Inteview with Pharmacokineticist and Kratom Researcher Dr. Abhisheak Sharma

For audio of this interview as well as studies cited here see Kratom Science Podcast #45

KratomScience: You have your background in pharmacokinetics. What made you interested in going into that field?

Dr. Abhisheak Sharma: So basically I did my PhD in 2015 and I moved to the States to do my post-doctoral studies with Dr. Bonnie Avery at University of Mississippi. Dr. Bonnie Avery and Dr. Christopher McCurdy are the experts in the kratom research. 

So I started working with Dr. Avery, and I just liked that work, and I’m still pursuing it.

We received lots of kratom samples from the market and we looked for opioids, illicit substances, and cannabinoids. We just wanted to make sure there was nothing bad going on. Then we found out there was 7-hydroxymitragynine. All of this afforded us to study all the kratom alkaloids. Then we got two NIH grants from NIDA. So that’s why all this research is going on.

I think the University of Florida is the one university in the world other than University of Science in Malaysia that’s doing the most of kratom research. You work with Dr McCurdy in the Translational Drug Development Core. Can you talk about that? Is the goal to develop kratom into a pharmaceutical?

So I will tell you, we have the kratom grant, the grants are funded according to Dr. Lance McMahon who is Chair of the Department of Pharmacodynamics and Dr. Christopher McCurdy. So we have a team of chemists, biologists, behavioral pharmacologists, pharmacokineticists, veterinarians as well as clinicians. So from isolating an alkaloid, we have taken it up to [animal] studies. So that’s the capability we have at the University of Florida. We can do a clinical trial if we want to. 

Translational Drug Development Core was established in 2017 when Dr. Avery and Dr. McCurdy moved to University of Florida. An overall objective of this core is to double up molecules. You know, in academic set-ups we have lots of active molecules. But those molecules just get published and never pursued further. So the Translational Development Core was hand designed to do all the pharmacokinetic studies, toxicology studies which are required for IND [Investigational New Drug] submission. And the same way, we are working with kratom alkaloids. So our objective is to generate the data related to kratom alkaloid as well as kratom as a whole, so people can see.

Because if you look in the surroundings there are two kind of personalities out there. One is a clear kratom supporter, and the second ones who are opposing the kratom. But there is nobody who is looking at the science. Is it really effective or not? That’s the question. Is it really toxic? Is it causing dependence? What is happening? What about metabolites? Can it cause any drug-drug interactions? Our one objective is to do with the real science, and then decide what should we do with it. So the Translational Development Core gave us capabilities to do analytical, bioanalytical, and to do pharmacokinetic studies at the University of Florida. 

A study you worked on that came out last year was “Assessing the therapeutic potential and toxicity of Mitragyna speciosa in opioid use disorder” . It said, “Substantially high levels of 7-hydroxymitragynine, an alkaloid with abuse potential, in commercial kratom products may be the cause of the harm that has been associated with kratom use in the United States”. I guess they’re not seeing the harm in Malaysia and Thailand where kratom grows naturally, but it seems there are elevated levels of 7-hydroxymitragynine in the products that get over here. Is that from purposeful adulteration or does that come from what happens in the drying process? 

Mitragynine is a partial biased opioid agonist. But mitragynine does not cause, according to the literature, it doesn’t cause any opioid addiction or withdrawal symptoms, as with morphine dependence. But when you come to 7-hydroxymitragynine, it is more potent than mitragynine. It causes all of those problems, which other opioids can do. So that’s the take. But now the question is do we have a 7-hydroxymitragynine in sufficient amount? 

So we had lots of samples from Malaysia, like fresh kratom samples. So we analyzed those for 11 kratom alkaloids, not just mitragynine and 7-hydroxymitragynine, but also other alkaloids, we have not seen any amount of 7-hydroxymitragynine in any of the fresh kratom products. We received some of the kratom juice which they sell in the Malaysia area. We have not seen 7-hydroxymitragynine there as well. But we are seeing it here.

So now the question is, is it intentional or not intentional? I cannot answer that. I think only certain vendors can answer that. But I can only tell certain things. If you take mitragynine, and you put some kind of oxidizing agent [with it] like hydrogen peroxide… it converts to 7-hydroxymitragynine. So there are multiple ways to make it, but I cannot say that they intentionally or not intentionally [make it]. But if people have higher 7-hydroxy contained in the kratom products, that’s what may cause a problem.

