Corynantheidine

Corynantheidine, also known as 9-demethoxy mitragynine, is a secondary indole alkaloid present in Mitragyna speciosa (kratom).
Although detected at lower concentrations than mitragynine or 7-hydroxymitragynine, corynantheidine contributes to kratom’s pharmacological complexity through mixed opioid and non-opioid activity.
Analytical characterization has identified it consistently in kratom leaves and commercial extracts, with validated UPLC–MS/MS and GC–MS methods available for quantification.
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).
Additional displacement at serotonergic receptor subtypes has been observed at micromolar concentrations, suggesting broader polypharmacology.
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.
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.
While human studies remain unavailable, current evidence suggests corynantheidine may contribute to the pharmacological and toxicological profile of kratom beyond its minor quantitative presence.
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

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.
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.
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.
Serotonergic interactions: Demonstrates measurable displacement at multiple 5-HT receptor subtypes at micromolar concentrations, indicating possible serotonergic involvement.
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.
Analytical validation: UPLC–MS/MS and GC–MS methods enable sensitive quantification in plasma, urine, and plant material, supporting pharmacokinetic and forensic investigations.
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.
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

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].
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].
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].
This dual pharmacology suggests corynantheidine contributes to kratom’s overall effects through both opioid partial agonism and adrenergic modulation.
Potential relevance includes analgesic properties, modulation of cardiovascular tone, and drug–drug interaction (DDI) risk via metabolic pathways.

Corynantheidine Review Aims

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

Methods

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.”
Articles published in English between 2000 and 2024 were considered [16].
Reference lists of retrieved studies were screened to identify additional relevant publications.

Inclusion and Exclusion Criteria

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

Data Extraction

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

Quality Assessment

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

Results: Chemistry & Identifiers

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.

Natural Occurrence & Quantification of Corynantheidine

In authenticated kratom preparations and U.S. commercial products, corynantheidine ranges from ~0.02–1.16% w/w of material analyzed; examples across an alkaloid fraction, lyophilized tea, and multiple retail products are shown below [22].

In controlled cultivation experiments (field vs. greenhouse), leaf corynantheidine (mg/g dry mass) was consistently low and not significantly affected by light regime, while per-plant alkaloid yield varied with biomass; detailed per-condition values are reported in Table 1 of the study [23].

Regional surveys and chemotype work confirm substantial between-product variability in kratom alkaloid profiles (including minor alkaloids); these studies support the product-to-product spread seen for corynantheidine [24, 25].

Receptor Pharmacology

µ-opioid receptor (MOR): Corynantheidine binds MOR with Ki ≈ 118 ± 12 nM (human) and ≈ 57.1 ± 8.3 nM (mouse); it is a partial agonist in functional assays (Emax ~74% in mouse [³⁵S]GTPγS; ~37% in hMOR BRET). [26, 27]

Adrenergic receptors: Show notably higher affinity at α1D-adrenergic (Ki = 41.7 ± 4.7 nM, human). [28]

Selected non-opioid targets: PDSP panel indicates hα2A (Ki ~74 nM) and hNMDA (Ki ~83 nM) among the higher-affinity non-opioid sites. [29]

Analytical Methods

Plasma (bioanalytical): FDA-guideline–validated UPLC–MS/MS assay quantified corynantheidine in rat plasma; supported PK and MSI work (accuracy, precision, selectivity, stability reported). [30]
Products & plant material: Validated UPLC–MS/MS method quantified 10 key kratom alkaloids (incl. corynantheidine) across leaf extracts and commercial products for QC/standardization. [31]
Expanded panels / HRMS: UPLC-HRMS quantified 14 alkaloids (indole + oxindole) in US-grown plants/products, illustrating chemotype variability. [32]
Legacy urine screening: GC–MS full-scan procedures monitor kratom intake in urine (mainly mitragynine); minor alkaloids like corynantheidine may be under-represented. [33]
Method landscape: Reviews summarize HPLC/UPLC-MS, HRMS, GC–MS platforms, matrices, and pitfalls (e.g., stability, stereoisomer resolution), including single-alkaloid PK assays. [34]

Safety & Drug–Drug Interactions

CYP2D6: Corynantheidine is a competitive CYP2D6 inhibitor (IC₅₀ ≈ 4.2 µM; Kᵢ ≈ 2.8 µM) in human liver microsomes → plausible interaction with CYP2D6 substrates (antidepressants, beta-blockers, certain opioids). [35]

CYP3A (probe-dependent): Inhibition seen with midazolam 1′-hydroxylase but not testosterone 6β-hydroxylase → substrate-dependent CYP3A signal; avoid over-generalizing across all CYP3A drugs. [36]

Translational context: PBPK/static modeling with kratom alkaloids shows clinically meaningful DDI potential with CYP3A substrates (demonstrated for mitragynine–midazolam; corynantheidine likely contributes additively). Human data for corynantheidine specifically are absent. [37, 38]

Transporters: P-gp inhibition reported for mitragynine in vitro; no direct transporter data for corynantheidine → unknown contribution to efflux-mediated DDIs. [39]

Practical implication: If corynantheidine-containing products are co-used with CYP2D6 or CYP3A substrates (especially narrow-therapeutic-index drugs), DDI risk exists. Clinical evidence for corynantheidine is lacking, so decisions should default to caution pending human studies. [40]

Discussion

Corynantheidine is a minor but pharmacologically relevant kratom indole alkaloid. Its mixed target profile—partial MOR agonism alongside higher-affinity α1D-adrenergic binding—supports dual opioid/adrenergic mechanisms at sub-micromolar levels [41]. Preclinical PK shows moderate oral bioavailability (~50%), Tmax ~4 h, and brain exposure by MSI, indicating CNS-relevant concentrations under studied dosing conditions [42]. Across leaves and products, quantity varies widely (≈0.02–1.16% w/w in a representative dataset), consistent with known chemotype and product variability [43]. In DDI risk, corynantheidine is a CYP2D6 inhibitor (Ki ~2.8 µM) and shows probe-dependent CYP3A inhibition, warranting caution with narrow-therapeutic-index substrates pending human data [44]. Overall, the most critical data gaps are human PK, dose–exposure–effect relationships, and clinical DDI studies; these are needed to translate preclinical findings to real-world safety and efficacy [45].

Corynantheidine