom. In 2015 one of my Masters students who works in the forensic field with a forensic toxicology lab down in South Florida submitted a paper as part of one of the courses he was taking with me. He mentioned kratom back then in his paper because it was involved in a fatal car accident of a relatively young person. That’s how I first heard about kratom. From there it just developed into kind of an interest of mine. We wrote the first review that was published in the International Journal of Legal Medicine together with another student who also was interest in kratom (Warner, 2016). From there, I became interested from the perspective of who is actually taking kratom in the United States, because we didn’t really know and understand, well, who is the consumer? Who is using kratom for what reasons? That led me to come up with a survey that garnered a lot of interest and yielded a lot of good result (Grundmann, 2017).
What did you learn from that survey about who uses kratom and why they use it?
There are certain limitations to anonymous self-reporting of health and in general drug use or substance use. If we open up a little more about ourselves, there tends to be slightly biased reporting. Nonetheless, I think the data overall represented quite well the current snapshot of users. We categorized intentionally for users of kratom. One was for those who used kratom for an illicit drug use, for self-treatment of illicit drug use in regards to preventing withdrawal symptoms, or the treatment of withdrawal symptoms related to illicit drug use – if that’s an opioid, if that’s a stimulant, if that’s anything else, a benzodiazepine, a barbiturate. Then we have the second category, if somebody was using a prescription drug, or misusing it or abusing it. We looked at if somebody had withdrawal symptoms or trying to basically substitute kratom for that prescription drug. Then we had a third category, if somebody self-treated acute or chronic pain and used kratom to do so. Or if somebody, that was the last category, was using kratom for a mental or emotional condition such as depression, anxiety, post-traumatic stress disorder, or even something like ADHD, attention deficit hyperactivity disorders. So those were the four broad categories which we were inquiring about.
This is from another survey analysis you contributed to (Bath, 2020): “Those taking kratom for an illicit drug dependency reported the best overall health with 74.9% reporting good or very good health.” Does this suggest kratom might be a harm reduction tool?
This has been proposed not only by our findings but by other smaller surveys, or even just case reports. So Kirsten Smith who has done that as part of her doctoral studies, and also where she’s working for NIDA in her role as a post-doctoral fellow, has done some investigations. It’s interesting to see how people do not prefer to take kratom as an agent to get high. Basically to say, I don’t currently have access to heroin, or to hydrocodone, or another drug that one used to get high on. But rather to use [kratom] as a mitigation tool, as a harm reduction tool, as a way to get off of a drug or to prevent withdrawal symptoms. Similar to what we use in harm reduction therapy or in long-term treatment of opioid substance use disorders. Kratom may be similar to this. Now, we haven’t conducted any clinical trials because that faces hurdles by the regulatory agencies, particularly FDA. We can’t tell how effective it would be compared to buprenorphine or methadone, but there seems to be some indication that it helps a certain group of people, at least, to overcome some of the withdrawal symptoms and to help them actually to get off of some of the opioids that they had been previously using. And not only opioids, but also some other stimulant drugs such as methamphetamine, for example.
There’s a study you contributed to called “The Potential for Kratom as an Antidepressant and Antipsychotic” (Johnson, 2020). Kratom acts on opioid receptors but it appears to act on other brain receptors, and it involves dopamine, serotonin, etc. What did you find in that study that found that kratom may be an alternative to anti-depressants and anti-psychotics?
Whenever we conduct surveys it’s hard to distinguish exactly what the mechanism of action is. So we basically just ask folks, what benefits did you see with the use? In this particular survey we also asked what potential detriments or what potential adverse effects did you experience with the use of kratom? We cannot necessarily narrow it down to what particular receptors or neurotransmitters were involved, but we can link the effects, both the beneficial and some of the adverse effects, to either associate them with animal studies that have been conducted, both with kratom and with the isolated agents mitragynine and 7-hydroxymitragynine, or we can by extension say, if kratom even taken in higher doses does not lead to a particular set of adverse effects or beneficial effects as do classical opioids (being heroin, oxycodone, hydrocodone, morphine) that there is something that is different in kratom that distinguishes it from the classical opioids in its mechanism of action. But we can’t narrow it down to a particular receptor system or neurotransmitter.