So one more thing I would say, not only is 7-hydroxymitragynine a minor kratom alkaloid, it is also a metabolite of mitragynine. That is also an important thing to understand. And it metabolizes comparatively slowly in humans, but we found… 7-hydroxymitragynine itself metabolizes in humans, converted to mitragynine pseudoindoxyl in human plasma. So that’s another mystery. So according to the available data right now, in animal models we have same problems associated with 7-hydroxymitragynine, but it will be hard to predict in humans, until we have a controlled clinical trial.

That was my next question, about the metabolism. One study that I believe Andrew Kruegel worked on shows that mitragynine metabolizes into 7-hydroxymitragynine, and the 7-hydroxy stayed constant. So my question about that was, does it matter, then, what you start with if the 7-hydroxy stays constant and the mitragynine is going to be metabolized into 7-hydroxymitragynine?

So if you read that study, that study has a drawback. So, you put mitragynine in liver microsomes. You isolate the metabolic enzymes out of the liver microsomes. Our body has two kind of metabolic enzymes. One is called Phase 1 metabolism and the other is called Phase 2 metabolism. So Phase 1 metabolism is a simple chemical reaction like oxidation, reduction, hydrolysis. And Phase 2 metabolism means the body, the liver will add a polar group to the molecule or its metabolite. That’s like glucunoride or certain amino acids. So the study was performed in liver microsomes, and liver microsomes cannot do that Phase 2 reaction. When we look at the structure of the 7-hydoxymitragynine, it has a free hydroxyl group. So it is very prone to glucunoride metabolism. So that study is like half, part of metabolism, because you’re not looking at the full metabolism.

But yes, it is true mitragynine converts to 7-hydroxymitragynine, but 7-hydroxymitragynine also metabolizes further into [mitragynine pseudoindoxyl]. So this is a debatable question and we did certain experiments in hepatocytes like human hepatocytes and dog hepatocytes or rat hepatocytes. We wanted to understand like what is the rate of formation, and then further metabolism…  We are not impressed that much with how much mitragynine is converting to 7 hydroxy, or that the whole therapeutic activity is coming just because of 7-hydroxymitragynine.

Does this lead to adverse drug interactions when kratom or mitragynine can possibly slow the metabolism of other drugs?

When we look at the structure of mitragynine there is a possibility it cam create certain reactive metabolites. There is a possibility, I cannot say for sure. It inhibits certain enzymes. So in the case of mitragynine and another kratom alkaloid, corynantheine, they inhibit CYP2D6. But our body needs a certain concentration to inhibit that.

So there are two or three cases if you look at a clinical study published by a Thai group, “Pharmacokinetics of Mitragynine in Men”. They did a pharmacokinetic study in native kratom users and they analyze the plasma samples for mitragynine. And you look at that data, so the maximum concentration of mitragynine in those healthy volunteers who are taking kratom was around 23 milligrams. So that particular concentration is not sufficient enough to inhibit enzymes.

But if we look at a few of the casualties associated in the United States – so there is a young guy died in Florida and the forensic science found the plasma concentration of the mitragynine was 1800 ng/ml. So that’s the problem. I read in a news report, in that one, a police officer died and they said, okay kratom may be responsible for that, and the plasma concentration of mitragynine was 3500 ng/ml. So now this difference between the Thai study and these two casualties is like 70 to 190 times higher. So you will reach that much concentration, that’s going to create a problem.

So everything, even we drink too much water, that is going to cause a problem. That same rule applies to here. So we have to control what we are taking, and how much should we take? Right? So that’s the concern. Up to a certain concentration, no problem. If you go beyond that concentration, in the long term, it is going to inhibit certain enzymes and if you have taken any other drug along with it, it will stay longer in your body…

I don’t remember if you have seen a news report on kratom in 2019 published in USA Today, with a broad headline written, “Herbal Drug Kratom Linked to Almost 100 Overdose Deaths, CDC States”.  So if you read that, and you read the whole news, and you come down, and the last line written is “In most of the kratom-related deaths, fentanyl was also a cause of death.”

