Corynantheidine

  1. Corynantheidine, also known as 9-demethoxy mitragynine, is a secondary indole alkaloid present in Mitragyna speciosa (kratom).
  2. Although detected at lower concentrations than mitragynine or 7-hydroxymitragynine, corynantheidine contributes to kratom’s pharmacological complexity through mixed opioid and non-opioid activity.
  3. Analytical characterization has identified it consistently in kratom leaves and commercial extracts, with validated UPLC–MS/MS and GC–MS methods available for quantification.
  4. Pharmacological investigations indicate that corynantheidine exhibits partial agonism at the µ-opioid receptor (MOR) with a binding affinity around 57 nM, while displaying comparatively higher affinity for α-adrenergic receptors, particularly α1D (Kᵢ ≈ 41 nM).
  5. Additional displacement at serotonergic receptor subtypes has been observed at micromolar concentrations, suggesting broader polypharmacology.
  6. Preclinical pharmacokinetic studies in rodents report oral bioavailability of approximately 50%, a Tmax of 4.1 hours, and distribution to brain regions including the corpus callosum and hippocampus.
  7. Toxicological data highlight its role as a potent inhibitor of CYP2D6 (Kᵢ ≈ 2.8 µM) with substrate-dependent effects on CYP3A, raising concerns regarding potential drug–drug interactions.
  8. While human studies remain unavailable, current evidence suggests corynantheidine may contribute to the pharmacological and toxicological profile of kratom beyond its minor quantitative presence.
  9. An integrated analysis of its receptor activity, pharmacokinetics, and metabolic liabilities underscores the need for translational research to clarify its role in both therapeutic potential and safety risks.

Key Findings
  1. Minor alkaloid in kratom: Corynantheidine (9-demethoxy mitragynine) occurs in low abundance in Mitragyna speciosa leaves and commercial preparations but is consistently detectable using validated LC–MS/MS assays.
  2. Opioid receptor activity: Acts as a partial agonist at the µ-opioid receptor (MOR) with reported Ki ≈ 57 nM, but shows weaker or negligible activity at δ- and κ-opioid receptors.
  3. Adrenergic binding preference: Displays higher affinity for α1-adrenergic receptors, especially α1D (Ki ≈ 41 nM), suggesting adrenergic modulation may contribute more strongly than opioid activity to its effects.
  4. Serotonergic interactions: Demonstrates measurable displacement at multiple 5-HT receptor subtypes at micromolar concentrations, indicating possible serotonergic involvement.
  5. Pharmacokinetics in rodents: Oral bioavailability of ~50%, Tmax ≈ 4.1 h, with distribution to brain regions including the corpus callosum and hippocampus, confirming central nervous system penetration.
  6. Analytical validation: UPLC–MS/MS and GC–MS methods enable sensitive quantification in plasma, urine, and plant material, supporting pharmacokinetic and forensic investigations.
  7. Safety and drug interactions: Potent CYP2D6 inhibitor (Ki ≈ 2.8 µM) and substrate-dependent CYP3A inhibitor, highlighting risk for drug–drug interactions with medications metabolized by these pathways.
  8. Clinical gap: No human pharmacokinetic or toxicological studies exist; current evidence is restricted to in vitro and animal models, necessitating translational research before clinical conclusions can be drawn.

Introduction

  1. Corynantheidine, also known as 9-demethoxy mitragynine (CAS 23407-35-4), is a minor indole alkaloid found in Mitragyna speciosa (kratom), structurally related to mitragynine but lacking the methoxy group at the C-9 position [1][2].
  2. Although present at lower concentrations than mitragynine (up to ~66% of total alkaloid content) and 7-hydroxymitragynine (up to ~2%), corynantheidine is consistently detected within the minor alkaloid fraction, typically ranging 0.01–2.8% (w/w) in kratom leaves and commercial preparations [3].
  3. Pharmacological studies highlight its distinct receptor binding profile, with relatively high affinity for adrenergic receptors, particularly α₁D (Ki ≈ 41.7 nM), and moderate µ-opioid receptor (MOR) binding (human MOR Ki ≈ 118 nM; mouse MOR Ki ≈ 57.1 nM), while showing weaker κ- and δ-opioid receptor binding [4]–[6].
  4. This dual pharmacology suggests corynantheidine contributes to kratom’s overall effects through both opioid partial agonism and adrenergic modulation.
  5. Potential relevance includes analgesic properties, modulation of cardiovascular tone, and drug–drug interaction (DDI) risk via metabolic pathways.