Do the animal studies show us anything about how that works?
Yes there has been animal studies that have been conducted. As you indicated in your Journal Club review of that review that we published of the potential use of kratom and its active ingredients, there’s more to it than just its opioid effects. “More to it” means that some animal studies have investigated not only its effects on opioid receptors but also its effects on other systems and neurotransmitters. You already mentioned dopamine. There is some activity at adrenergic receptors that have been studied for mitragynine itself. At the moment, much focus is being placed on mitragynine and 7-hydroxymitragynine as the active ingredients in kratom. But kratom overall when we look at the whole leaf, the powdered leaf which is primarily being consumed, there are hundreds of different compounds in it. Not only the alkaloids, but also a range of other compounds that are not alkaloids. We know from the literature that some of these other non-alkaloid compounds may contribute to the full spectrum of effects that kratom may exert. We haven’t yet explored many of these compounds and their potential contribution to the effects that kratom shows on the user.
Have you found much recreational use of kratom anywhere? I think in Southeast Asia there’s a certain cocktail that’s used recreationally. Have you seen in your surveys use that would be considered “recreational”, whatever that means?
So kratom by itself when we look at the leaf, the powdered leaf, and I intentionally don’t want to use the word “extract”, because “extract” implies that you use basically a solvent to extract certain compounds to enrich certain substances from the leaf and get rid of certain other compounds… that is often done for herbal supplements. We often have extracts to enrich certain compounds because they are considered the active principles. We see that for St. John’s Wort for example. We see that for passion flower extracts because we often use something like alcohol, or something like it, to enrich these compounds, which we don’t see in kratom at the moment. We have specialized extracts that are being sold, either in liquid or in a powdered form, but primarily what we see still being used is basically the ground-up leaf. It’s dried, it’s ground up into a powder, and people are ingesting it in various doses. What we do not see is somebody tries to inject the powder, that somebody tries to smoke the leaf. Sometimes you can just buy loose leaf material that is almost like a tea. So that indicates, from a perspective of somebody who is concerned about an addiction, that there is not a drive to really increase the delivery, get it into the central nervous system or into the bloodstream much faster, basically bypassing the oral route of administration. When you talk about ingesting it, it goes through the stomach, it has to go through the intestine, from there it has to first go through the liver, before it actually goes into the bloodstream. That has shown to be a very inefficient way to deliver mitragynine, for example. So there isn’t much that gets into the bloodstream that way. About 3% of the mitragynine that’s present in the powder actually gets into the bloodstream. If folks were really interested in using or abusing it for recreational purposes to get high, they would try to find ways to circumvent the liver, circumvent the oral route, smoke it, find other ways to get the mitragynine into the central nervous system. We don’t see that happening.
That gets me into the toxicity of kratom. There was a report done by Eggleston (2019) called “Kratom Use and Toxicity in the United States”. He used kratom exposures reported to the National Poison Data System and also county medical examiners’ office records. You wrote along with a few others a critique of that. Why do you think this report needed a critique? You have a background in forensics so I was interested in your opinion in particular about this.
What the FDA and other agencies is tracking is the severe effects requiring hospital admissions and also the deaths associated with kratom exposures. I’ve had ongoing discussion with folks involved in the sphere of conducting research on kratom. When you look closer at these cases being labelled as being associated with kratom, what often emerges as a theme is, these are not kratom-only exposures. They are polydrug exposures, meaning more than just kratom is involved. It might be alcohol. It might be benzodiazepines, it might be another opioid that is involved. I think we can all agree that kratom is not innocuous. It’s not to be taken like chocolate. It’s not like gummy bears. It is definitely something that has pharmacological effects, and it should be treated as such. So somebody who takes kratom should take it responsibly for themselves and especially if they are caretakers for others. There is a certain manageable risk associated with taking kratom, especially if somebody has an underlying health disorder and is taking another medication for it. In that regard, I do advocate that somebody who wants to take kratom for the self-treatment of a pre-existing health condition and is already on medication should consult with a healthcare provider, should consult with their physician, or with their pharmacist, or with a nurse practitioner, because there is a potential for drug interactions. The problem we are facing at the moment is that we do not know a lot about kratom, and many healthcare providers are not well educated about kratom. Some treat it just as a supplement and might discourage any and all use of it. To many kratom users, that is just basically a sign that they do not want to disclose its use, understandably so, because there is basically a disinterest with engaging with the patient. If that is not addressed in a reasonable manner, then I understand that patients who are kratom users do not want to disclose that use. There is a stigma associated with it as well. You might be seen as a drug user, basically, because you’re using kratom, which I think is also a very wrong approach. It is being in part perpetuated by the FDA, by regulatory agencies, which doesn’t help either. People who are using kratom for self-treatment of pain are afraid to lose access to kratom, because then they might only have the other option of taking opioids. Either they have developed a dependence on opioids before, and have managed to get rid of that dependence, or they are afraid to develop a dependence in the first place. So I do understand why people are hesitant to disclose their use of kratom, but it is important to consult with a healthcare provider. If you have a healthcare provider who is not open to discussing the use, then I would go to another healthcare provider, until you find somebody that is open to discuss it with you in a meaningful and welcoming manner, because there is a way to integrate kratom into therapy.