Now as a pharmacokineticist, if I look at what can happen, if I were to take mitragynine with fentanyl, what is going to happen? So according to the publications mitragynine is a PGP integrator. PGP [P-glycoprotein] is a transporter which cleans certain drugs out of our brain. It does the same thing with fentanyl. Right? So if I took fentanyl along with mitragynine, then what is going to happen? My brain is not going to clear that fentanyl. And it will stay there forever, and that’s the problem associated with this thing. So whenever we have been taking some herbs, it’s not always safe, so we always have to think about having drug interactions, and yes, mitragynine is prone to cause herbal drug interactions and we have to take it carefully if we are taking more than one drug.

There was a study about lyophilized kratom tea that came out last year that we talked about on the podcast. It was a study in mice but you calculated for human equivalent dose. A lot of the studies seem to give mice very massive amounts of mitragynine and it shows that they would get damaged. But the amounts are so high, and people don’t take those amounts. And just a broader question – these studies are on animals, so human metabolism is different. So how important it is to do clinical trials on humans, instead of just the animal trials?

I will answer both of your questions. The first question is how do we calculate the mouse equivalent dose from the human dose, right? Can we reach a certain concentration to have that problem? In Malaysia, Thailand? No, never. You will have to eat kilos to achieve goals like that high concentration which I was talking about that are problematic.

But when you come to the United States, look at the kratom products. You can see there are multiple products that are organic extracts. So first thing, we have a leaf, then you boil it, you make a water extract and that’s different thing. But when you boil it with certain solvents, to isolate that alkaloid rich fraction and put it in a capsule. Then you can reach that. If I would take 20 capsules of those, I will reach those very high concentrations which can cause the problem.

So you have to think about it. There is a simple way. So we drink our coffee, right? We boiled it and we drink it. But we don’t take coffee capsules. We can take caffeine but that will have a different effect. The same rule applies here. So you boil your tea. It’s absolutely different than the organic extracts available in the marketplace. Those are very highly – I call those standardized extracts because their content never changes. You analyze those, every time you will get the same mitragynine content. We are even using a few of those extracts to isolate our alkaloids, because it is cheaper to isolate those extracts from the leaf in those capsules. So just think about it, those differences there. You will take one kilo of kratom tea, it will be equal to like 20 capsules. So that’s the problem. So that’s why I’m saying, you can achieve it, but be careful what we are taking.

And your second question was related to the lyophilized kratom tea. Can you translate it from animals to humans? So yes, we have seen absolutely different metabolism between rodents and human systems. But if you want to do a clinical trial, you need one rodent data and one non-rodent data to do a toxicity study. If you can achieve certain exposure in humans, yes, you can do it in control, where everything will be controlled – you will standardize your product, you will have chain of custody, your products have been standardized for everything, like heavy metals, pesticides, toxins… and minor alkaloids as well.

It looked like the lyophilized kratom tea was shown to be advantageous over methadone and other opioids for withdrawal and to get off of opioids. “These results support the anecdotal claim that kratom produces less physical dependence then mu opioid receptor agonists like morphine”. So how was the kratom shown to be advantageous over other methods to treat opioid dependence?

So if you think about what we need for any opioid dependence or opioid withdrawal symptom – like what kind of treatment do we need? So what is in the marketplace, either they will give you a weak opioid agonist so it will occupy the receptor, but it will not activate that particular pathway which is responsible for the problem. The second treatment is you will go through alpha-2 agonist properties. Like, you do clonidine, you do lofexidine. But when you look at the mitragynine molecule and you look at the mitragynine receptor binding data, so first thing, mitragynine is a partial opioid agonist. You give any amount of mitragynine, the maximum effect you can achieve is 40% of any full opioid agonist like Demerol or morphine. So you will never reach that particular high effect. Then, it shows activity through alpha-2 receptors. The same activity you get through clonidine and lofexidine. And then it acts through serotonin receptors as well as dopamine. So the mitragynine itself is a combination of four drugs given for receptor binding and receptor occupancy, which you need to treat opioid withdrawal. And that is the reward that this molecule has. It’s like you’ve mixed four drugs in a treatment therapy to treat opioid dependence and you can get the same thing with one mitragynine molecule. So that is the basic difference.

“Kratom tea may be acting through non opioid means such as the alpha 2 adrenergic receptor”, which you mentioned. The fact that it acts on so many of the receptors, is that why people say kratom helps them abstain from not just opioids but alcohol, cocaine, and methamphetamine?