Corynantheidine Review Aims

  1. Chemical identity and structural classification: Summarize its chemical identity and structural classification [7][8].
  2. Natural occurrence and abundance: Report its natural occurrence and abundance in kratom leaves/products [9].
  3. Receptor pharmacology: Evaluate receptor pharmacology across opioid, adrenergic, and serotonergic targets [10][11].
  4. Pharmacokinetics and brain distribution: Review pharmacokinetics and brain distribution in preclinical models [12].
  5. Analytical methods: Summarize analytical methods for quantification in biological and plant matrices [13].
  6. Safety and DDI potential: Assess safety and drug–drug interaction potential via cytochrome P450 inhibition [14][15].

Methods

  1. A structured literature review was conducted across PubMed, Scopus, Web of Science, and Google Scholar databases using the keywords “corynantheidine,” “9-demethoxy mitragynine,” “kratom alkaloids,” “receptor pharmacology,” “pharmacokinetics,” “CYP inhibition,” and “analytical methods.”
  2. Articles published in English between 2000 and 2024 were considered [16]
  3. Reference lists of retrieved studies were screened to identify additional relevant publications.

    4. Inclusion and Exclusion Criteria

    1. Included: Peer-reviewed experimental studies, pharmacological profiling reports, analytical method validation papers, and systematic reviews reporting original data on corynantheidine.
    2. Excluded: Non-peer-reviewed content, anecdotal reports, studies without specific data on corynantheidine, and duplicated datasets.

    Data Extraction

    1. Chemistry/Identifiers: CAS, PubChem CID, molecular formula, stereochemistry.
    2. Occurrence: Concentrations in plant material or commercial preparations.
    3. Pharmacology: Binding affinity (Ki), efficacy (Emax), receptor subtype specificity.
    4. Pharmacokinetics: Cmax, Tmax, clearance, bioavailability, tissue distribution.
    5. Analytical Methods: Matrix, assay platform (UPLC–MS/MS, GC–MS), linear range, LOQ, validation parameters.
    6. Safety/Interactions: CYP inhibition (isoform, Ki/IC50), transporter interactions, potential drug–drug interaction predictions.

    Quality Assessment

    1. Use of validated assays or analytical methods.
    2. Replication or independent confirmation of results.
    3. Transparent reporting of sample size and assay conditions.

Result

  1. Corynantheidine is classified as a corynanthe-type indole alkaloid, structurally related to mitragynine but lacking the methoxy group at the C-9 position. It is also referred to as rauhimbine in older pharmacognosy literature, although “corynantheidine” is the most widely used name in kratom-related research.

Preferred name Corynantheidine
Synonyms (-)-Corynantheidine; 9-demethoxy mitragynine
CAS Registry Number 23407-35-4 [17]
UNII QMP2RF3L41 [18]
PubChem CID 3000341 [19]
Molecular formula C₂₂H₂₈N₂O₃ [20]
Molecular weight 368.47 g/mol [21]
InChIKey NMLUOJBSAYAYEM-QALMDFCDSA-N
SMILES CC[C@@H]1CN2CCC3=C(NC4=C3C=CC=C4)[C@@H]2C[C@@H]1\C(=C/OC)C(=O)OC