When it comes to the Eggleston paper, my discussions that have looked at different cases of kratom – like I said, polydrug use. Attributing causation to the role of kratom in either the severity of the adverse effects, or saying kratom was causatively linked in the deaths of a person, if other compounds were present, cannot be established at this point. Because once you have a benzodiazapene, another opioid present, then we simply cannot reach the conclusion that kratom was the one compound that was causative in the fatality because of the presence of other compounds that could just as likely have contributed to the fatality.
It seems like all the “kratom alone deaths” involved polydrug use. Do we even know the lethal dose of mitragynine in humans? Is there other evidence of kratom-alone toxicity?
So, that’s the problem. I have to admit that for many compounds we do not have a human lethal dose, because obviously it’s unethical to conduct any trials that would establish a lethal dose. What we have are extended reports over years, sometimes over decades that we can say with a degree of certainly that if you reach a certain dose, it is quite likely that you will die from that particular dose or from that particular blood concentration. Now the trouble with kratom – and that was actually the title of a publication from earlier this year by Papsun, et al (2019), is that the range of reported concentrations of mitragynine in blood samples, both involving people who were intoxicated, for example driving under the influence, where mitragynine was found, and also postmortem, so fatalities where mitragynine was determined [to be in the bloodstream], was all over the place. So in some cases it was as low as 50 ng/ml of mitragynine, and in other cases it was as high as over 10,000 ng/ml. So we certainly cannot establish what we call an LD50 – lethal dose where 50% of a population that is exposed to the drug is basically dying from the exposure. We cannot establish that in humans. And interestingly enough, we do not have an LD50 for mitragynine in animals yet. At least not in rodents, which are commonly used to establish an LD50, at least not in acute exposure to mitragynine.
I saw one study (Smith, 2019) where they tried to find the LD50 and it was determined to be something like 550 mg/kg of mitragynine. I tried to convert that into Human Equivalent Dose, and found that in an average batch of kratom, it would be like eating a whole kilo in one sitting. So it doesn’t seem like we have really good information there. When coroners label a death a “kratom-caused death”, what mistakes are they making? Is it because they don’t have any other answers and they don’t know what this kratom is?
That’s a good question. I cannot speak for a coroner or a medical examiner who conducts the autopsy in every single instance. I think sometimes it’s an exclusion diagnosis basically because they cannot find anything else in a drug screen or that everything else seems to be fairly normal, and they cannot find any other indications that could have caused the death, other than the mitragynine. They then conclude that it has to be the mitragynine or the kratom. I wouldn’t necessarily say that is unusual because of the way kratom is currently being viewed, because there are compounds in kratom that can interact with opioid receptors. It may impair your ability to operate a vehicle. So for example, if a death occurs while operating a vehicle, if it’s a fatal accident for example, there could be a reasonable assumption that somebody lose control over the vehicle, and that basically kratom was involved in that. It’s a complicated issue.
