Interview with Dr. Lance McMahon, Chair of Dept of Pharmacodynamics, UF College of Pharmacy

Dr. Lance McMahon is Chair of the Department of Pharmacodynamics at University of Florida College of Pharmacy. Dr. McMahon is involved in pioneering kratom research that looks at the various kratom alkaloids, how they function on our brain receptors, and how that creates kratom’s complex effects on our bio. We talk about this research, where it’s been, and where it’s headed. 

An audio version of this interview can be found on Kratom Science Podcast #59.

Kratom Science: You’re a professor and chair of the Department of Pharmacodynamics. 

Dr. Lance McMahon: Pharmacodynamics – it’s a mouthful. It’s really a pharmacology/physiology department that you would traditionally find in a medical school. We have those departments in our medical school in the University of Florida, and therefore our name has to be different, which is why we have that odd name. 

Do you have a layperson’s definition of pharmacodynamics? 

It is the study of how drugs impact biological systems very simply. So, pharmacology is a scientific discipline that is then subdivided into the two sub-disciplines of pharmacodynamics and pharmacokinetics. Pharmacokinetics, we generally understand as, how biological systems transform drugs, metabolize drugs, excrete drugs. Once drugs go into a biological system – human beings for example – those drugs are metabolized, excreted, they’re transformed. Pharmacodynamics is the other sub-discipline, and that’s the opposite relationship. That is how drugs impact biological systems, how they change biological systems. And when you’re thinking about a drug like kratom, you’re thinking about how kratom changes an individual’s mood, their physiology, and all of those therapeutic effects that we think about when we’re talking about kratom. 

Had you researched kratom before Dr. McCurdy and Dr. Avery brought their kratom research from University of Mississippi to Florida? Had there been anything going on prior?

For me, no. I’ll tell you when when Chris McCurdy and Bonnie Avery were at the University of Mississippi, or Ole’ Miss, they were collaborating and part of a team that included Steve Cutler. At the time I was a chair of their pharmaceutical sciences department. This was the School of Pharmacy. At Ole Miss they have a long history and tradition of natural products pharmacy and drug development from natural products. That’s where the cannabis farm that the government managed and funded for for decades existed, and they have a very strong reputation in cannabinoid pharmacology. At this point it must have been 15 years ago, but certainly in the mid-2000s he was looking into this plant. 

As academic researchers we spend our time writing grants to the National Institutes of Health and other funding organizations, but the NIH is the big dog, the biggest government agency that funds biomedical research. At the time, he was trying to develop kratom as a medicine, and in particular medicinal chemists are always interested in creating intellectual property. You can’t easily create intellectual property from a plant that belongs to mother nature, so they try to modify those chemicals. Long story short, he submitted a grant to suggest that synthetic derivatives of the natural product could be good medicines.

I’ll say up front that I think that continues to be an innovative and untapped direction to go. But the funding agency and the reviewers were not interested. So he continued to work on kratom with some clinical investigators, in particular one at Harvard University. His name is Ed Boyer. But then, because of lack of funding, the interest or at least Chris McCurdy’s ability to study kratom sort of waned. 

Then he joined the University of Florida in 2017, at the beginning of the year. I joined later that year into 2017, and with the two of us got together, and really it was a win-win relationship. He had the chemistry background, and pharmacology. I had the whole animal pre-clinical pharmacology. We designed a grant that targeted kratom and its alkaloids for therapeutic development. In particular, the treatment of various opioid use disorders. Part of that success was based upon the government and its increased funding to address the opioid crisis and the opioid epidemic. Now that we have COVID, we hardly remember that, although it’s still a very big problem in the country, and in fact I would argue COVID is probably making it even worse. But because of the additional funding from the government on opioid-crisis-related research, and its interest in kratom, we were able to get that work funded with a very large grant, a couple of grants. 

Those were the NIDA grants, right? 

Correct.

We were happy to see that happen. Is kratom unique in that it hits so many of the brain receptors, or are there other plants that kind of work like this, with so many alkaloids hitting so many different brain receptors?

There are a variety of plants that probably hit numerous brain receptors. Cannabis is probably a bit more selective for the canonical sort of what we call the THC, cannabinoid CB1 receptor. So as a comparator, while cannabis has 200 active chemicals including cannabinoids, the ones that we’re most interested in act fairly selectively at the CB1 receptor, at least with respect to central nervous system activity. That’s of course what we become interested in when we’re changing our mood. Drugs have to get into the brain to do that, for the most part. I guess there’s some exceptions, but that’s a tangent. 

