Kratom has been consumed for at least four centuries in Southeast Asia, and likely longer. Southeast Asian drug policy expert Pascal Tanguay told Kratom Science about the earliest documented evidence he’s seen: “Kratom was referred to as a medicinal herb in Thai pharmacopeias dating from the 1650s, as was indicated for the treatment of stomach aches, severe diarrhea, and opium withdrawal.”
Kratom began to grow in popularity in the West in the early to mid 2000 and its popularity continues to this day. But most Americans are not consuming kratom in the traditional form of chewing and spitting out fresh leaves or brewing a tea. This is still the practice in Thailand and in Malaysia, where kratom “juice” is prepared from fresh leaves consumed fresh, as according to Dr. Darshan Singh. In traditional use, eating dried leaf powder is uncommon. Americans are eating quantities of kratom powder that no one has previously, and consuming strong liquid extracts, sometimes sold as brands that advertise opioid effects.
A recent review entitled “What Is the Kratom Overdose Risk? A Systematic Literature Review” takes a closer look at the mechanisms of toxicities, including fatalities, when kratom is present (Stanciu et al., 2022). The authors of the study include three past Kratom Science Podcast guests: Cornel Stanciu, an addiction psychiatrist, Christopher McCurdy, a medicinal chemist, and Abhisheak Sharma, a pharmacokineticist. The authors point out that while a toxicity using traditional methods “would require a tremendous amount of kratom to be ingested”…
Evidence from case reports suggests that use of the kratom products sold in the USA, especially when combined with other sedative illicits and prescribed medications in clinical populations, can have detrimental and lethal consequences due to synergistic drug effects and pharmacokinetic interactions.
The stronger doses of mitragynine consumed in the USA, while not necessarily toxic alone, may pose an increase risk of drug interactions. The authors refer to a study by Sharma that “contrasted differences in plasma concentrations of MG between native kratom users in Thailand (Cmax, 0.05–0.26 µM) and autopsy samples in the USA (Cmax upwards of 8.8 µM), which further provide evidence for MG-mediated herb:drug interactions”.
The review examines “12 preclinical studies, 23 case reports, and 15 observational studies/reports”. Of the case reports examined, all the ones involving “fatalities involved opioids and other illicits, as well as prescription pharmaceuticals” and the autopsies mostly demonstrated opioid-like toxicities.
Very much appreciated and often pointed out by Kratom Science, Stancui et al. describe some of the limitations of these case reports:
few describe clear clinical paradigms, MG concentrations are not uniformly reported; the analytical means of detection is not defined, and the time from collection/death to assessment is often unclear. Where MG concentrations are reported, these are not indicative of clear toxicities. Higher concentrations are not always attributed to kratom toxicity, given the confounding coingestion of other drugs. Additionally, in evaluating concentrations from fatalities and near fatalities, MG concentrations span a large concentration range with a significant amount of overlap
Mechanism of Action
Interestingly, “Of near fatal cases, the majority documented various hyperadrenergic outcomes such as nausea, vomiting, restlessness, palpitations, acute kidney injury, and rhabdomyolysis due to vasoconstriction, and seizures” and only “one case report documented a decreased respiratory rate, which improved with naloxone administration” which may demonstrate that while kratom can slow metabolism of other opioids to contribute to an overdose, toxic events involving high doses of kratom alone may be more attributable to the kratom alkaloids’ effect on adrenergic, rather than opioid receptors.
Kratom Science recently asked an open question about the cause of rare kratom-alone deaths on Twitter.
We received the following reply from Justin Brower, one of the authors of “The Trouble With Kratom: Analytical and Interpretative Issues Involving Mitragynine” that examined 1,001 postmortem blood specimens containing mitragynine.
Daniel Overbrook’s reply corroborated the Stanciu et al. review that opioid-like toxic symptoms are rare with mitragynine or kratom.