I believe it might be the same report your student worked on. It’s a young man in Pennsylvania who died in a car accident. His parents ended up suing a kratom company. There was a journalist Nick Wing who tried to get the toxicology reports from the medical examiner, and it was listed as “acute mitragynine intoxication” as the cause of his death. I don’t know if you have an opinion about that, but the coroner fought to keep the reports hidden, and it seems like there’s something suspicious going on there. That gets to the question of – you said the FDA is presenting hurdles to research. Are those hurdles mainly political, or is it a result of other research that they’re promoting that kind of shows negative reports that the FDA wants to promote?
The intentions of a regulatory agency sometimes remain a little opaque, I would say. The FDA has been very vocal about the opposition to kratom for years now. They haven’t reversed their course even with transition to a new commissioner when Dr. Gottlieb stepped down. The DEA has not followed through with an 8-factor analysis recommendation or in the conclusions that the FDA reached based on their 8-factor analysis, which is still not completely publicly known, what the actual 8-factor analysis is. Not all pages are publicly available. When it comes to regulatory agencies in general, I think their mission to protect public health is in the forefront. I can understand, in part, that when they hear the word “opioid receptor” that some red lights go on for them. Especially if it’s potentially touted as a dietary supplement, that they see another potential source of an opioid emerging in the midst of an opioid pandemic. Not using the word “opioid pandemic” lightly here, but we really have a severe opioid substance use disorder problem in the United States, and its ravaging through communities, has done so for years. The reaction on the state and federal level has been a little sluggish, to say the least. So the FDA may have overreacted, and they stay their course because they cannot necessarily try to provide a middle ground for kratom in terms of scheduling action. It’s a dietary or herbal supplement, so the only thing that they can really do is to basically say, we recommend placing it on Schedule I for now. What has been done by states, taking their own actions, is basically to say we want products on the market that consumers can rely on in terms of quality. We want them labelled accurately so that consumers know what they get when they buy it, and there needs to be a limitation on how much mitragynine and thereby also 7-hydroxymitragynine is contained in these products, and thereby not adulterated. I think that is essential. I would potentially go a step further and say that you need to talk to a healthcare provider before you can access these products because it is important that you are aware of potential drug interactions that are associated with the use of kratom. That would be my thing that I would potentially add to it. But I can understand the FDA being concerned about it. But when you look at what the science has been reporting, and all the facts that have been emerging over the years, it is clear that kratom, mitragynine, 7-hydroxymitragynine so far are not the same. You cannot categorize mitragynine as being the same as a classical opioid receptor full agonist like fentanyl, like heroin, like morphine. I think that is something that the FDA continues to ignore in their considerations.
Why is it difficult for scientists to study a controlled substance?
I like to compare it, as I’m sure others have done before me, to the whole issue with marijuana research. We still face significant hurdles in obtaining marijuana, or if we look at many of the other psychoactive substances, if we talk about psilocybin, if we talk about MDMA, LSD for research purposes. The hoops and hurdles one has to step over, jump through, in order to get these products for pre-clinical, so animal studies, in vitro studies on cells – even higher, so obviously, if you actually want to study them in humans – is significant. For marijuana, because that’s the closest comparison when we talk about a natural product, when we talk about a plant, we only have one facility in the United States that’s federally approved to grow marijuana, and that’s at the University of Mississippi. The marijuana that is grown there is not close to the quality of commercial marijuana products that are available in Colorado, Washington, or other states that allow medical or recreational marijuana. So what we currently study in the limited clinical trials on marijuana is not up to date of what is available on the market, or what people can actually purchase and use in therapy at the moment. We have a disconnect. If we now schedule kratom, through scheduling mitragynine and 7-hydroxymitrgynine, it would basically set us back to the beginnings of marijuana. It would take us years to get to the point where marijuana is at the moment. I don’t know if states could maintain their independence with their scheduling activities. I don’t know if the federal scheduling activity would initially overrule and put everything back. I don’t know. So you have to jump through all these hurdles to even get to it, and obviously you wouldn’t even have access to the kratom users who are currently using. We wouldn’t be able to actually study how people are using it now, what the behavior is, who’s using it. That’s the other thing, obviously, kratom users would not have access to it any longer, and you’re talking about millions of kratom users in the United States.
