Comment on HHS-OASH-2026-0232, HHS-OASH-2026-0232-0001, 2026-13608
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Summary: The commenter, representing Taibah University, submits a peer-reviewed review article arguing that current scientific literature does not support a non-zero safety threshold for 7-hydroxymitragynine. They argue that because clinical evidence documents serious human toxicity without establishing a validated safety level, a 0% allowable standard is the more protective public health approach.
Begum et al. (2024): Mitragyna speciosa Korth Toxicity: Experimental Findings and Future Prospects
This peer-reviewed review article should be considered evidence supporting a 0% allowable 7-hydroxymitragynine standard because it comprehensively reviews the available scientific literature and concludes that clinically significant toxicities have been reported across multiple organ systems while important questions regarding alkaloid composition and exposure remain unresolved.
The authors summarize evidence from in vitro studies, animal studies, and numerous published human case reports, documenting hepatic injury, cardiotoxicity, nephrotoxicity, respiratory toxicity, neurologic complications, opioid-like withdrawal, and death associated with kratom exposure. They further describe inhibition of multiple cytochrome P450 enzymes by kratom alkaloids, creating the potential for clinically significant drug-drug interactions.
Importantly, the authors acknowledge that many reported toxicities involve commercially available kratom products of unknown or highly variable composition. They specifically note that most published case reports did not report 7-hydroxymitragynine concentrations in blood or urine, identifying this as an important limitation that should be addressed in future investigations.
From a regulatory perspective, this observation is highly significant. If the existing clinical literature generally lacks quantitative 7-hydroxymitragynine measurements, it cannot be used to establish that a 0.05% 7-hydroxymitragynine threshold reliably separates products that are safe from those capable of producing serious toxicity.
The authors also emphasize that commercial kratom products may differ substantially from natural leaf because of differences in composition, potency, adulteration, and preparation methods. They recommend additional research to define dose-response relationships, characterize alkaloid exposure, and better understand toxicity before firm conclusions regarding safety can be reached.
Accordingly, this comprehensive review does not validate the safety of a non-zero 7-hydroxymitragynine threshold. Instead, it demonstrates that the existing scientific literature documents serious human toxicity while simultaneously acknowledging that critical quantitative exposure data remain unavailable. Until human clinical evidence establishes a scientifically validated safety threshold, this review supports consideration of a 0% allowable 7-hydroxymitragynine standard as the more protective public health approach.