Findings
Corynantheidine (COR) toxicology and safety summary:
- 1) Acute and repeat-dose toxicity (COR, isolated): No LD₅₀ or GLP-style repeat-dose toxicology studies identified for isolated corynantheidine in rodents or other species. Reviews of kratom safety note the paucity of alkaloid-specific toxicology beyond mitragynine/7-OH [8].
- 2) Hepatic safety (clinical/forensic signals): Clinical DILI case reports and series exist for kratom products; diagnoses range from cholestatic to mixed patterns. Causality to a specific alkaloid (e.g., COR) cannot be assigned from current evidence [9]. FDA cautions consumers against kratom due to reports of liver toxicity and other serious adverse events; no approved kratom-containing drugs [10].
- 3) Cardiac safety: In vitro: mitragynine inhibits hERG/IKr in multiple systems with low-μM potency—an arrhythmia risk signal for kratom exposures; COR-specific hERG data not found [11]. Clinical reports: kratom-associated QT prolongation/Brugada-pattern presentations have been reported; attribution to mixtures; mechanism may involve hERG block and/or autonomic effects [12].
- 4) Drug–drug interaction potential (CYP450): COR inhibits CYP2D6 competitively (IC₅₀ ≈ 4.2 μM; Kᵢ ≈ 2.8 μM). MTG is stronger (IC₅₀ ≈ 2.2 μM). These values suggest DDI risk with CYP2D6 substrates (e.g., certain SSRIs/SNRIs, β-blockers, opioids, TCAs), contingent on exposure (Cmax, unbound fraction) [13]. Reviews highlight broader CYP time-dependent inhibition by kratom constituents (not specific to COR), implying potential CYP3A and CYP2D6 liabilities at the product level [14].
- 5) Exposure context (occurrence → potential dose): COR content is low relative to MTG (validated QC ranges in products ~0.01–2.8% w/w), but chemotype and processing drive variability. Lower content does not preclude DDI risk if unbound plasma levels approach CYP2D6 IC₅₀.