Natural Occurrence & Quantification of Corynantheidine

  1. Analyses of authenticated kratom preparations and U.S. commercial products show corynantheidine levels typically ranging from ~0.02–1.16% w/w. Reported values include alkaloid-enriched fractions, lyophilized teas, and various retail formulations [22]
  2. Controlled cultivation studies (field versus greenhouse) found that leaf concentrations (mg/g dry mass) remained consistently low and were not significantly affected by light regime. However, overall per-plant alkaloid yield varied with biomass. Detailed per-condition results are provided in Table 1 of the original study [24].
  3. Regional surveys and chemotype comparisons confirm substantial variability in kratom alkaloid composition, including minor constituents such as corynantheidine. These findings align with the broad product-to-product differences observed across commercial markets [25][26].

Receptor Pharmacology

  1. µ-Opioid receptor (MOR): Corynantheidine binds MOR with Ki ≈ 118 ± 12 nM (human) and ≈ 57.1 ± 8.3 nM (mouse). Functional assays indicate partial agonist activity (Emax ~74% in mouse [35S]GTPγS; ~37% in hMOR BRET) [26][27].
  2. Adrenergic receptors: Displays higher affinity at α1D-adrenergic receptors (Ki = 41.7 ± 4.7 nM, human) [28].

    Selected non-opioid targets: PDSP panel screening identified notable binding at hα2A (Ki ~74 nM) and hNMDA (Ki ~83 nM) receptors, suggesting broader modulatory activity [29].

  1. Plasma (bioanalytical): FDA-guideline–validated UPLC–MS/MS assay quantified corynantheidine in rat plasma, supporting PK and MSI studies (accuracy, precision, selectivity, stability reported) [30].
  2. Products & plant material: Validated UPLC–MS/MS method quantified 10 major kratom alkaloids (including corynantheidine) across leaf extracts and retail products for QC/standardization [31].
  3. Expanded panels / HRMS: UPLC-HRMS profiled 14 alkaloids (indole + oxindole) in U.S.-grown plants and products, highlighting chemotype variability [32].
  4. Legacy urine screening: GC–MS full-scan assays detect kratom intake in urine (primarily mitragynine); minor alkaloids like corynantheidine are often underrepresented [33].
  5. Method landscape: Reviews summarize HPLC/UPLC-MS, HRMS, and GC–MS platforms, highlighting key challenges such as stability, stereoisomer resolution, and the development of single-alkaloid PK assays[34].

Safety & Drug–Drug Interactions

  1. CYP2D6: Corynantheidine is a competitive CYP2D6 inhibitor (IC₅₀ ≈ 4.2 µM; Kᵢ ≈ 2.8 µM) in human liver microsomes, suggesting potential interactions with CYP2D6 substrates such as antidepressants, beta-blockers, and certain opioids [35].
  2. CYP3A (probe-dependent): Inhibition observed with midazolam 1′-hydroxylase but not testosterone 6β-hydroxylase → indicates substrate-dependent CYP3A inhibition. Generalizing across all CYP3A drugs may be misleading [36].
  3. Translational context: PBPK and static modeling of kratom alkaloids demonstrate clinically meaningful DDI potential with CYP3A substrates (e.g., mitragynine–midazolam). While direct human data for corynantheidine are lacking, additive contributions are plausible [37][38].
  4. Transporters: P-gp inhibition has been reported for mitragynine in vitro; no data exist for corynantheidine, leaving its role in efflux-mediated DDIs uncertain [39].
  5. Practical implication: Co-use of corynantheidine-containing products with CYP2D6 or CYP3A substrates—especially those with narrow therapeutic indices—carries potential DDI risk. Pending human studies, clinical caution is recommended [40].

