Are all animal studies showing beneficial kratom effects funded by the AKA?

Photo by Giorgio Trovato on Unsplash

At last week’s Judiciary Committee hearing on HB181, the bill to criminalize kratom consumers in Georgia, personal injury lawyer Drew Ashby claimed of kratom science (not us, the entire science of kratom) showing results that may indicate that kratom is beneficial, that “all those are animal studies. Those animal studies have been paid for by the AKA [American Kratom Association]”.

Ashby is representing the parents of a man who died after ingesting multiple kratom extract shots while prescribed antihistamines and an antidepressant.

A similar but broader accusation in an article written by a family member of a man who died after choking on kratom powder claimed, “The American Kratom Association — monopolizes both public discussion and scientific study of the drug”.

For this article I’ll put aside that identifying funding sources isn’t the total “gotcha” that political operatives, conspiracy theorists, and personal injury lawyers seem to think it is. Not all science showing that kratom can have beneficial effects is funded by the AKA. Similarly, not all science showing kratom can have detrimental effects is funded by big pharma or prohibitionists. Following the money can be a starting point to critique the motivations of the highly qualified authors of peer-reviewed articles published in established medical science journals. Dr. Jon Cachat and I, in recording the “Journal Club” series of the Kratom Science Podcast, have often pointed out institutional biases toward the use of unapproved drugs. But a true critique of the science has to follow the science itself. Simply identifying funding sources and jumping to conclusions, as Ashby did at the Georgia hearing, is a disingenuous argument that relies on an audience uneducated in the subject.

Animal studies are only partial indicators of what may happen in human beings, but many of the animal studies in kratom science are showing remarkably similar results not only to hundreds of years of traditional use but to the thousands of reported anecdotes posted to, Reddit, and in multiple peer-reviewed scientific surveys and assessments that are becoming more and more rigorous. From these experiences and the fact that most people do not become addicted to or overdose on most drugs, including heroin, it would be reasonable to assert that most kratom consumers are not lying when they say they have beneficial outcomes.

In putting Ashby’s claim that all “those animal studies have been paid for by the AKA”, let’s review a partial list of kratom animal studies.

We can safely assume that Ashby was talking about animal studies that at least partially conclude that kratom is relatively safe or has potential benefits since that would support the position of a pro-kratom lobbying group, rather than studies showing kratom’s potential toxic or detrimental effects for humans (those exist too). So we’ll look at studies that show potentially beneficial outcomes.

I’ve included all animal studies I could find that were funded either by the AKA or an affiliated organization. I’ve indicated that the conclusions are only “in part”, and I encourage anyone to read the entire study, as the job of a scientist is to find what’s true by testing against a hypothesis, and present as complete a picture as possible. It’s unlike the job of a lawyer or a professional lobbyist: to present the side of the argument of whomever is paying you.

Study: Henningfield et al. 2022
Funding: American Kratom Foundation, an offshoot of the AKA (POINT Ashby!)
Conclusion in part: “mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans”

Study: Macko et al. 1972 (One of the et al.’s here is Jerry Weisbach who led the team that invented life-saving atorvastatin, or Lipitor)
Funding: Smith, Kline, and French (precursor to GlaxoSmithKline)
Conclusion in part: Similar to Henningfield in that extremely high doses of mitragynine were tested on animals, 42 years before the formation of the AKA. “No evidence of toxicity was observed after doses as high as 920 mg/kg in the mouse..In the rat, oral doses as high as 807 mg/kg failed to produce lethality”.

(Macko et al, 1972)

Study: Chen et al 2022
Funding: Two authors are from Wuhu Second Peoples Hospital in China, and one is from Traditional Thai Medical Research and Innovation Center, Prince of Songkla University. “This research received no external funding.”
Conclusion in part: “The findings from this study demonstrated that the administration of MSE [mitragyna speciosa or kratom] attenuated depressive and anxiety-like behaviors induced by fructose/STZ diabetic rats. The alleviative effects of MSE were mediated through the reduction of oxidative stress and neuroinflammation…Overall, the results highlighted the potential biological effects of MSE in the treatment of diabetes and its associated comorbidity.”