LD50 of Kratom
The authors also reviewed LD50 studies. LD50 is the dosage it takes to kill 50% of animals in a toxicity study. For total kratom alkaloid (or “full spectrum”) extracts, researchers measured LD50 in the various studies as 591, 200, and 193 mg/kg. With mitragynine alone, LD50 was observed at 960, 547.7, 477, and 126 mg/kg. LD50 was measured at 27.8 and 24.7 mg/kg using a combination of mitragynine and the much more potent 7-hydroxymitragynine.
These measurements are converted from animal to Human Equivalent Dose according to FDA draft guidelines. In every finding, for a human to die from kratom alone, combined with no other drugs and with no pre-existing conditions that may be exacerbated by kratom, that would have to consume a massive amount of plain dried leaf kratom powder, and an even larger amount of fresh leaf tea, in a sitting.
Other data reviewed
The authors also examined poison control center data, observational studies, and government databases that track kratom toxicities. Of these, the vast majority involved co-ingestion of other substances, with only a handful of cases among all datasets reported as “kratom only”.
One data set the authors examined is the State Unintentional Drug Overdose Reporting System (SUDORS). In press releases about kratom, the FDA often employs numbers obtained from SUDORS, using descriptions like “kratom-related deaths” or “deaths associated with the use of kratom”. Outside of the political context, the authors explain that out of 27,338 overdose deaths reported in 2016-2017,
Kratom was believed to be the cause of death for 91 (59.9%). Of these, only seven tested positive for kratom only, among substances tested for. Postmortem tests detected multiple other substances including fentanyl and analogues, heroin, and benzodiazepines.
Atypical
The debate around whether kratom is or isn’t an opioid rages on. This has a political element, as opioids, though beneficial for most humans most of the time, are stuck in the national psyche as “bad”. Most consumers of kratom who had previous addiction to classical opioids like oxycodone or heroin report a much milder experience with kratom in its effects and the intensity of physical dependency.
However many kratom alkaloid do indeed attach to opioid receptors, so outside of politics, it is perhaps correct to say kratom IS and opioid, and incorrect to say kratom IS NOT an opioid. However, as multiple kratom scientists have expressed to us, the adrenergic, seratonergic, and dopaminergic activity of kratom’s alkaloids, along with the apparent lack of intensity of respiratory depression, certainly make kratom an atypical opioid. Of kratom toxicities, the authors of this review observe that they are mostly dissimilar to opioid toxicities, unless combined with opioid drugs.
Observational studies of toxicological data show mostly adrenergic toxicities, with very few opioid-like effects. Reports based on laboratory and autopsy data show fatalities involving kratom almost always involve coingestions of other sedative agents. It is evident that kratom is not a traditional opioid and has both adrenergic and opioidlike toxicities, with the first much more likely to occur in a dose-related fashion than the latter.
References
- Papsun, D. M., Chan-Hosokawa, A., Friederich, L., Brower, J., Graf, K., & Logan, B. (2019). The Trouble With Kratom: Analytical and Interpretative Issues Involving Mitragynine. Journal of analytical toxicology, 43(8), 615–629. https://doi.org/10.1093/jat/bkz064
- Stanciu, C.N., Gnanasegaram, S.A., Rader, G.L., Sharma, A., McCurdy, C. (2023) What Is the Kratom Overdose Risk? A Systematic Literature Review. Current addiction reports, 9(4). https://doi.org/10.1007/s40429-022-00464-1 https://link.springer.com/epdf/10.1007/s40429-022-00464-1?sharing_token=LqivffQCpBTr7Voboij-TPe4RwlQNchNByi7wbcMAY5UICd72CwKA2tX4B8OLZ3my4ZzGCp0tVTQvhu2gAM1PpnmlQSo1KKoY6OdDfMm1SMN6yJO3qDxQBISKIF1ZPhRVOBD9D7leOCQgxdL-8OzflH8fkJHRvWY97kpgfxz-TQ=
###