Discussion

  1. Pharmacology: Corynantheidine is a minor but pharmacologically relevant kratom indole alkaloid. Its mixed target profile—partial MOR agonism together with higher-affinity α1D-adrenergic binding—supports dual opioid/adrenergic mechanisms at sub-micromolar levels[41].
  2. Preclinical PK: Animal data show moderate oral bioavailability (~50%), a Tmax of ~4 h, and brain penetration confirmed by MSI, indicating CNS-relevant exposure under studied dosing conditions[42].
  3. Natural Occurrence: Reported quantities vary widely (≈0.02–1.16% w/w across leaves and commercial products), consistent with known chemotype and product-to-product variability [43].
  4. DDI Potential: Corynantheidine inhibits CYP2D6 (Ki ≈ 2.8 µM) and displays probe-dependent CYP3A inhibition. This raises concern for interactions with narrow-therapeutic-index substrates, though no human studies have confirmed the risk [44].
  5. Key Gaps: Human pharmacokinetics, dose–exposure–effect relationships, and clinical drug–drug interaction studies remain uncharacterized. These are critical for translating preclinical observations into real-world safety and efficacy guidance [45].

Refernces

  1. Cayman Chemical – Corynantheidine reference standard
  2. WHO Expert Committee on Drug Dependence – Kratom review (PDF)
  3. León et al., 2021 (Front Pharmacol; receptor profiling)
  4. Obeng et al., 2020 (Drug Metab Rev; receptor/enzyme interactions)
  5. Cayman Chemical – Opioid receptor binding data
  6. PubChem – Corynantheidine (CID 10566)
  7. NCATS Inxight Drugs – Corynantheidine
  8. Sharma et al., 2019 (J Pharm Biomed Anal; quant)
  9. León et al., 2021 (Front Pharmacol)
  10. Obeng et al., 2020 (Drug Metab Rev)
  11. King et al., 2020 (PK/MSI; full text)
  12. Kamble et al., 2020 (J Chromatogr B; LC–MS/MS assay)
  13. Kamble et al., 2019 (Toxicol Lett; CYP2D6/CYP3A)
  14. Todd et al., 2020 (Biopharm Drug Dispos)
  15. PubMed – database portal
  16. CAS Common Chemistry – 23407-35-4
  17. Precision FDA – UNII QMP2RF3L41
  18. NCATS Inxight Drugs – same UNII record
  19. PubChem – Corynantheidine (CID 3000341)
  20. ChemSpider – Corynantheidine (ID 2271987)
  21. Sharma et al., 2019 (Drug Test Anal; open access)
  22. Zhang et al., 2022 (PLOS ONE; cultivation/leaf mg·g⁻¹)
  23. Chear et al., 2021 (J Nat Prod; Malaysian leaves)
  24. Manwill et al., 2022 (Planta Med; UPLC-HRMS)
  25. Obeng et al., 2019 (J Med Chem; α1D & MOR Kᵢ)
  26. Chakraborty et al., 2021 (ACS Chem Neurosci; mouse MOR, hMOR BRET, PDSP)
  27. Váradi et al., 2016 (J Med Chem; pseudoindoxyl SAR)
  28. King et al., 2020 (PubMed record for PK)
  29. Kamble et al., 2021 (J Nat Prod; oral products PK in rats)
  30. Tanna et al., 2024/2023 (DMD; translational PK/DDI pdf)
  31. King et al., 2020 (PK paper; also methods)
  32. Sharma et al., 2019 (Drug Test Anal; methods)
  33. Manwill et al., 2022 (Planta Med; methods)
  34. (GC–MS urine screen; legacy)
  35. Citti, 2023 (review PDF)
  36. Kamble et al., 2019 (CYP inhibition)
  37. Tanna et al., 2021 (CPT: PSP; PBPK/static modeling)
  38. Tanna & Paine, 2023 (DMD review)
  39. Obeng et al., 2019 (J Med Chem; receptor panel)
  40. Chakraborty et al., 2021 (ACS Chem Neurosci)
  41. King et al., 2020 (PK/MSI)
  42. Sharma et al., 2019 (quant, % w/w)
  43. Kamble et al., 2019 (CYP2D6 Kᵢ ≈ 2.8 µM)
  44. Tanna & Paine, 2023 (human data gaps)