Study: Hughes et al. 2022
Funding: Center for Plant Science and Health, an offshoot of the AKA (POINT Ashby? But wait…*)
Conclusion in part: “Taken together, the data from C. elegans suggest that kratom is not toxic and is also unlikely to act via the opioid-signalling pathway. Due to the conservation of biological processes between nematodes and humans, this would suggest that toxic effects observed in the nematode could be related to humans. Further, as molecular signalling and pathways are conserved [42,43], we are able to hypothesise that if kratom is unlikely to act via the opioid-signalling pathway in nematodes, this can be extrapolated to the molecular mechanism of kratom action in humans. However, further detailed analysis using cell-based assays to confirm the lack of action of kratom via opioid signalling in humans would be required, but this is beyond the scope of this current work. Ultimately, experiments using C. elegans have provided a unique opportunity to explore the toxicity of kratom. Further, the data suggest that kratom acts via an alternative pathway to opioid signalling; however, the full dissection of this pathway is deserving of future exploration.”
KS Comments: *…Doesn’t seem like a home run for the kratom team to me, even with the funding source. It’s not toxic and doesn’t signal opioid receptors in nematodes. Wooptie doo! Didn’t those highly trained and respected scientists check the couch cushions for all those big bucks? You’re supposed to say “Since kratom isn’t toxic in worms, buy up all the kratom at the nearest two gas stations and gulp it down with your prescription meds!”

Study: Hill et al, 2022
Funding: Biotechnology and Biological Sciences Research Council, Grant/Award Number: BB/T013966/1; Hope for Depression Research Foundation, Grant/Award Number: N/A; Academy of Medical Sciences, Grant/Award Number: AMSPR1\1013. Conflict of Interest Disclosure: “ACK is a co‐founder and shareholder of Kures, Inc…Kures is currently developing a mitragynine analogue as a potential pharmaceutical. No funding was provided by Kures for this work.” [Kures is conducting human clinical trials for a deuterated form of mitragynine, which is essentially a way to patent the mitragynine molecule since it cannot be patented on its own]
Conclusion in part: “Both the anti‐nociceptive effects and the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7‐OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built‐in ceiling effect of the mitragynine‐induced respiratory depression. These data suggest that such ‘metabolic saturation’ at high doses may underlie the improved safety profile of mitragynine as an opioid analgesic.”
KS Comments: You could make a case that mitragynine is being shown to be safer by a scientist who is developing a mitragynine-based drug. But to repeat, that in no way debunks the published science here any more than AKA money debunks the science it funds.

Study: Gutridge et al, 2021
Funding: “This research was supported by funds awarded to AG by the American Foundation of Pharmaceutical Education in the form of a pre-doctoral fellowship; to RvR by the National Institute on Alcohol Abuse and Alcoholism (AA025368, AA026949, and AA026675) and the National Institute on Drug Abuse (DA045897) of the National Institutes of Health; to SM by the National Institute on Drug Abuse (DA045884)”
Conclusion in part: “Derivatizing kratom alkaloids with the goal of enhancing δOR potency and reducing off-target effects could provide a pathway to develop novel lead compounds to treat alcohol use disorder with an improved therapeutic window.”
KS Comments: Reminder that placing kratom on Schedule 1 stifles research. Labs that can now easily and legally obtain kratom would have to go to great lengths to access a DEA license that is very rarely granted.

Study: Yusoff et al, 2021
Funding: “This work was supported by Ministry of Higher Education Malaysia for Fundamental Research Grant Scheme with Project Code: FRGS/1/2020/SKK0/USM/02/5 and the German National Science Foundation (Deutsche Forschungsgemeinschaft [DFG]), grant MU 2789/8–2, in part by the Federal Ministry of Education and Research (BMBF) under the e:Med Program (031L0190B and 01KC2004B), Committee for Aid and Education in Neurochemistry (CAEN), International Society for Neurochemistry (ISN) (304. CDADAH.6501086. I143)”
Conclusion in part: “These findings suggest a strong and prolonged effect of MIT [mitragynine] on DA [dopamine] synthesis/metabolism, but not on extracellular DA activity, which may limit the addiction risk of MIT, in contrast to MOR [morphine] and METH [methamphetamine].”

