Acute, Sublethal, and Developmental Toxicity of Kratom ( Korth.) Leaf Preparations on as an Invertebrate Model for Human Exposure.

Kratom ( Korth.) is a tree native to Southeast Asia with stimulant and opioid-like effects which has seen increased use in Europe and North America in recent years. Its safety and pharmacological effects remain under investigation, especially in regard to developmental and generational toxicity. In the current study, we investigated commercial kratom preparations using the nematode as a translational model for toxicity and pharmacological effects. The pure alkaloids mitragynine and 7-hydroxymitragynine as well as aqueous, ethanolic, and methanolic extracts of three commercial kratom products were evaluated using a battery of developmental, genotoxic, and opioid-related experiments. As determined previously, the mitragynine and 7-hydroxymitragynine content in kratom samples was higher in the alcoholic extracts than the aqueous extracts. Above the human consumption range equivalent of 15-70 µg/mL, kratom dose-dependently reduced brood size and health of parent worms and their progeny. 7-hydroxymitragynine, but not mitragynine, presented with toxic and developmental effects at very high concentrations, while the positive control, morphine, displayed toxic effects at 0.5 mM. Kratom and its alkaloids did not affect pumping rate or interpump interval in the same way as morphine, suggesting that kratom is unlikely to act primarily via the opioid-signalling pathway. Only at very high doses did kratom cause developmental and genotoxic effects in nematodes, indicating its relative safety.