Kratom has at least 40 alkaloids. We know that mitragynine is usually the most abundant, not always, though. We’re finding that depending upon where it grows, the profile of alkaloids that are generated in the plant can vary. But mitragynine, as the most abundant kratom alkaloid, has multiple sites at which it acts in the brain, including opioid receptors, but [also] other receptors. Then there are the other kratom alkaloids present in the plant to a significant degree that also act at additional brain receptors. So it’s heterogeneous, in the sense that not only is its primary alkaloid, mitragynine, hitting numerous different kinds of receptors, but the other alkaloids that are present are hitting, even still further, other receptors. It’s a fascinating plant in that regard, yeah.

There was a study that we looked at on Kratom Science Journal Club with Dr. Jon Cachat. He’s a neuroscientist who’s done a lot of cannabis research. We looked at the aritcle “Pharmacokinetics of Eleven Kratom Alkaloids”. That was interesting because you use commercial products, and lyophilized kratom tea was kind of the traditional kratom tea, and then there was a liquid extract. You looked at 11 alkaloids in blood plasma in rats. What did you learn about how the alkaloids work together in the consumer products versus how they work in isolation? Because a lot of the studies have been mitragynine alone. When I was talking to Dr. Sharma, he emphasized that the main alkaloid doesn’t do the same thing as kratom does as a plant. So what did you learn in that study that stood out about how alkaloids work together?

You make a number of important points in your question, and let me answer the question before I then comment on a few of the components of the question, which is a very good one. Well, bottom line is, kratom is a complex mixture of different drug-like chemicals, and anytime we focus on a single chemical we are simplifying the material in an important way. As scientists, we have to break complex issues down into individual parts. It’s important to understand the individual parts before you can then begin to understand what happens when you put those individual parts together. That’s true for drugs. That’s true for any kind of scientific exercise. But you can’t forget, when we’re doing that, that the individual parts do not represent or reflect the complexity of the whole material. We have a long way to go, a very long way to go, because we have made tremendous strides in the last two to three years understanding the pharmacology of the individual alkaloids. 

That includes both pharmacodynamics and pharmacokinetics. So remember what those definitions are. We talked about the pharmacokinetic paper. So the absorption – when we’re talking about pharmacokinetics, right? You eat a substance, it has to be absorbed through the gastric lining. It goes through intestinal absorption. It enters the bloodstream. There’s first-pass metabolism through the liver. When we’re talking about CNS [central nervous system] substances, eventually it has to get through the blood-brain barrier which is a pretty significant barrier – which is a good thing. We don’t want any old thing that we consume to be able to get into our brain, especially toxins. So that blood-brain barrier is important. So you have to remember all of those things when you know you’re drinking a tea or consuming a liquid extract. Ultimately, the material has to get to the brain. What we learned is that the absorption, the distribution of the material through different tissues, the metabolism and the excretion, so-called ADME – it’s an acronym that we use for Absorption Distribution Metabolism Excretion. The ADME properties can change considerably when you have multiple alkaloids together in the mixture. So you can establish the pharmacokinetics of an individual alkaloid, and that profile changes when you put alkaloids together. So for example, the absorption and the distribution of one alkaloid might be enhanced by the presence of another. That’s at the PK, the pharmacokinetic level. Where we have a lot of work to do, and we’re funded to do this work, is to look at what happens to the biological systems when we combine the different alkaloids, so we understand what the individual alkaloids are doing in terms of changing the biological system, changing our mood, changing our behavior, binding to opioid receptors, binding to other receptors, and then it increases in complexity when we add alkaloids – a second, or a third alkaloid, or a fourth. We’ve learned some, and we have some pretty good predictions about what will happen when the alkaloids are combined, but ultimately you have to do the experiments to confirm or dis-confirm what your predictions are. 

For pharmacokinetics, let’s say we’re talking about a mood alkaloid. Well, there may be another alkaloid in there that further enhances mood, or enhances the effect of that of the first alkaloid. We know from natural products that sometimes there are chemicals in a product that cancel each other out. Without going into detail, there are agonists – those are drugs that can activate receptors,  and then there are antagonists – those are drugs that bind to the same receptor, but they do not activate the receptor, they serve to block the effects of other drugs that activate the receptor. This is true for cannabis and it may also be true for kratom. There may be agonists and antagonists in the same plants. So that depending upon the relative balance of those two things, they may cancel each other out. So it’s a pretty fascinating pharmacological puzzle that we’re studying. 

There was a study, “Investigation of the Adrenergic and Opioid Binding Affinities…” . The one alkaloid corynanthedine, “a minor kratom alkaloid acts as a functional antagonist at the mu opioid receptor and can reverse morphine induced inhibition of twitch contraction and guinea pigs.” 

That’s a fancy description, and Brian you nailed it. The point I just made, that corynanthedine can potentially cancel out the effects of mitragynine, or it’s more active mu metabolites 7-hydroxymitragynine. 