Study: Nukitram et al, 2021
Funding: “supported by a grant from the professional development project under the Science Achievement Scholarship of Thailand (SAST). Partially financial support was also from the Program of Physiology, Division of Health and Applied Science, Faculty of Science, Prince of Songkla University, Thailand.”
Conclusion in part: “the present study proposed beneficial effects of 80 mg/kg KT [kratom] alkaloid extract for treatment of METH [methamphetamine] dependence. The data from CPP [conditioned place preference] paradigm revealed that the extract successfully reversed METH CPP scores. This would suggest therapeutic property of KT plant in treatment of abnormal behaviors induced by METH dependence.”

Study: You et al, 2021
Funding: “Short-term Grant from Universiti Sains Malaysia (304/CDADAH/6315183) and Higher Education Centre of Excellence (HICoE) special funding (311/CDADAH/4401009).”
Conclusion in part:These data support the idea that mitragynine could be used as safe medication therapy to treat opiate addiction with beneficial effects on cognitive deficits.”

Study: Buckhalter et al, 2021
Funding: “Jason Martin and Susan Bedford of Mitradyne Corporation (Toronto, ON, Canada) to TA. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. SB was supported by scholarships from the Natural Sciences and Engineering Research Council of Canada and the Ontario Graduate Scholarship Program”
Conclusion in part:“the repeated administration of high dose kratom did not result in the accumulation of ΔFosB in any of the regions studied. Whereas this latter finding may indicate a lack of addictive potential, caution is warranted as only a single dose of one specific extract was evaluated. This study provides a promising direction to explore the untapped potential of kratom-based alkaloids for the management of mood and pain related disorders.”

Study: Wilson et al, 2021
Funding: “This research was supported by grants from the National Institute on Drug Abuse R01DA046487 and R21/R33 DA045884 (to SM), Cancer Center Support Grant P30 CA008748 from the National Cancer Institute (to MSKCC) and funds from the University of Florida (to JPM).”
Conclusion in part: “administration of combined Kratom alkaloid extract or mitragynine each demonstrated minimal symptoms of withdrawal alone, suggesting these agents produce less physical dependence than the full MOR agonist morphine”

Study: Wilson et al, 2020
Funding: “a Centers of Biomedical Research Excellence (COBRE) P20GM104932 from the National Institutes of Health to CRM, a McKnight Fellowship (to LLW) and the University of Florida to JPM”
Conclusion in part: “The present study confirms the MOR agonist activity and therapeutic effect of LKT for the treatment of pain and opioid physical dependence.”

Study: Benood-Rod et al, 2020
Funding: “This work was supported by NIH grants DA47855 and DA48353.”
Conclusion in part: “These initial findings indicate that mitragynine and 7-hydroxymitragynine are not rewarding in the ICSS procedure. The present results suggest that these kratom alkaloids do not have abuse potential.”

Study: Maxwell et al, 2020
Funding: “This study was supported by UG3 DA048353 and R01 DA047855 grants from the National Institute on Drug Abuse and the University of Florida Clinical and Translational Science Institute, which is supported in part by the NIH National Center for Advancing Translational Sciences under award number UL1TR001427”
Conclusion in part: “No major adverse events were noted in either study, although all subjects experienced mild transient sedation immediately after dosing.” “No clinically significant changes in vital signs, physical examinations, or clinical laboratory tests were observed for both oral and intravenous pharmacokinetic studies.”

Study: Hassan et al, 2020
Funding: “This work was supported by the Higher Education Centre of Excellence (HiCoE) PHASE II special funding (304/CDADAH/4401009) and Yang di-Pertuan Agong (BYDPA) scholarship.”
Conclusion in part: “The present study suggests that mitragynine may serve as an alternative treatment for opiate withdrawal effects as they occur in opiate addiction. Although mitragynine may possess some addictive properties on its own, it may, in low-medium doses, in which humans voluntarily use it, help to manage opiate addiction. The current report details the efficacy in comparison to methadone and buprenorphine. While mitragynine is equally effective in reducing opiate withdrawal effects in rats, it may be the safer drug with less undesired side-effects.”

