HerbalEGram: Volume 16, Issue 4, April 2019

By Connor Yearsley

In December 2018, the US National Institute on Drug Abuse (NIDA) awarded researchers at the University of Florida (UF) College of Pharmacy a $3.5-million, two-year grant to study the therapeutic and abuse potential of alkaloids from the leaves of the Southeast Asian tree kratom (Mitragyna speciosa, Rubiaceae).¹

Kratom has received a significant amount of media coverage in the past several years and was featured in an extensive cover story in HerbalGram issue 112,² with a follow-up article in issue 119.³ The species is a tropical evergreen tree that can grow to 25 meters (82 feet) tall and whose broad leaves produce compounds with opioid-like effects. It is native to Thailand, Malaysia, and other Southeast Asian countries, where leaf preparations have been used in traditional medicine for centuries. Now, an estimated three million to five million Americans use kratom regularly (as powders and teas) for many purposes, including to manage fibromyalgia and other chronic pain conditions (sometimes as an alternative to prescription opioids), recover from alcoholism, and cope with post-traumatic stress disorder (PTSD). There is interest in the potential for new pharmaceutical therapeutics derived from the leaves, either as single compounds or whole-plant preparations, to become safe and effective pain-relievers and opioid recovery aids.^2,3*

Unlike grants in which only the principal investigators control all the studies, the NIDA grant is a cooperative agreement between UF in Gainesville, Florida, and NIDA, which is one of the 27 institutes and centers that form the US National Institutes of Health (NIH). NIDA will therefore coordinate and plan studies with UF researchers led by Christopher McCurdy, PhD, professor of medicinal chemistry in the college; Lance McMahon, PhD, professor and chair of the college’s department of pharmacodynamics; and Bonnie Avery, PhD, clinical professor of pharmaceutics in the college. According to McCurdy, NIDA has set a goal of evaluating 11 kratom alkaloids, although it is possible that more may be isolated and analyzed (oral communication, February 7, 2019).

The research will investigate the alkaloids’ pharmacodynamics, or what the compounds do to the body (e.g., their mechanisms of action), and their pharmacokinetics, or what the body does to the compounds (how they are absorbed, distributed to tissues, metabolized, and ultimately eliminated from the body).

According to McMahon, $3.5 million is “huge” for a preclinical grant that does not involve human subjects, and it will allow the researchers to combine chemistry and pharmacology in a way that has not yet been possible for this plant.

UF researchers will collaborate with Eurofins, an international company based in Brussels, Belgium, with numerous analytical and research laboratories in the United States. Eurofins conducts comprehensive, but preliminary, screening of activity at numerous potential receptor targets and catalytic enzymes. The company will analyze if and how the kratom alkaloids interact with about 100 targets in the central nervous system. This work will be done in isolated tissue, which allows cells to be manipulated more selectively than is possible in whole, live animals. UF researchers will then perform much more in-depth analysis (dose and concentration response functions), as well as whole-animal (rodent) pharmacology, therapeutic, and adverse effect profile testing.

“So, we will get a better picture of what these alkaloids are doing individually, and then we will look at those in terms of their ability to produce pharmacological effects similar to those of opioids,” McCurdy said. 

“We are essentially taking a symphony orchestra and taking out [some] of the individual instruments in that orchestra and looking at what they are responsible for in terms of the overall song,” he continued, adding that the compounds will eventually be analyzed in different combinations. “But that is not the initial goal of the grant.” The initial goals are to isolate the alkaloids in adequate quantities, purify them, and then perform the pharmacodynamic and pharmacokinetic studies.

Most of the past scientific literature has focused on mitragynine, one of kratom’s major alkaloids, and some has focused on 7-hydroxymitragynine, a minor alkaloid, according to McCurdy. “But people have not paid much attention to any of the other alkaloids that are present in the plant,” he said. “For instance, paynantheine and speciogynine are two other…major alkaloids within the plant matrix, and nobody has really investigated those. So, this grant is obviously going to help advance the understanding of [some of] the other compounds in the plant, along with furthering the understanding of mitragynine and 7-hydroxymitragynine.”