You recently did a study on toxic metals and salmonella present in kratom (Prozialeck, 2020). If it was sold on the illegal market, you wouldn’t be able to measure these things. As it is now, you found a lot of toxic levels of metals in kratom available in the Western suburbs of Chicago. We’ve also had kratom contaminated in salmonella. How does this happen?
Regarding the supply chain of products, because kratom is currently not regulated, there’s really no incentive – well I’m not saying no incentive because you could lose your kratom users if you put out a product that is contaminated. But initially, there is obviously a risk to those who are purchasing it and then get sick from it. The FDA regulates food and regulates supplements that are recognized as such to adhere to certain microbial contamination standards. That goes throughout the supply chain. So it starts at the source, and then you go through different steps where you have microbial monitoring up to the end product. That doesn’t happen currently with kratom. If the leaves are not dried properly, mold can grow on them. If they’re in an environment where mold is allowed to grow, if the leaves are kept and dried fully, you get mold growth, you get bacterial growth, and that’s how the spores are then introduced, basically, and that’s when you have contamination with potentially salmonella as well. That can be introduced at various stages. Usually it happens at the drying stage, so relatively early on. There’s no way of telling that unless you actually test the product for microbial contamination.
I’ve also heard that sometimes it’s dried outdoors and animals can walk over it and leave droppings, and it can be contaminated that way. The other was the presence of toxic metals which you actually found in those samples. Do you think it might be from old machines used to grind the kratom into powder? Also, the study mentions that there are metals present in volcanic soil in Indonesia. If the metals are coming from the soil, is there really any way to ensure the safety of kratom from Indonesia?
We were a little bit speculating about where the contamination came from, because we don’t have soil samples to match it. To be honest, we don’t know to what degree that comes from mining run off, for example. Kratom trees are known to grow close to little freshwater streams. So it could be runoff from mining. It could be indeed directly in the soil from volcanic soil. Or it could be from the grinding process. We were speculating there. We would have to go and get soil samples to see if this is from the soil, if it’s introduces from the grinding process, from the manufacturing process, or where it is introduced, to then conclude if there are measures that can be taken to avoid heavy metal introduction during the process. Or if it is directly in the leaves, we need to find other ways to get rid of the heavy metals.
There was another concern about Acinetobacter in the loose leaf material. What is that, and is it dangerous?
Naturally if you have leaf material, or any plant material, you will always find some degree of bacteria and fungi or stuff like that on it because it’s a plant. It’s just natural. When we eat our food, you will not get rid of all of the bacteria that naturally are just present. If you take a carrot out of the earth, you wash it, but that doesn’t get rid of all of the bacteria that are naturally in the soil. So some contamination with bacteria is always present, is always to be expected. When these bacteria reach a certain level, there is a small risk that, for example, an imbalance in the gastrointestinal bacteria may occur. So the risk of Acinetobacter is you might get diarrhea, potentially, for a little while. So that’s for an otherwise healthy person. The risk is a little bit higher for people who are immunocompromised. So for example, somebody who has Crohn’s Disease or something, that has an immunocompromised intestinal barrier, for example, that tend to have intestinal inflammation, that can then lead to a stronger immune response. So that’s when we get into specific populations that might be more vulnerable and might have a flare up of their intestinal condition. Those people in general are more prone to developing a reaction to most ingested food items that cannot be cooked. What I would recommend that if you take kratom, then brew a tea with hot water, because that will eliminate quite a few of these bacteria. So, instead of making it with orange juice for example where you don’t necessarily cook the powder, it’s not heated to higher temperatures make it with hot water first.
Would testing and labeling requirements of companies take care of most of these toxicities or would the tests make kratom far too cost prohibitive?
It would certainly make the products, on average, more expensive. I think it’s something we need to consider in the interests of safety. How much is safety worth to us as the consumer? I would argue that it’s definitely worth paying more. But I’m not a kratom consumer. I have actually never consumed it, so I cannot speak to it. And I also realize that compared to some other products, kratom is actually fairly expensive as it is already. I hope though that the market can find a good balance once it has adjusted to some of these changes, because I think it is important to provide consumers with a product they can trust, that it has the quality, basically that kratom products can be marketed with the same FDA requirements which include quality and labeling as is now being implemented by certain states. It’s not that the FDA can’t implement and oversight kratom products as dietary supplements, if they would allow it to be grandfathered in under the Dietary Supplement Heath and Education Act of 1994.