Study: Obeng et al 2019
Funding: “This work was supported by National Institute on Drug Abuse grants DA47855 and DA48353. This work was also supported by funds from the State of Florida and a generous gift through the University of Florida Foundation.”
Conclusion in part: “The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.”

Study: Harun et al 2019
Funding: “This research received financial support from Higher Education Centre of Excellence (HICoE) special funding (311/CDADAH/4401009) and USM Short Term Research Grant (304/CDADAH/6315105).”
Conclusion in part: “The findings suggest that MG does not induce physiological dependence but can alleviate the physical symptoms associated with morphine withdrawal which represent the desired characteristics of novel pharmacotherapeutic interventions for managing opioid use disorder”

Study: Henningfield et al 2019
Funding: “Preparation of the commentary was not supported by external grants, funding or any clients that these authors have consulted to. Support of salary and expenses for Henningfield, Cone, Fant, and Wang was provided by PinneyAssociates.” “Declaration of competing interest: Jack E. Henningfield, Reginald V. Fant, and Daniel W. Wang provide consulting support through PinneyAssociates on the development of abuse potential assessments and eight factor analyses according to the Controlled Substances Act the dietary industry including the American Kratom Association” (POINT Ashby!)
Conclusion in part: “Kratom is not without risk, but the risk estimates as calculated by any of the approaches used, relative to opioids, suggest that morphine-like opioids carry an overdose risk of a thousand or more times greater than kratom. This conclusion has the limitation that some kratom users inherently carry or assume factors that might greatly increase the risk of kratom-associated mortality, e.g., use in combination with opioids, sedatives, alcohol or other drugs, or some preexisting disease states”

Our Conclusion

Kratom is a complex plant that has been consumed for at least hundreds of years. Traditionally there are reports of dependency but not toxicity. Toxic adverse events relative to the use of kratom is new and relatively unique to the United States. The most likely culprit of toxicity in the US is 1) kratom mixed with other drugs 2) contaminated or adulterated kratom and 3) high doses of kratom (especially extract) taken over time. These ongoing problems will only be exacerbated by creating an illicit kratom market through a ban. The evidence that the drug war only exacerbates drug problems is not only too big for this post, but would fill a library.

The majority of kratom consumers report beneficial outcomes. The majority of kratom consumers who report a dependency say it is manageable and mild.

Posted above is partial list of peer-reviewed kratom animal studies published in established medical science journals that conclude possible beneficial outcomes in humans. We obtained this list from a PubMed search. Only 3 out of 18 studies were funded by the American Kratom Association or an affiliated group. Therefore 84% of kratom animal studies showing beneficial outcomes draw funding from other sources, and Drew Ashby’s assertion that they are all funded by the AKA is wrong. A claim that the AKA “monopolizes” the science of kratom is from either ignorance or dishonesty.

Published animal studies, whether the reader perceives them as “positive” or “negative”, certainly don’t paint the whole picture on the human relationship with psychoactive substances. We hope kratom human clinical trials will be funded by NIH or NIDA very soon, rather than a lobbying group, a prohibitionist group, or a pharmaceutical company.

Scientific studies referenced (all other articles/video linked in text)