I’m not an expert in pharmacodynamics but I will tell you one thing. So first of all we always have one problem, that we replace mitragynine with kratom. We have to think about it – kratom is a composition of at least 40 different alkaloids. We have seen when we study an individual alkaloid, we saw it cover almost all of the spectrum. I cannot comment on it – like is it going to treat cocaine or cocaine withdrawal or cocaine dependence, or is it going to treat alcohol dependence? I would only say that most of the alkaloids cover broad CNS [Central Nervous System] targets. It can, theoretically, but we need systemic studies. We should take caution before claiming anything, right? We should do systemic studies in animal models, and if we are seeing any activity, then we can say that. So again I will say mitragynine and 7-hydroxymitragynine are not the only opioid active component.

We have sent a study, you will see it in Journal of Natural Products https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c01163, it should be out in one or two weeks. We studied different alkaloids apart from mitragynine and 7-hydroxymitragynine. You can see that 7-hydroxy is not the only alkaloid showing mu-opioid activity. There are multiple. For example corynoxine is showing 2-digit molecular activity at mu-opioid receptors. But will it survive in vivo? That is the question. A very simple answer: in the test tube, I can see that activity because of compounded binding to the receptor. But can this molecule cross the blood-brain barrier or not? Will it survive in the liver for a long time to cause any pharmacological activity? That is also the important question about it.

Kratom has poly-pharmacology and we have to study it one by one, then only can we say “This can do that” or “This cannot do that.”

I was just looking at the study we did for our last podcast – the investigation of the adrenergic an opioid binding affinities, that showed how various alkaloids blinded to various receptors. I just had a question in general just about the process of a plasma protein binding properties. What do we learn about when we look at plasma protein binding?

Think about one thing. Whenever a compound in circulating through the blood, only the molecule which is traveling freely can bind with the receptor. So in our body, the compounds – we have a large supply of proteins like albumen, globulin – so when a molecule has an affinity to those, it will bind to that molecule. This is a reversible process.. For example my molecule has 99% protein binding. If I have 100 molecules in my system in circulation, 99 will bond to the plasma, and then only one will be available for the metabolism as well as the therapeutic activity. But as soon as this molecule is metabolized by the liver, then that 99 will move in that direction. And then instead of 99% bound, it will be 98.11%, and then 0.99 will come off. Sometimes it will affect the compound’s overall exposure, but this is an important parameter to tell the therapeutic activity.. like how much free concentration do you need to occupy that many receptors? That’s why we need this data.

The other one that we talked about on the podcast was the study of the trees that were in the greenhouse. That that you have down there in Florida and as far as we could tell that was the first study of actual trees that were grown for the purpose of looking at the alkaloids. What part did you do work on in this study?

So my part was to do analysis. So once we have leaf, then Dr. McCurdy’s medicinal chemistry lab will do the extraction of those leaves, and then I will have those extracts, and I quantified all those leaf materials for the kratom alkaloid contents, like mitragynine, speciogynine, speciociliatine, all of those.

It seems like there was not a lot of the alkaloids that are in some of the commercial kratom products. Do you think the young age of the trees accounted for that or were there any other factors?

I will tell you one thing. I have a few samples — yeah this is right. There are anecdotal evidences, like there is a way in Malaysia that they don’t do use a kratom product up to a certain year, and then they start harvesting after a certain time.

But no systemic study has been performed. That might be the reason here but…when we got a few samples from Malaysia and when we saw a few of those kratom products, they didn’t have any mitragynine. So it’s like you have some versus you have none… but both are effective and that’s why I want to say mitragynine is not kratom and kratom is not mitragynine. There are different alkaloids which are also responsible for the activities.

What do you think accounts for the different rates of alkaloids found in some of the native plants? In this study they mentioned in the discussion section that there’s 66% of mitragynine in Thailand and a different percentage in Malaysia and they found some plants in the Philippines that had virtually no mitragynine. What do you think accounts for the way that even the native plants are different?

So they say it’s kind of different phenotypes, like you have cannabis sativa, so you have both marijuana and you have hemp. So one is making THC, the other one is making CBD. The same process is going on. So we know the two part ways and you will see it some time, whenever we publish it. They follow two different pathways. One pathway will go through mitragynine, the other pathway will go through another alkaloid. I just don’t want to disclose it, but yes we know that if you don’t have mitragynine, then what will you have? We know that and we have that information.