McCurdy, who has been studying the plant for about 15 years, also mentioned that most of the focus on the activity of kratom alkaloids has been centered on opioid receptor interactions, but the grant will enable a more complete understanding of the compounds’ other activities. “We really think that these alkaloids are special and different from the traditional opioids…because of their…polypharmacology, meaning that they interact with so many more targets than just opioid receptors,” he said. “And some of those other target action sites may be why they [seem to have a] better safety profile, because some of those targets may be implicated in helping with blockade of respiratory depression, or easing withdrawal symptoms, or improving mood.

“Mitragynine interacts with serotonin receptors, which would be involved with mood improvement, and adrenergic receptors, which would be involved in reducing withdrawal symptoms that we might see from opioids,” McCurdy continued. “It also interacts with opioid receptors, and so, by slightly activating the opioid receptors, it could somewhat attenuate the withdrawal that people go through when they start to move off of prescription opioids.”

McCurdy thinks it is possible that kratom-derived therapeutics, as single medications, could be used for opioid withdrawal or helping people to stay off of traditional opioids (e.g., morphine, hydrocodone, oxycodone), which normally requires multiple medications. “Maybe these alkaloids and their polypharmacologic mechanisms could be very interesting from a single-drug standpoint,” he said. “A single drug that could be used to treat withdrawal symptoms is much more attractive.... You would not have as many drug interactions to worry about.”

Kratom is controversial, partly because of a lack of data about its safety and abuse potential; disagreement about whether it is helping the opioid epidemic or contributing to it; the fact that such a large number of Americans are using it to self-medicate, without guidance from trained medical professionals; and a lack of quality control for many available kratom products.^2,3

Amid the controversy, the NIDA grant was not necessarily unexpected. “I almost want to say I’m not surprised at all,” McMahon said. “In these institutes — and I can tell you this from great experience working with the NIDA — these are first and foremost scientists. They want to objectively understand the chemistry, pharmacology, and human behavioral effects of drugs. They definitely appreciate the fact that their mission is to try to mitigate the public health consequences of drug abuse… but I think that there is a very strong sense among most NIDA program officials that the science is paramount.”

NIDA will use the results of the research in discussions with US Food and Drug Administration (FDA) and US Drug Enforcement Administration (DEA) officials about whether kratom should be placed in a schedule of the Controlled Substances Act, which would likely limit access to the plant. “We won’t have pretty much anything to do with the regulatory aspects or side of it,” McCurdy said. “I don’t think the government is softening on [kratom] at all, but I do think that the government is being wise to listen to the public outcry to get some science-based information behind this. And it is putting its money into that and really trying to collect some of the scientific data to understand if there is abuse potential and if there is medical potential.”

McMahon thinks the “floodgates are going to open. I think you are going to see a pretty major increase in funding of kratom-related research. That is a prediction. We don’t have any hard evidence to support that prediction, but, if…the NIDA wants to generate science, it is going to be increasing funding in this area.”

Although the grant might have significant implications for government opinion and actions regarding kratom, that won’t be a distraction. “As scientists…you try to objectively design experiments that yield objective data that can speak for themselves,” McMahon said. “So, in that sense, there’s no pressure. We will do the best we can, and the experiments will speak for themselves…. Now, we are also human…. We want the best possible outcome for the public, whatever that is.

“And, if it is determined that this is a safe product, or a safe chemical class, and its access is increased, then great,” McMahon added. “If…, from the data we generate, it is determined that [kratom] is more dangerous than we thought, then, obviously, we would hope that, in terms of protecting the public, the appropriate decisions would be made, in terms of access.”

This grant could also help lay the groundwork for future kratom-related developments, possibly including human clinical trials. “The hope is that, if things can move in the proper direction, maybe within three to five years there might be some clinical trials,” McCurdy said. “It all depends on support. It costs a lot of money to do all the studies that are required by the FDA to move to the investigational new drug, or IND, stage.

“We are investigating the options and opportunities to move toward human clinical trials,” McCurdy added. “That would take separate funding mechanisms and separate researchers to come onboard with us, as well. But, those are things that we would like to see, ultimately. I believe the NIDA would like to see that.”

The grant may also have implications for the eventual development of a standardized kratom product, because it is necessary to understand what the individual alkaloids are doing separately and together before an informed decision on standardization can be made. “That is something I have been interested in for a long, long time,” McCurdy said. “Part of the problem with that is there is still no control over the plant material, where it is coming from, and how it is getting into the US marketplace. When we tried to develop kratom for human clinical trials before, we ran into this problem because we don’t know the chain of custody of the biomass. We don’t know if the biomass has been exposed to certain [contaminating] chemicals.