  • Behnood-Rod, A., Chellian, R., Wilson, R., Hiranita, T., Sharma, A., Leon, F., McCurdy, C. R., McMahon, L. R., & Bruijnzeel, A. W. (2020). Evaluation of the rewarding effects of mitragynine and 7-hydroxymitragynine in an intracranial self-stimulation procedure in male and female rats. Drug and alcohol dependence, 215, 108235.
  • Buckhalter, S., Soubeyrand, E., Ferrone, S. A. E., Rasmussen, D. J., Manduca, J. D., Al-Abdul-Wahid, M. S., Frie, J. A., Khokhar, J. Y., Akhtar, T. A., & Perreault, M. L. (2021). The Antidepressant-Like and Analgesic Effects of Kratom Alkaloids are accompanied by Changes in Low Frequency Oscillations but not ΔFosB Accumulation. Frontiers in pharmacology, 12, 696461.
  • Chen, L., Fei, S., & Olatunji, O. J. (2022). LC/ESI/TOF-MS Characterization, Anxiolytic and Antidepressant-like Effects of Mitragyna speciosa Korth Extract in Diabetic Rats. Molecules (Basel, Switzerland), 27(7), 2208.
  • Gutridge, A. M., Chakraborty, S., Varga, B. R., Rhoda, E. S., French, A. R., Blaine, A. T., Royer, Q. H., Cui, H., Yuan, J., Cassell, R. J., Szabó, M., Majumdar, S., & van Rijn, R. M. (2021). Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder. Frontiers in pharmacology, 12, 764885.
  • Harun, N., Johari, I.S., Mansor, S.M. et al. Assessing physiological dependence and withdrawal potential of mitragynine using schedule-controlled behaviour in rats. Psychopharmacology 237, 855–867 (2020).
  • Hassan, R., Pike See, C., Sreenivasan, S., Mansor, S. M., Müller, C. P., & Hassan, Z. (2020). Mitragynine Attenuates Morphine Withdrawal Effects in Rats-A Comparison With Methadone and Buprenorphine. Frontiers in psychiatry, 11, 411.
  • Henningfield, J. E., Grundmann, O., Babin, J. K., Fant, R. V., Wang, D. W., & Cone, E. J. (2019). Risk of death associated with kratom use compared to opioids. Preventive medicine, 128, 105851.
  • Henningfield, J. E., Rodricks, J. V., Magnuson, A. M., & Huestis, M. A. (2022). Respiratory effects of oral mitragynine and oxycodone in a rodent model. Psychopharmacology, 239(12), 3793–3804.
  • Hill, R., Kruegel, A. C., Javitch, J. A., Lane, J. R., & Canals, M. (2022). The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine. British journal of pharmacology, 179(14), 3875–3885.
  • Hughes, S., van de Klashorst, D., Veltri, C. A., & Grundmann, O. (2022). Acute, Sublethal, and Developmental Toxicity of Kratom (Mitragyna speciosa Korth.) Leaf Preparations on Caenorhabditis elegans as an Invertebrate Model for Human Exposure. International journal of environmental research and public health, 19(10), 6294.
  • Macko, E., Weisbach, J. A., & Douglas, B. (1972). Some observations on the pharmacology of mitragynine. Archives internationales de pharmacodynamie et de therapie, 198(1), 145–161.
  • Maxwell, E. A., King, T. I., Kamble, S. H., Raju, K. S. R., Berthold, E. C., León, F., Avery, B. A., McMahon, L. R., McCurdy, C. R., & Sharma, A. (2020). Pharmacokinetics and Safety of Mitragynine in Beagle Dogs. Planta medica, 86(17), 1278–1285.
  • Nukitram, J., Cheaha, D., Sengnon, N., Wungsintaweekul, J., Limsuwanchote, S., & Kumarnsit, E. (2022). Ameliorative effects of alkaloid extract from Mitragyna speciosa (Korth.) Havil. Leaves on methamphetamine conditioned place preference in mice. Journal of ethnopharmacology, 284, 114824.
  • 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.
  • Wilson, L. L., Chakraborty, S., Eans, S. O., Cirino, T. J., Stacy, H. M., Simons, C. A., Uprety, R., Majumdar, S., & McLaughlin, J. P. (2021). Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal. Cellular and molecular neurobiology, 41(5), 1131–1143.
  • Wilson, L. L., Harris, H. M., Eans, S. O., Brice-Tutt, A. C., Cirino, T. J., Stacy, H. M., Simons, C. A., León, F., Sharma, A., Boyer, E. W., Avery, B. A., McLaughlin, J. P., & McCurdy, C. R. (2020). Lyophilized Kratom Tea as a Therapeutic Option for Opioid Dependence. Drug and alcohol dependence, 216, 108310.
  • You, C. Y., Hassan, Z., Müller, C. P., & Suhaimi, F. W. (2022). Mitragynine improves cognitive performance in morphine-withdrawn rats. Psychopharmacology, 239(1), 313–325.
  • Yusoff, N. H. M., Hassan, Z., Murugaiyah, V., & Müller, C. P. (2022). The effect of mitragynine on extracellular activity of brain dopamine and its metabolites. Brain research bulletin, 178, 1–8.

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