Yeah, I thought that was interesting. So that would be an example of how they work together versus alone. You see a lot of things where 7-hydroxymitragynine is in some ways more potent than morphine on how it acts alone. I remember a sheriff in Mississippi who wanted to outlaw kratom, pointed to that and said, ‘This stuff is worse than morphine.’ On the other side, somebody might find an alkaloid that’s proven to be a cancer fighting agent, and then write a blog post that says ‘kratom cures cancer’, which is seriously irresponsible. 

True, true. You know, 7-hydroxymitragynine is an interesting alkaloid because, in fact, it may not be present in the plant naturally. In reference to the comment about its abuse liability – because you’re right, if you’ll allow me to use a loose term, it’s a “cleaner” opioid-like substance. It does have more pharmacology that resembles a drug, like morphine or oxycodone or even heroin or fentanyl. But then of course the reaction is ‘oh my goodness you have this natural product and you use that product and heroin in the same sentence’. That sets off alarm bells. Well, this particular metabolite may not be present in the plant, and in fact our group in particular, Dr. McCurdy has collaborations with the plant biologists at the Max Planck Institute in Germany, and they’ve yet to find the enzymatic machinery, if you will, that would be necessary to create 7-hydroxymitragynine in the plant. So we believe it’s formed outside the plant, through a variety of means. It’s a labile metabolite, meaning if you expose the plant material to heat, it may generate some 7-hydroxymitragynine. We also know it’s an active metabolite that’s formed in animals – humans, monkeys, dogs, rodents. All of the animals that we have tested in conducting pharmacokinetic studies show that you get conversion of mitragynine into 7-hydroxymitragynine. 

Now, the important caveat is that the amount of 7-hydroxymitragynine that is formed does not seem to be of concern. In other words, you don’t get such a large amount of 7-hydroxymitragynine that’s formed through this metabolism where it would become pharmacologically or biologically or behaviorally relevant. That’s sort of the position that we have right now, the interpretation that we would apply to all of the data and the experiments we’ve conducted. 

I was under the impression that it’s not in the natural leaf, but when it becomes dried, then that does something that adds 7-hydroxymitragynine to the dried product that most people in the United States consume. Is that not true? 

No that’s exactly right. We have not done the work yet to determine what the factors are that lead to its formation in dried material. We think it has something to do with heat. It could be the dehydration process. My background is not in chemistry, so I would not give you an informed response on that. Somehow it gets there, and the amount that is present certainly will vary by product. I think that’s really one of the unknowns, at least as far as we’re concerned, and from our research program we’ve not yet been able to know with any certainty how the 7-hydroxymitragynine winds up getting there.

I’m looking at another study from 2020 about metabolism of 7-hydroxymitragynine and human plasma. It says 7-hydroxymitragynine was the least stable. Does that mean it metabolizes more quickly into this other, more potent opioid, mitragynine-pseudoindoxyl? Does it happen very rapidly after it’s consumed? 

So the timing of its formation is such that, if enough of it were formed you would see effects pretty soon after. When I say “pretty soon after”, the onset to drug effect is usually delayed the most when drugs are consumed orally, just because of the process that is required to get distribution into plasma in blood circulation. That’s an interesting chain of events. We’ve talked about mitragynine in conversion to 7-hydroxymitragynine and I already mentioned that it does not appear that the amount of 7-hydroxymitragynine that’s formed generally speaking would be of concern, or at least enough to be behaviorally relevant. I use terms like “behaviorally relevant”, meaning, is it going to do anything to the person who’s taking it? Are they going to feel any different? Is the behavior going to change? Probably not enough. There’s not enough 7-hydroxymitragynine formed. 

Now, pseudoindoxyl’s interesting because you’re right, that’s the next step in the metabolic chain. You’ve got mitragynine and the 7-hydroxymitragynine in vivo and then 7-hydroxymitragynine is converted into mitragynine pseudoindoxyl. And mitragynine-pseudoindoxyl is even more potent than 7-hydroxymitragynine. You start with mitragynine and then it tries to form into better opioids, if you will, but the amount of those metabolites or those quote unquote better opioids is relatively small. In pharmacology we talk about binding affinity or we talk about potency. We also talk about efficacy. I won’t go into all those those disciplinary definitions, but it’s really the relative amount of drug you need to produce an effect and for pseudoindoxyl, you’re going to need the least amount as compared to 7-hydroxymitragynine and the parent mitragynine, meaning it’s more potent. It’s the most potent of those three by far, so it increases its chances that it might be able to do something if enough of it were formed. But it turns out, just like with 7-hydroxymitragynine in the amount of pseudoindoxyl that’s formed may not be behaviorally relevant. 

Now let me insert one caveat. Much of what I’m describing is based upon what we know from acute single-dose administration. Some of what I’m saying may not generalize or hold up to be true in individuals or situations where the drug is repeated or dosed repeatedly. So if individuals are taking relatively large doses multiple times either daily or across days, there could be a situation where you might get enough formation of these metabolites to where it’s behaviorally relevant. I think is a caveat that we have to consider as scientists, and thinking about kratom and its science is what we’re finding when we do acute dosing, does that generalize to situations that are obviously more relevant in the human situation where people are taking drugs like this daily? 

