Paynantheine: Toxicology & Safety

Toxicology and Safety Assessment of Paynantheine

  • General observation: Compared to Mitragynine and 7-Hydroxymitragynine, Paynantheine has been less studied for toxicological properties but does not appear to be a major driver of toxicity.
  • Animal studies: Detected in pharmacological assays, but no lethal dose (LD₅₀) established specifically for Paynantheine. Most studies assess kratom extracts rather than the isolated alkaloid.
  • Relative toxicity: Weaker CNS activity than Mitragynine and 7-OH Mitragynine, suggesting a lower toxicological burden [1].

Metabolism and Biotransformation

  • Hepatic metabolism: Paynantheine undergoes metabolism via CYP450 enzymes, particularly CYP3A4 and CYP2D6 [2, 3].
  • Biotransformation pathways: Likely involves oxidative demethylation and hydroxylation, based on analog studies with Mitragynine.
  • Drug–drug interactions: In vitro studies suggest Paynantheine and other kratom alkaloids may inhibit CYP3A4 and CYP2D6, potentially affecting the metabolism of opioids, benzodiazepines, and antidepressants [4].

Human Safety Observations

  1. No direct human trials exist for isolated Paynantheine; safety data are derived from whole-plant kratom use.
  2. Adverse effects such as nausea, dizziness, and liver enzyme elevations are reported with kratom, but Paynantheine’s specific contribution is unclear [5].
  3. Its opioid receptor antagonism may offer a protective/modulatory role, though this requires further validation.

Risk Comparison with Other Alkaloids

Alkaloid Opioid Potency Toxicity Risk Safety Notes
Mitragynine High Moderate–High Partial MOR agonist, dose-dependent toxicity
7-OH Mitragynine Very High High Potent MOR agonist, most associated with adverse effects
Paynantheine Very Low Low MOR/KOR antagonist, minimal direct toxicity data

Summary

  • Paynantheine Safety Profile: Appears favorable relative to Mitragynine and 7-OH Mitragynine.
  • Data Limitations: Lack of direct toxicity data; most evidence comes from whole-plant kratom extracts.
  • Pharmacological Role: Acts as an opioid modulator, potentially contributing to a safer pharmacological balance.
  • Research Needs: Further studies required to determine LD₅₀, metabolic pathways, and human clinical safety.

References

  1. Ellis, C. R., Racz, R., Kruhlak, N. L., Kim, M. T., Zakharov, A. V., Southall, N., & Hawkins, E. G. (2020). Evaluating kratom alkaloids using PHASE: Opioid receptor binding of mitragynine, 7-hydroxymitragynine, and related compounds. PLOS ONE, 15(2), e0229646. https://doi.org/10.1371/journal.pone.0229646
  2. Philipp, A. A., Wissenbach, D. K., Weber, A. A., Zapp, J., & Maurer, H. H. (2010). Metabolism studies of the kratom alkaloids mitragynine and speciociliatine, using rat and human urine and liver microsomes, and LC–MS/MS and LC–HR-MS. Analytical and Bioanalytical Chemistry, 398(5), 2221–2234. https://doi.org/10.1007/s00216-010-4191-0
  3. Kong, W. M., Chik, Z., Ramachandra, M., Subramaniam, V., & Mohamed, Z. (2011). Development of an HPLC method for the determination of mitragynine and its application to human plasma pharmacokinetics. Journal of Chromatography B, 879(28), 3341–3347. https://doi.org/10.1016/j.jchromb.2011.09.038
  4. Kruegel, A. C., & Grundmann, O. (2018). The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology, 134, 108–120. https://doi.org/10.1016/j.neuropharm.2017.08.026
  5. World Health Organization. (2021). Review of kratom and its alkaloids by the Expert Committee on Drug Dependence. WHO Technical Report. https://www.who.int/medicines/access/controlled-substances/ecdd_44_meeting/en/
  6. León, F., Habib, E., Trojahn, T., Adkins, J. E., Furr, E. B., McCurdy, C. R., & Cutler, S. J. (2021). Phytochemical characterization of Mitragyna speciosa (Kratom) and evaluation of serotonergic and opioid activity of its alkaloids. Frontiers in Pharmacology, 12, 640236. https://doi.org/10.3389/fphar.2021.640236