This is from a 2018 study “Comparative Pharmacokinetics of Mitragynine After Oral Administration…” Is it because of the metabolism that mitragynine, even alone, works better or has stronger effects orally than intravenously?

There are three ways to take mitragynine. One way, I will take mitragynine only. I will go to the FDA, I will submit an IND, and I will do a clinical trial and I will come up, hey, take mitragynine pills or capsules and it will treat your “XYZ” disease. The second way to take it is you go to the marketplace and you buy kratom capsules which contains concentrated organic extracts. The third way is the Malaysian way where you boil it in the water and you drink the juice. So these are the three ways in which you can take the mitragynine. And fourth, you give an intravenous injection, for the oral bioavailability purposes to calculate which route has maximum exposure in the systemic circulation. So in this study, we gave an equal dose of mitragynine, but one group of rats it was just mitragynine, second group of rats it was mitragynine along with other alkaloid rich fractions, and the third one is mitragynine along with other water soluble extracts. In one study there was only mitragynine, and in another two studies there were other alkaloids as well. So that’s the reason we saw the better exposure when we gave organic extract of lyophilized tea. So there are two possibilities. One possibility – if the other components present in the kratom tea or organic extract have increased the absorption, increased the chain of permeability. Increased the soluability of that compound in the systemic circulation. Or they inhibited the metabolism of mitragynine so that’s why it could survive longer than the mitragynine alone.

The second question you asked, can IV mitragynine be more potent than oral? I don’t think so. Because oral bioavailability of mitragynine is around – we have done multiple studies – it’s ranged from 20% to 40%. It depends on what formulation you gave and what product you are using. So if you give it orally you can get maximum 40% of mitragynine in your systemic circulation, while in IV it will be immediately available. Now the difference is mitragynine metabolizes into 7-hydroxymitragynine … So when you give it orally, there is a vey good chance that you will have better exposure of 7-hydroxymitragynine, than if you give it intravenously. So if you count for the 7-hydroxymitragynine is adding the effect, that is the only argument where we can say that it is more active when we give it orally. But that study doesn’t have any pharmacological activity. It has pharmacokinetics. We are looking at how much mitragynine is systemically available.

This is a 2019 paper, “Quantification of 10 Key Kratom Alkaloids in Leaf Extracts and Commercial Products”. It said, “the amount of mitragynine present in the samples analyzed by previous methods may have overestimated the levels of mitragynine.” What was the previous method of analysis that caused over-estimations of mitragynine and how did the new analysis change that?

So if you open that paper you know you look at the chemical structures. There are ten alkaloidal structures there. And if you look closely at mitrgynine, speciogynine, speciocliatine, and mitraciliatine. By normal eyes you cannot find the difference. You need like really good eyes to find the difference. So these four molecules are diastereomers. So they are absolutely the same in their structure. They are like identical twins. The molecules work the same. The physical chemical properties are the same. But the hydrogen at position 3 is either below the plane or above the plane, and there is a … group at the 20 position which can be below the plane or above the plane. Which makes those four different alkaloids. So if I’m using, for example, quadruple mass spec to analyze my mitragynine and my chromatography is not good enough to separate these four – mitrgynine, speciogynine, speciocliatine, and mitraciliatine, – I will quantify all those as a mitragynine. And that’s the problem that occurred earlier. So people have quantified total mitragynine contents and that was not only mitragynine, it was also having speciogynine, speciocliatine, and mitraciliatine. Because those are identical structures, they’re diastereomers. If you look at the paper, you have to look at it very carefully. They are the same molecule, and the same fragment…there is no difference in all four. You have to use a better chromatography to separate these four.

Did that have any effect on the toxicity studies and autopsies of people who had mitragynine in their blood?

Yes. There is a possibility in many of the studies. Because there is no way, when you look at the chromatograms in different reports, you will see only one peak. This is only possible when I’m taking mitragynine only. But if I’m taking a kratom product, then I should have all four diastereomers in my system. If I am not seeing four peaks in that chromatogram, all four quantify as mitragynine.