You can use coffee as an example. I’ve had several cups today, I’ll probably have several more cups, and I’ll continue doing it every day. So, chronic consumption of natural psychoactive natural products is nothing new for kratom, that’s for sure. 

Does that mean if you get a powder that might already have 7-hydroxymitragynine in it, then that’s just generally going to be more potent than traditional use with fresh leaf boiled in the tea? 

I think that’s the concern, going back to the sheriff that you mentioned earlier, that if there’s enough of these metabolites, which we’ve been talking about their formation biologically once mitragynine or kratom is consumed, if they’re already there, in the product, yeah, then I think there is some issue with respect to safety, and the overall experience and the effects it produces. The more of it that’s there already, and how it gets there again is a little bit open to debate. I think the more potent, more active the effect is going to be, the bigger the effect you’ll get when there’s 7-hydroxymitragynine in the product already. 

In that study with the lyophilized tea versus the commercial extract shot, the extract shot clearly took far longer to metabolize than the tea did. Is that just simply due to the abundance of alkaloids in the shot? 

No, I think the key point there is all things being equal and this goes back to our single versus multiple alkaloids. Whether you’re studying the complex mixture or the single alkaloid, the putting the alkaloids together changes their individual pharmacokinetics. So it’s not just a matter of there being more. Instead what’s happening is that their metabolism is delayed simply due to the presence of multiple alkaloids, and that could be for a number of reasons. They compete for the same enzymes that are there to break them down. Obviously if you’ve got Drug “A” being metabolized by a particular enzyme, and Drug “B” also being metabolized by that same enzyme, you can imagine that there’s going to be competition between those two drugs to be metabolized by that single enzyme. You put A and B together, the longer they’re going to stick around. So that’s one simple explanation for why the metabolism is delayed and the presence of the compounds might be extended.

That gets me into the idea of drug-drug interactions with kratom. There’s been a lot of cases of  people that had a lot of fentanyl in their system, but they also had kratom alkaloids. They might have just overdosed from fentanyl. What do we know so far about the dangers of drug-drug interactions with kratom?

Yeah, that’s obviously a hot topic and one that we have to be very careful about in terms of getting an answer. I’d say that with reference specifically to how safe or dangerous is kratom alone… You make a good point. You’ve got a toxic or an adverse effect and somebody who tests positive for kratom, but they also have fentanyl or any number of other drugs. Drug-drug interactions are of concern no matter the drug class. This is true for all kinds of prescribed drugs and illicit drugs and natural products. 

My colleague Dr. Sharma may have talked about this, and he’s really knowledgeable about this. We go back to the blood-brain barrier, for example. It’s known that kratom or mitragynine for example, or alkaloids and kratom, can modify how well fentanyl gets into the brain and how effectively it’s either e-fluxed out of the brain. So yeah, drug-drug interactions are hugely important. 

Dr. Sharma talks about the pharmacokinetic interactions, but remember I talked about pharmacodynamics. What do these drugs do to the biological systems when they’re combined? We don’t know yet. I would predict based upon what we know so far that up to a certain point, kratom may be just fine to consume. I mean, I have to be very careful about what I’m going to say. I don’t want it to be misconstrued, but the dangers of combining kratom with, let’s just say a number of substances, may not be as much of a concern as we think. If there is a concern, it may be at very large doses of kratom that greatly exceeds its basic pharmacology. You’re going to have toxicity with any substance consumed in very large amounts, and also potential toxic interactions of substances that are combined. There are certain drugs that you’re warned to be careful of when combining with grapefruit juice, for goodness sakes, because grapefruit juice is known to interact with a key enzyme that metabolizes a number of therapeutically useful drugs. So I guess I’m giving a very messy answer to a complex question. Ultimately what we want to know as scientists is what is the toxicity and adverse effects of a single substance? That’s something that we ask for in everything that we study. It’s not unique to kratom. We’re not unique to the individual alkaloids, but certainly it’s an it’s a issue that we need to resolve for the individual kratom alkaloids and in particular mitragynine, since that’s the one that’s most abundant in most of the products that are being consumed. 

There’s the other issue of respiratory depression. I still see on the FDA site that they claim that kratom can cause respiratory depression. But we found that the way it acts on the mu opioid receptor, it doesn’t recruit beta arrestin, which the classical opioids do, to cause respiratory depression. In the one study, the adrenergic and opioid binding affinity study, it says “adrenergic antagonists have been shown to be effective in reversing the rigidity in the diaphragm chest wall and upper airway produced by fentanyl which suggests that mitragynine may be useful in curbing fentanyl-related overdoses”. I’m sure there’s probably not been enough research to conclusively say anything, but is that another reason why kratom has shown not to cause respiratory depression?