You worked on a paper called “Public Perceptions Toward Kratom Use in Malaysia” (Singh, 2020). How do public perceptions different in Southeast Asia vs. the West? Does this public perception lead good or bad drug policy in general?
That’s a great question. Kratom has been traditionally used quite frequently and is still quite frequently used in Malaysia, in Southeast Asia, by folks that just basically have a kratom tree in their backyard, and they pick the leaves off and use it either to just chew on a leaf and stay awake, or increase their stamina when they are day laborers, or they buy kratom tea in little bags from a local vendor to self treat primarily pain after a hard day’s work. It is used by more rural inhabitants, not necessarily in large cities. It is seen as a traditional drug that is tolerated there. It is not seen as a bad habit. Certainly nothing like an opioid or like amphetamine, which is a large problem in Malaysia as well as in Thailand. It’s definitely distinct from that because it has such a long use history. The reason that it was banned but is still kind of tolerated, is because it has interfered with the opium business that has grown in Malaysia in the 1960s and 1970s. That kind of led to its ban, but even now that is being reconsidered. At least for medical users, kratom may be made available again, or may be used by folks in Malaysia again, and Thailand as well.
In the West, I think what is really surprising to me is to see that the average kratom user when we look at the demographics is not like an opioid or illicit opioid users, like a heroin or illicit drug users in general, in terms of their age range. They tend to be middle aged. They tend to be employed. They tend to be married. They tend to have a middle class income. They tend to have health insurance. This is not the profile of an illicit drug user that we usually see. So there’s definitely a distinction for kratom users in the United States. It’s primarily still used in the self-treatment of acute and chronic pain and mental and emotional conditions. Its used is not even primarily focused on mitigation strategy. It is used for that purpose – I’m not saying it’s not. But it’s not the primary use. I see it used in a very different manner from a recreational drug in the West.
In the news or when you Google kratom for the first time, kratom seems to be treated as a recreational legal drug like bath salts or spice were a few years ago. Do you think there’s a way to get around that perception? Because that doesn’t seem to reflect the reality of why people are using kratom.
When we look at spice or synthetic cannabinoids, or when we look at the pyrovalerones, the bath salts, I have yet to find somebody who is using those for a medical condition. Granted, I haven’t necessarily looked for them. But I haven’t heard anybody use those to treat a really medical condition. So, no. I don’t think that you can – it is really like apples and oranges. Not even fruit. It’s more like a salad and a candy bar. If you want to treat kratom as a salad and the other one as a candy bar. So, no. I think what we see in media, at least in the click-bait media, they want to jump on a headline and draw folks in because it is sensationalized. We see that in all parts of our daily life. Once you actually question it, when you think critically about it, when you do some research on your own and you look in the scientific literature, you see a distinction. I know that sometimes policy is influenced by public perception, but what I found astonishing about public perception when it comes to kratom, is that I don’t think that it’s a one-sided issue for kratom in the public. I think that people realize that kratom is not like a bath salt, or K2 spice. I think people realize that. I’ve had community engagements where I’m located, where I talk to folks who wanted to know more about it. I’ve had engagements with healthcare professionals who wanted to know more about it. Either they didn’t know before about kratom, or they had heard about it but they didn’t really have an opinion yet. Once we got into the topic, and we had a Q&A going back and forth, it became very obvious that they understood relatively quickly what the applications and what its uses were.
Like I said here, I’m not treating it as an innocuous, completely free of any adverse effects, substance. It’s not. So I tell people what I think about it very openly and let them make their own decisions.
I hope that kratom remains available as a safe and high-quality product. I really encourage anybody who is currently using kratom to seek out vendors that actually label their products accordingly, and ask their vendors to actually label them.
There are a few studies in the works. Most of them are pre-clinical. We don’t have any human studies at the moment. But there is a lot of movement when it comes to clinical studies. We are trying as a community, and that’s the good thing about the kratom research community. We’re not competing with one another. We really are working together. There’s a lot of collaboration going on in trying to find out the pharmacology and the toxicology of kratom to serve consumers and move things forward on the regulatory front.
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