“Due to the great variation in the range of alkaloid content between kratom samples and commercial products, it is necessary to standardize the dose and dosage regimen of kratom products and the developed analytical method can be helpful towards this goal.” This speaks to the issue that a lot of kratom consumers bring up, where they have a certain product that has a certain effect, and when they change products it has a different effect. Do you think its important to pass laws that require lab testing of these products?

Law-wise, I don’t want to comment on the law. I have concern with the import ban. Because of this import ban, kratom is coming into the US market with alleged contaminates. You must agree with that, that makes it a bad thing. If things will come properly, at the checkpoints, kratom has been tested like we see millions of food material and all supplies around the globe, then why can’t we have this product? We do systemic studies,or find those who can do system trials – either allow it, or completely do the full stop thing. I don’t think there’s any way they can do the full stop thing. But I don’t understand the meaning of the import ban. I think that’s the major cause behind all these problems that are happening.

The second question you asked – yes we need standardization of kratom products, like we do with all the herbal supplements. For example, the kratom was grown in Farm XYZ, and the farmer is using pesticides. Now are we testing our kratom supplies here for pesticides? I’m not sure if everybody is doing it. And because some people, their body, may have a capability to metabolize those pesticides, sometimes, but here you may not, because you are eating a different kind of food than other parts of the world is eating. So the capability, the self-expression, the enzyme expression is different. So the capacity of metabolizing certain drugs is also different. It depends on our races, our genetics… the same rule applies here.  If we have control, or if we can grow kratom within the United States with equal potency of kratom alkaloids, that’s the best thing that can happen. In that case, you can control everything. Like in the nicotine industry, the cigarette industry. They control everything. I’m not comparing these two, but I’m just – like the tea industry is the best example. So they are maintaining their quality. You drink it ten years ago, you drink it today, you will get the same flavor and taste because they are maintaining that quality. But this rule doesn’t apply to kratom, and the main reason is the raw material supply. And that’s why we have seen, these minor kratom alkaloids are really very potent. And if their numbers are up or down, you will have different effects. You can have, certainly, different activity, and you may feel different. So that’s why we ask, that we should standardize the kratom product before putting those on market shelves. I cannot comment on it – the rule and regulation part – because there are multiple things associated with it. But yes, this is our moral responsibility, as well as the kratom user should make sure that they’re getting the right product. Because we have seen multiple cases where kratom products have been spiked with synthetic cannabinoids, we have seen all this with tramadol, lots of psychoactive substances. Even in our lab, Dr. Avery’s lab, we saw the product was spiked with hydrocodone. There are multiple things going on. But I’m not seeing this from the last, like, one year. So the kratom market is improving. Vendors are putting a certificate of analysis along with the product on their websites. But there are a few bad guys also there. That’s why standardization is required. Somebody should take that initiative who has the power and capacity to do that.

I just interviewed Dr. Prozialeck who did the study on toxic metals. Have you found toxic metals in any of the kratom samples?

Yeah.

Do you think it’s from the grinding equipment in Indonesia?

I cannot say for sure, but maybe yes. Because sometimes they don’t use food-grade material to do grinding…and their soil is very rich in those kind of things. Multiple reasons can be possible. That’s why I’m saying we need controlled farming. We have to put US standards if we are importing anywhere.

Is that one of the reasons to grow kratom in the greenhouse and study it, so we can come up with standards eventually for a domestic kratom agriculture?

Yeah that’s a huge business. You know better than me. If you have it US grown then you can control it. And you can improve certain things. You can work on certain varieties which are more helpful to kratom users according to their requirements.

Are there going to be further studies from that greenhouse. Are the trees still growing there?

Yes we will have trees and we need those to fulfill our requirements. So, yes, we should continue it unless there’s a funding issue or something else going on. But if I am seeing the next three years or four years, we will have kratom trees and we will do continued research, and we will have farmers as well, if somebody is interested to go in that direction.

We’ll definitely be paying attention to that. As far as human clinical trials, are we close to doing those for kratom?

For clinical trials we have to file IND [Investigational New Drug]. We need GMP [Good Manufacturing Practices] material. We need general custody of the material. This is really hard to find. You can do a clinical trial with mitragynine only – that’s a different thing. But I think kratom and mitragynine are different. So we are actively looking for the suppliers and there are multiple problems associated. We have to answer certain questions even for thinking about it. But we are very much interested to do a controlled clinical trial of kratom products instead of individual alkaloids.

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