As everything in kratom tends to be, it’s complicated, and that’s because kratom is a complex plant. Any time you have complexity it’s not easy. You made a couple of important points. Drugs bind to mu opioid receptors and they can either signal through different pathways. The beta arrestin pathway is thought to lead to respiratory depression and yes, it’s been suggested that certain kratom alkaloids don’t signal through that problematic pathway. That is an area that is still hotly debated in opioid pharmacology. That is, the extent to which that beta arrestin versus the other pathways is really a critical determinant of the adverse effect profile. There’s some good science out there and some of it supports that hypothesis, but the data is not unanimous. So you have new opioid receptors, which is a particular kind of receptor where opioids are acting, and then you have this additionally complex, different signaling cascades that can be initiated by that binding. You have other receptor types. You talked about the adrenergic receptors, and we think that mitragynine and perhaps some of the other kratom alkaloids have reasonably high enough affinity or activity at those adrenergic receptors to where it could be biologically relevant. As you pointed out, some of that adrenergic activity may cancel out some of the adverse effects associated with fentanyl use, for example, the wooden chest syndrome. 

So for example, let’s just talk simply about respiratory depression. Now I think it’s important to comment about preclinical work – preclinical meaning work that you do not in humans and using animal models, and when I say animal models, we’re talking about certain things that we measure in rats, sometimes monkeys, sometimes other animal species, non-human species that help us translate into humans. What we’re finding, interestingly, is that the degree of opioid activity that’s produced by mitragynine, and that includes respiratory depression, varies pretty considerably depending upon the type of animal that you’re studying. Even differences between rats and mice. I don’t want to get really geeky about about the preclinical pharmacology, but we’ve done a lot of work in rats, and the work in rats has suggested that respiratory depression is probably not such a problem with mitragynine. For example, if you have an adverse effect from a large dose of mitragynine, it may not be the respiratory depression that’s the issue. There may be some other things going on that we haven’t been able to get our hands on. But then you take the studies into mice, and you begin to see greater respiratory depression. So all that to say, that if you look at all of the data, I think it’s pretty safe to say that the degree of breathing depression produced by mitragynine is not so great as many of the classical opioids, and in fact if mitragynine is an antagonist at opioid receptors, and some people think it may be under some conditions, it may be able to block the effects of the traditional opioids. So at a minimum, I think the respiratory depressant concerns are less with mitragynine – and I’m going a little bit on the limb when I say that, and that would probably contradict what you just noted on the FDA website. But, you know, I try to follow the data. 

Now I say all that and I remind you that I’m talking about preclinical work. Ultimately the human being is our gold standard. Obviously for ethical and humane reasons it’s not easy to do these kinds of studies in humans, but I think it’s going to be important to find out in human beings whether the respiratory depression activity is less of a concern with mutual guidance as with other classical opioids. I think that may turn out to be the case.

There was a recent study on beagles, and even with rhesus monkeys. Is the significance of that to try to find a variation in mammal metabolisms?

There are people who do comparative biology just for the sake of comparative biology, and I know you probably have a pretty general audience. One of the things that I’ll acknowledge up front is I have a very extensive background doing animal research. These can be difficult discussions with respect to animal welfare and animal ethics. Ultimately where the rubber hits the road for me is can we help the human condition? Can we make the human experience a better experience? Can we cure disease? Can we prevent drug overdoses? Can we prevent drug-induced deaths? That’s another philosophical topic probably for another series of podcasts. But when we’re developing drugs, some of us make the hard choice that we’re going to do these experiments on rats and monkeys and sometimes dogs, because they’re highly predictive of human activity. So let me answer your question very simply. I want to choose the model or the species that’s going to give me the best predictive outcome for what will happen in humans. That for me is the key. Ordinarily we think the closer we get to a human in terms of the phylogenetic scale and size, we think of non-human primates as being the most predictive of the human primates, and that’s true a majority of the time. But there can be exceptions depending upon what you’re studying. Interestingly enough for some things, oddly enough a rat or a mouse, may be just as good as a monkey, and maybe depending upon what you’re studying even have better predictive validity for the human biology. So comparative biology is a whole area of study and that is just genuine interest in understanding how how organisms differ from one another, just from a basic research standpoint. But in terms of drug development and understanding the effects of drugs in humans the key is to choose the species and the model that gives you the best translational outcome or the one that is going to be most predictive of what happens in a human being. 

With the opioid crisis, I guess there’s a demand for safer pain meds. We talked about this a little before, but has that been where the recent interest and grant funding has been coming from?

