Study: Mitragynine does not rely on its metabolism into 7-hydroxymitragynine to produce pain relieving effects

7-hyrdoxymitragynine

In a new study by the team at University of Florida, scientists found that the metabolite 7-hydroxymitragynine does not account for the pain-relieving effects of its parent alkaloid, mitragynine (Berthold et al., 2021).

Here we investigated the hotplate antinociception, pharmacokinetics, and tissue distribution of mitragynine and 7-hydroxymitragynine at equianalgesic oral doses in…mice to determine the extent to which 7-hydroxymitragynine metabolized from mitragynine accounts for the antinociceptive effects

(Berthold et al., 2021)

The two most widely-studied kratom alkaloids are, mitragynine (MTG), the most abundant alkaloid, and 7-hydroxymitragynine (7HMG). 7HMG has been found in fresh kratom leaf in tiny, insignificant amounts, but in dried plant material at around 1-2% of total alkaloids. Whether in the kratom drying process or in the metabolism, oxygen binds with MTG to create 7HMG.

Both alkaloids act on opioid receptors, but “MTG and 7HMG differ at μ-opioid receptors…7HMG is a high affinity, partial agonist whereas MTG is a low affinity, partial agonist”. The alkaloids differ in what pharmacologists call “abuse potential”. “MTG has limited abuse potential while also functionally antagonizing the reinforcing effects of opioids” but “7HMG has a high abuse potential” (Berthold et al., 2021).

Studies in mice have shown 7HMG administered alone produced pain-relieving effects more potent than morphine (Matsumoto et al., 2004). Researchers in the Berthold study found, “When administered alone, 7-hydroxymitragynine was 2.8-fold more potent than mitragynine to produce antinociception” or pain relieving effects (Berthold et al., 2021).

But kratom contains over 40 alkaloids acting in concert, and alkaloids in concert do not act the same as a single alkaloid in isolation. Speciociliatine, for example, was shown to have pain relieving effects when isolated, but killed 5 of 21 lab rats at the dose necessary for those effects (Obeng et al., 2020).

Yet the information about 7HMG’s potency gave prohibitionists like Lowdnes County, Mississippi Sheriff Eddie Hawkins the ammunition to declare in 2019 that kratom is “13 times more powerful than morphine. So kids have access to morphine simply by buying this in a convenience store.” On the other side, pro-kratom advocates have taken MTG’s limited abuse potential to make claims about the low “addiction potential” of kratom as a whole.

Given the controversial nature of the potent 7HMG alkaloid, researchers have been trying to understand how it functions as a metabolite of mitragynine. A 2019 study concluded “7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects” (Kruegal et al., 2019). University of Florida pharmacokineticist Dr. Abhisheak Sharma disagreed with this conclusion. He told Kratom Science in a 2021 interview:

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…part of metabolism, because you’re not looking at the full metabolism.

In contrast, the Berthold study, which Dr. Sharma co-authored, found the concentrations of 7HMG were “11-fold lower as a metabolite of mitragynine” than when administered alone. And “the amount of 7HMG present in the brain after MTG administration alone cannot account for the functional activity of MTG, refuting an earlier study (Kruegel et al., 2019)” (Berthold et al., 2021).

Key takeaways for kratom consumers

The team at University of Florida is trying to develop a pain relieving drug with fewer risks than opioids. So far, it appears that mitragynine alone meets this criteria. Because it not only acts on opioid receptors, but also adrenergic and serotonin receptors, MTG also meets the criteria for an opioid dependence treatment drug, in that, as Dr. Sharma explained to Kratom Science, “It’s like you’ve mixed four drugs in a treatment therapy to treat opioid dependence…with one mitragynine molecule.”

According to one estimate, 40% of manufactured drugs come from plant sources (US Forest Service, n.d.). Manufacturing the extracted compounds of these plants into drugs does not automatically mean outlawing access to the plants themselves, or the list of substances scheduled under the Controlled Substances Act would be much larger. For example, digitalis and digoxin derived from foxglove are sold as FDA-approved drugs. Another example: the FDA-approved drug Epidiolex is simply a purified form of CBD, which legally available as an extract or in the legal hemp plant, defined under the 2018 Farm Bill as the cannabis sativa plant containing less than 0.3% THC.

Choosing a kratom product lower in 7HMG may put the consumer at lower risk for dependency issues than a high 7HMG product, even though 7HMG is still a partial opioid agonist while morphine is a full agonist. Of all kratom products,

  • extracts that artificially increase the amount of 7HMG may pose the greatest risk,
  • dried crushed leaf or leaf powder may be less risky than extracts because of the small amount of 7HMG (less than 2% of alkaloids),
  • fresh leaf that contains virtually zero 7HMG may be considered the least risky.

This supports the argument that (a) the right of kratom consumers to grow their own plants and thus have access to fresh kratom leaves should not be infringed upon, and (b) eventually, the alkaloid profiles of all kratom products should be available to consumers so they can better understand what they are putting into their bodies.

  • Berthold, E. C., Kamble, S. H., Raju, K. S., Kuntz, M. A., Senetra, A. S., Mottinelli, M., León, F., Restrepo, L. F., Patel, A., Ho, N. P., Hiranita, T., Sharma, A., McMahon, L. R., & McCurdy, C. R. (2021). The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice: A Pharmacokinetic and Pharmacodynamic Study. Drug metabolism and disposition: the biological fate of chemicals, DMD-AR-2021-000640. Advance online publication. https://doi.org/10.1124/dmd.121.000640
  • Kruegel, A. C., Uprety, R., Grinnell, S. G., Langreck, C., Pekarskaya, E. A., Le Rouzic, V., Ansonoff, M., Gassaway, M. M., Pintar, J. E., Pasternak, G. W., Javitch, J. A., Majumdar, S., & Sames, D. (2019). 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. ACS central science, 5(6), 992–1001. https://doi.org/10.1021/acscentsci.9b00141
  • 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
  • Matsumoto, K., Horie, S., Ishikawa, H., Takayama, H., Aimi, N., Ponglux, D., & Watanabe, K. (2004). Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa. Life sciences, 74(17), 2143–2155. https://doi.org/10.1016/j.lfs.2003.09.054
  • U.S. Forest Service. Medicinal botany. (n.d.). Retrieved December 29, 2021, from https://www.fs.fed.us/wildflowers/ethnobotany/medicinal/index.shtml

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