“Even if you do have a reliable source, there is little to nothing known about the monthly changes in the plant chemistry,” McCurdy continued. “You have a wet season and a dry season, essentially, in the tropical monsoonal forest, and the alkaloid contents would probably be very different between the rainy season and the dry season. They could differ between times of day even…. There is a lot of understanding that has to be done on the plant chemistry side before we can even think about making a consistent, standardized [drug] product.”

He said that it would be possible to do a batch harvest at a certain time, standardize the formulation, and do a clinical trial with that formulation, but the FDA will require consistent batch-to-batch comparativeness. “And that is going to be difficult to attain…until we can get a solid and reliable source of biomass. There are potential farmers to work with in Thailand, Malaysia, and other countries. Now that Thailand has decriminalized kratom, it may be a place that we could identify someone to partner with…. But it is a much more complex question than just creating a standardized formulation.”

McMahon thinks it is important to emphasize that the UF researchers appreciate the value of kratom. McCurdy added: “We want to understand the plant. We believe in the plant. We believe that there are potential medical benefits to this plant. But somebody has to do the science to support that. That is what we are here to do.”

David J. Kroll, PhD, a professor of pharmacology at the University of Colorado School of Pharmacy who has reported on kratom for Forbes.com, wrote: “The UF kratom research team wisely tailored its proposed work on kratom to this NIDA research funding mechanism. Some kratom researchers have been waiting for a specific NIH call for applications to investigate kratom’s pharmacology and potential therapeutic uses” (email, March 26, 2019).

“But the UF team proactively responded to an existing NIDA request for applications (RFA) titled, ‘Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose,’” Kroll continued. “Therefore, they framed the cooperative research project to understand the botanical components in the context of preventing and treating opioid use disorders, a medical indication for which some consumers are already using kratom to self-medicate, much to the dismay of the FDA. But I think this approach may keep regulators at bay until the benefits and risks of kratom constituents can be well-understood, as outlined in the UF project.”

* In November 2017, the FDA identified 36 deaths associated with the use of kratom-containing products.⁴ In most, if not all, of these cases, it is difficult or impossible to establish a causal relationship between kratom and the deaths. Many of these cases also involved other substances, but to the FDA this means that potentially lethal interactions could occur when kratom is used with other substances. A 2019 study⁵ (authored by UF researchers) showed that drug-drug interactions mediated by liver enzymes could be problematic for mitragynine, as they can for most drugs. UF researchers have a pending grant proposal that would further investigate potential kratom-drug interactions.

Image captions (top to bottom):

Dried kratom leaves. Image courtesy of the US Drug Enforcement Administration.
University of Florida logo.
Molecular model of mitragynine.
Bonnie Avery, PhD, and Christopher McCurdy, PhD. Image courtesy of the University of Florida.
The team at the University of Florida. From left to right: Jenny Wilkerson, PhD; Francisco Leon, PhD; Bonnie Avery, PhD; Christopher McCurdy, PhD; Lance McMahon, PhD; Jay McLaughlin, PhD; Joanna Peris, PhD; and Takato Hiranita, PhD. Image courtesy of the University of Florida.

References

1. Baltich D. UF College of Pharmacy receives $3.5 million NIDA grant to bolster kratom research. University of Florida Health website. December 10, 2018. Available at: https://ufhealth.org/news/2018/uf-college-pharmacy-receives-35-million-nida-grant-bolster-kratom-research. Accessed March 14, 2019.
2. Yearsley C. Kratom: Medicine or Menace? HerbalGram. 2016;112:46-59. Available at: http://cms.herbalgram.org/herbalgram/issue112/hg112-feat-kratom-med-men.html. Accessed March 14, 2019.
3. Yearsley C. Kratom Crackdown: FDA Intensifies Warnings with Limited, Inconclusive Data. HerbalGram. 2018;119:56-60. Available at: http://cms.herbalgram.org/herbalgram/issue119/hg119-legreg-kratom.html. Accessed March 14, 2019.
4. Statement from FDA Commissioner Scott Gottlieb, MD, on FDA advisory about deadly risks associated with kratom. FDA website. November 14, 2017. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584970.htm. Accessed March 14, 2019.
5. Kamble SH, Sharma A, King TI, León F, McCurdy CR, Avery BA. Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom). Xenobiotica. 2019. doi: 10.1080/00498254.2018.1552819.