The National Institutes of Health is divided into several sub-institutes and we are funded by the National Institute on Drug Abuse. In addition to just having a fundamental bylaw, understanding of the biology responsible for drugs that humans take repeatedly for whatever reason, if they have, let’s call it habit-forming, and that’s not a very good term, but drugs of abuse or abused drugs – and we have to be careful, that’s a whole other sidebar – drugs don’t have personalities, it’s what the human does with the drug that’s important. So we’re always talking about human behavior. We’re studying the potential of these compounds, in the grants that we have, to serve as medications for opioid use disorder. Clearly, there’s evidence, and Oliver Grundmann, another one of your podcast guests, has a lot of knowledge on trends and patterns of use in human beings, and there’s a clear signal that people who take prescription opioids or illicit opioids will consume kratom as a substitute to help them. So there’s good epidemiological evidence emerging, or at least human-derived data that suggests that our goal of looking at kratom alkaloids as medications for opioid use disorder is supported. 

You mentioned pain, and of course that’s another huge interest of the NIH. That’s actually been sort of put into a different institute in terms of the mission. That’s the National Institute on Neurological Diseases and Stroke, or the NINDS. They’re the ones who are focusing more on the pain side of things in terms of coming up with better pain medications, and certainly kratom has huge potential for that kind of direction. We know that also from the survey data from individuals who will say that kratom has helped to alleviate certain kinds of pain. I will tell you we’re studying that, and the NIH is not our only source of funds. We have funds that we get from the University of Florida. We have contracts and other grant sources that enable us to study pain, and we are doing that, but certainly not as extensively as we are on the opioid use disorder indication. 

I have a question for you about the possible international scheduling recommendation that’s happening with the WHO. Would their decision severely restrict research if they would decide to recommend to the UN an international restriction on kratom?

It could, yeah. It depends upon the sourcing of the material. Much of the material that we study, we derive from the natural product itself. So if we are unable to obtain the kratom plants the mitragyna speciosa trees from other countries, then yes that’s gonna severely restrict research. So the answer is yes. 

Kratom grows in tropical climates and you know that we live in a state that has a sub-tropical climate: Florida. I can tell you that these trees can be grown in the United States. Looking at the geography and the climate of the different contiguous states, and then, oh by the way, Hawaii is in a very tropical climate as well. There are opportunities and I can tell you, you wouldn’t be surprised there are people who are taking advantage of some of the favorable growing areas in our country to produce kratom trees and kratom products. So the WHO can do whatever it wants, but I can tell you that it’s possible to grow kratom in the US, which would alleviate some of that international control issue. 

But then ultimately that takes us to the next step down in terms of what’s happening in our country with the Food and Drug Administration and Drug Enforcement Agency with respect to whether or not they decide to control kratom alkaloids, and by that I mean schedule them into the Controlled Substances Act. 

Yeah and we’ve seen with cannabis, there’s a lot of research that could have been done 80 years ago.

Oh goodness, and hindsight’s 2020, and you look at my CV and I’ve studied, in fact I got my independent research, my strongest boost in studying cannabinoid pharmacology. I can just take the gloves off and say that because of the – they say “follow the science”, that’s a catchword you hear. Our government has not been following the science for decades when it comes to cannabis, and that’s unfortunate because I think there’s a lot we could have learned during that time when, because THC was a the most tightly controlled schedule, Schedule I, tetrahydrocannabinol being one of the critical components of cannabis. Because it was Schedule I, it was very difficult to study. You have to have a specialized kind of license in order to do that, and a lot of scientists are unwilling to take that chance because you’re taking on risk when you get those licenses. The Drug Enforcement Agency and the people that I’ve worked with are very very good people. They, for the most part, want to help research, but they also have laws and rules that they have to follow. So yeah, if we get to the point where we’re outlawing, if you allow me to use that term drugs, that up until now have been widely accessible anywhere, you’re going to really put a major obstacle in the way of progress in research. 

I think as early as four days from now in Thailand, they’ll be able to sell kratom products. I’ve seen in some of the studies that Dr. Singh has done over in Malaysia, the kratom that grows wild in Thailand has a completely different alkaloid profile than in Malaysia, and I imagine the stuff grown in Florida has a completely different alkaloid profile than in the Philippines and what’s most commercially available from Indonesia. Is it tough to draw standard conclusions about how kratom works given the various alkaloid profiles in different regions? Does that affect the research at all?

Oh, absolutely. Standardization has major implications for not only the research side, but the government agencies. The Food and Drug Administration you can sometimes agree with what they do, sometimes not agree with what they do, but they have been hugely helpful in terms of protecting human beings. It came about over a hundred years ago to protect humans from taking things that were mislabeled or poorly regulated, or had things in them that were dangerous. The FDA serves a very important purpose and this is the type of thing that drives the FDA crazy in terms of being able to — because fundamentally, they want to facilitate access. There are some exceptions. We just we just talked about one, but I think in general the government is trying to facilitate access to things that are going to make our lives better, within reason. 

