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Preclinical herb-herb interaction of cannabidiol and kratom in rats

Erin Berthold
University of Florida

Co-authors: Abhisheak Sharma1, Michelle A. Kuntz1, Shyam H. Kamble1, Siva Rama Raju Kanumuri1, Alexandria S. Senetra1, Christopher R. McCurdy1
1University of Florida

Objective: Consumer use of cannabidiol (CBD) continues to increase. Another natural product, kratom, has also seen increased use in the western world and drawn the attention of regulatory bodies as its abuse liability is not well characterized. The major chemical component of kratom is mitragynine, an atypical opioid agonist that is being investigated as a potential aid to individuals suffering from opioid use disorder, though kratom commercial products contain many additional compounds. Individuals are beginning to combine these products, yet nothing is known about their potential to interact. The goal was to characterize the interaction between CBD and kratom.

Methods: For the oral single-dose study, male Sprague Dawley rats (weight 250 ± 25 g) were dosed with 50 mg/kg CBD and after 30 min, 0.8 mL/kg OPMS. OPMS is a commercially available liquid kratom product with a mitragynine content of 12 mg/ mL. For the multiple dose study, rats were pretreated with 25 mg/kg CBD and after 30 min received 0.4 mL/kg OPMS. This dosing schedule was repeated every 12 hr (0900 and 2100) for four days. Plasma samples collected throughout the study were analyzed for content of CBD and kratom alkaloids mitragynine, corynantheidine, speciociliatine, speciogynine, paynantheine, and 7-hydroxymitragynine.

Results: With CBD pretreatment, the maximum concentration of mitragynine increased 2.3-fold and the exposure increased 2.8-fold. After a single oral dose an overall increase in the time to maximum concentration, the maximum concentration, and the exposure was observed for all minor alkaloids. Steady state concentrations of mitragynine and CBD showed similar behaviors as those observed after a single oral dose with an increase in both the maximum concentration achieved and the exposure.

Conclusion: All kratom alkaloids had increased exposure with concomitant CBD administration. These results raise concerns for consumers who are taking kratom products and CBD together. The safety and toxicity of minor kratom alkaloids has not been reported but they have shown activity at a variety of receptor subtypes including adrenergic, dopaminergic, opioid, and serotonergic. Until kratom alkaloids are more widely understood and regulated caution should be taken if used in combination with CBD.

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