Corynantheidine: Toxicology And Safety Assessment

Toxicology And Safety Assessment Of Corynantheidine

Evaluate the toxicology and safety of corynantheidine (COR) using peer-reviewed data on (i) acute and repeat-dose toxicity (if available), (ii) clinical safety signals reported for kratom at the product level, (iii) drug–drug interaction potential via CYP450 inhibition, and (iv) mechanistic context from receptor pharmacology. All claims are evidence-bounded; if no direct data exist for COR, this is stated explicitly and distinguished from kratom-level evidence.

Data sources

Regulatory/toxicology overviews for kratom: WHO ECDD pre-review (2021; not controlled but under surveillance) [1]; FDA public health page (updated Jul 29, 2025) noting risks such as liver toxicity, seizures, SUD; no FDA-approved kratom drugs or ingredients [2].
CYP450 DDI risk (in vitro): COR is a potent CYP2D6 inhibitor (IC₅₀ ~ 4.2 μM, Kᵢ ~ 2.8 μM) in human liver microsomes; mitragynine (MTG) ~2.2 μM; competitive inhibition.
Subchronic/acute toxicology (extracts or MTG): subchronic rat studies on kratom extracts and mitragynine (not COR), with dose-dependent findings [3].
Hepatotoxicity case literature: multiple kratom-associated DILI case reports and series; attribution to COR not established [4].
Cardiac risk signals: hERG/IKr inhibition shown for mitragynine in vitro and case reports of arrhythmia-like presentations with kratom; no COR-specific hERG dataset [5].
Mechanistic anchor: COR is a partial hMOR agonist (EC₅₀ ~67 nM; Emax ~37%; no β-arrestin-2) with high α₁D binding and weak KOR binding; these inform hazard hypotheses (respiratory depression risk likely lower than potent MOR agonists; α₁D engagement may have vascular/smooth-muscle implications) [6].
Exposure/analytics enabling PK: validated bioanalytical method for COR in rat plasma (enables in vivo detection to support PK-toxicology) [7].

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.

Risk characterization

COR Safety & Toxicity Highlights

Systemic organ toxicity (COR-specific): insufficient data.
Hepatotoxicity: documented at the kratom product level; cannot assign causality to COR.
Cardiotoxicity/arrhythmia: mechanistic concern from hERG block by MTG; COR-specific hERG unknown [15].
DDI risk (CYP2D6): supported for COR in vitro; clinical magnitude depends on exposure and co-medications.

Reporting guidance for future COR safety work

COR Analytical & Study Considerations

Provide complete analytical method: instrument, column, gradient to enable cross-study comparison.
Internal standards, calibration & LLOQ, QC metrics: include validated internal standards, calibration curves, lower limit of quantification, and QC parameters.
Link in vivo findings to plasma concentrations: evaluate DDI risk against IC₅₀/Kᵢ using measured unbound plasma levels.
Quantify co-alkaloids in kratom extracts: to interpret mixture effects alongside COR.

Summary

COR Toxicology & Mechanistic Overview

Direct toxicology datasets: Sparse for isolated corynantheidine; no rodent LD₅₀ or GLP-style repeat-dose studies found.
Product-level hepatic and cardiac signals: Documented in kratom case literature and regulatory advisories; causality to COR cannot be assigned.
DDI liability (CYP2D6): COR inhibits CYP2D6 competitively (IC₅₀ ≈ 4.2 μM); co-administration with narrow-therapeutic-index CYP2D6 substrates warrants caution.
Mechanistic pharmacology: Partial MOR agonism with absent β-arrestin-2 signaling suggests a different risk profile than potent MOR agonists (e.g., 7-hydroxymitragynine); high α₁D binding raises hypotheses for non-opioid physiological effects needing functional confirmation.
Overall risk assessment: Limited by missing COR-specific toxicology data; emphasizes the need for well-controlled in vivo studies with exposure–response linkage and DDI evaluation against measured unbound concentrations.