That’s the idea anyway. 

There’s some people who might be listening to this like, “Oh my goodness, Dr. McMahon, you’re so naive, there’s politics in there, let me give you so many examples of things that don’t work and that are broken in the system.” So I get that. 

Going back to not only just creative but natural products, this makes standardization of the content difficult, not only to know with any precision scientifically what the effects are, and what you might expect. That then makes it difficult for the FDA to then approve substances for medical claims or medical indications. 

The FDA does not like complexity. They like individual compounds, or the smallest number of ingredients in a particular drug product. So I count my response in terms of the FDA. Ultimately, you raise an important point, not only with respect to comparing studies – if I’m studying a Thai plant or a Malaysian plant or a Florida plant – ultimately I got to know what the individual alkaloid content is, what’s the amount of the various alkaloids? In science we like to change one thing at a time, right? When you’re doing systematic study and you have five variables, let’s say 10 variables, and you can think of that as different alkaloid contents, we want to hold nine of them constant and change one to see how changing that one impacts it. This gets back to the complexity. The complexity is really an issue with respect to being able to predict you know what one kratom plant’s going to do versus another, and that’s true for cannabis. Different kinds of cannabis, different concentrations of delta-9 tetrahydrocannabinol, or different percentages of cannabidiol. There’s a lot of overlap, actually. I think cannabis provides a useful comparator for thinking about kratom, not so much because of the political part of it, but just in terms of thinking about the individual components and trying to understand what the individual components do and cannabis is not cannabis is not cannabis. There is hemp, right? It’s supposed to not have the good stuff that people like. The reason why most people smoke it is they want the one thing that’s missing in the product. So yes, the answer to your question is it becomes difficult when the products vary by region.

I’ve read about how childhood trauma fundamentally changes brain chemistry. That makes some people more susceptible to addiction. Is there research you do that takes into account individuals who are more prone to addiction?

That is not a variable or a general area that we actively study. You raise an important point. I’’ll rephrase it. You’re talking about environmental influences, environmental factors. What does experience do to the nervous system that may or may not predispose individuals to certain drug effects? It’s not only true for abused drugs, but it’s also true for the medically useful drugs, the antidepressants, the anti-anxiety medications, and other drugs that act in the central nervous system. 

So trauma is one. There are others. There’s biological sex: male versus female. There’s the hormonal environment. There is the nutrition of the animal – whether they have a high fat or a high carb diet, or they’re obese or they’re lean. So there are a lot of environmental influences on the central nervous system, that’s for sure. And in turn, those changes in the nervous system produced by the particular environment can then change drug outcomes or the effects of drugs. 

So you ask an excellent question, and going back to our preclinical models we do the best we can to try to model the human condition and sometimes we’re more successful than not, depending upon what we’re studying. Generally speaking, the more complex the behavior, psychiatric condition, drug abuse, and say trauma – I mean you could you could think about how to model trauma in a non-human experimental animal, and there are ways to do that, but you can imagine that introduces another layer of complexity in terms of developing our models. It’s not only that the drugs are complex and challenging, but increasingly complex human behaviors and human conditions introduce even more difficulty with respect to doing our preclinical work. 

Especially given the last the past year. That’s kind of a random thing that went in there in terms of stress levels on the brain.

Yeah, you get stress levels on the brain, and then just more more basic things. COVID is producing long-haul COVID, or whatever, and maybe some neurological thing. So I get your point. Your point is we’re all stressed out because of the COVID stuff, but I think, add that to the milieu. So I think scientists will will be kept busy for as long as humans are in existence. 

Hopefully longer than sooner. 

Yeah.

How close are researchers to studying human clinical trials? Is there any upcoming studies that you can talk about that we should look out for? 

I can talk about it and I can just sort of generally speak to the issue. I mean there are some proprietary areas where I’m working, but I can speak generally. There are at least one or two groups that are funded to study kratom products in clinical trials, and we’ve had a long discussion, and I’m blanking on the universities that are doing those studies, but there’s at least one or two groups. I know Johns Hopkins, they’ve been very active in the therapeutic use of psychedelics. Johns Hopkins has a great group and they’ve always been on the forefront of human drug abuse related work and therapeutics. 

When we talk about drug abuse – let me stop there and just say that drugs of abuse are a thing. We get into them and they’re hotly debated and contested, because those drugs also have some very significant therapeutic uses in humans if they’re used under the right conditions. That’s what makes them a hot topic. I mean they work and they help if used in moderation, or if used absolutely the way they’re supposed to. But then of course the issue becomes, if they’re used beyond what is indicated or what is prescribed, then they can become problematic.  

The group at Hopkins, I think, is going to be coming up with some human studies of kratom products. Now we [at University of Florida] are also. So in terms of the standardized clinical Phase 1, Phase 2 studies to look at medical indications of, and potential for, either some combination of the alkaloids or individual – like I said the FDA likes simplicity, and sometimes when you go simple it takes away some of the value of the complex natural product, but you’ve got to start somewhere. And so there’s great interest, and we’re currently working with the government, who are contracting out with different organizations to help create a clinical formulation of mitragynine that will then be used, if approval can be gained by the FDA for an investigational new drug, an IND, to do Phase 1 trial safety testing, and then the Phase 2 application. 

As I’ve mentioned, we’re most interested in its ability to facilitate recovery in opioid-using subjects. How far away are we from those? It’s interesting. We just had a meeting a couple hours ago with our group and I’d say we’re still a few years off. It’s a long systematic, sometimes tedious, frustrating [process], but as you can imagine when we’re talking about human safety these things take time. If everything goes according to plan, I would think that this formulation of mitragynine will be available for its first clinical studies within two years, maybe. And then, it may be very soon after that, where it becomes available to other research groups so that they can conduct their own clinical studies. So we’re getting close, but we’re probably pretty far off, and this is true for any natural product. Again, you’re talking about natural products, standardization becomes an issue and it may be some time before we get definitive answers about what the complex natural products benefits, versus its adverse effects might be.

Two years is quick in science years, I think? 

We’ve been working on it now for two, three years, so we are soldiering on and doing our part. We just want the answer. I try to be as unbiased as I can be, and you’ll get as straight an answer from me as you’ll get from anybody. I think we’re close to getting to the point where we can get some good clinical data.

Great. That’s awesome and I’ll be there to try to summarize it on my blog, and hopefully talk to more folks from my favorite College of Pharmacy! 

Absolutely! I’ll give you a shout out to some of the people who’ve not yet been on.

Anybody who wants to talk about kratom science is welcome, and thank you, and everybody. Thank you for your patience in trying to simplify these complex issues as my untrained-in-science brain tries to learn about them. 

Well, that’s our mission as scientists and as employees of the state of Florida and the government. Our goal is to educate people. So, happy to do it

It was a privilege. Thank you so much Dr. McMahon and University of Florida College of Pharmacy.

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Lance McMahon’s bio at UF https://pharmacy.ufl.edu/profile/mcmahon-lance/

Studies referenced in this interview:

• Kamble, S. H., Berthold, E. C., King, T. I., Raju Kanumuri, S. R., Popa, R., Herting, J. R., León, F., Sharma, A., McMahon, L. R., Avery, B. A., & McCurdy, C. R. (2021). Pharmacokinetics of Eleven Kratom Alkaloids Following an Oral Dose of Either Traditional or Commercial Kratom Products in Rats. Journal of natural products, 84(4), 1104–1112. https://doi.org/10.1021/acs.jnatprod.0c01163
• Obeng, S., Kamble, S. H., Reeves, M. E., Restrepo, L. F., Patel, A., Behnke, M., Chear, N. J., Ramanathan, S., Sharma, A., León, F., Hiranita, T., Avery, B. A., McMahon, L. R., & McCurdy, C. R. (2020). Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids. Journal of medicinal chemistry, 63(1), 433–439. https://doi.org/10.1021/acs.jmedchem.9b01465
• Kamble, S. H., León, F., King, T. I., Berthold, E. C., Lopera-Londoño, C., Siva Rama Raju, K., Hampson, A. J., Sharma, A., Avery, B. A., McMahon, L. R., & McCurdy, C. R. (2020). Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy. ACS pharmacology & translational science, 3(6), 1063–1068. https://doi.org/10.1021/acsptsci.0c00075
• Kamble, S. H., Sharma, A., King, T. I., Berthold, E. C., León, F., Meyer, P., Kanumuri, S., McMahon, L. R., McCurdy, C. R., & Avery, B. A. (2020). Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids. Toxicology letters, 319, 148–154. https://doi.org/10.1016/j.toxlet.2019.11.005
• McMahon L. R. (2016). Enhanced discriminative stimulus effects of Δ(9)-THC in the presence of cannabidiol and 8-OH-DPAT in rhesus monkeys. Drug and alcohol dependence, 165, 87–93. https://doi.org/10.1016/j.drugalcdep.2016.05.016
• Maxwell, E. A., King, T. I., Kamble, S. H., Raju, K., Berthold, E. C., León, F., Hampson, A., McMahon, L. R., McCurdy, C. R., & Sharma, A. (2021). Oral Pharmacokinetics in Beagle Dogs of the Mitragynine Metabolite, 7-Hydroxymitragynine. European journal of drug metabolism and pharmacokinetics, 46(3), 459–463. https://doi.org/10.1007/s13318-021-00684-2

Disclaimer: None of the content of this interview nor anywhere on KratomScience.com constitute medical claims or medical advice.