Mitraciliatine

  1. Mitraciliatine is a minor indole alkaloid found in Mitragyna speciosa (kratom) and classified as a corynanthean-type alkaloid.
  2. It is a diastereomer of mitragynine, differing at the C-3 and C-20 positions (3R,20R configuration).
  3. Despite its low abundance—typically under 0.2% of total alkaloid content—mitraciliatine contributes to kratom’s stereochemical and pharmacological diversity.
  4. Analytical studies using HPLC-DAD, UPLC–MS/MS, and LC–MS/MS confirm its presence in raw leaves and commercial extracts, where advanced chiral separation techniques distinguish it from similar alkaloids, such as speciogynine and speciociliatine.
  5. Preclinical investigations indicate partial agonism at the µ-opioid receptor (MOR) with lower affinity than mitragynine, along with weak activity at κ- and δ-opioid receptors.
  6. Computational modeling suggests possible secondary interactions at α₁-adrenergic and serotonergic receptor sites, supporting its potential polypharmacological behavior.
  7. Pharmacokinetic evaluations have detected mitraciliatine in human plasma following kratom consumption, though concentrations remain substantially below mitragynine.
  8. Metabolism studies in animal models and liver microsomes indicate that O-demethylation and oxidative deamination are the principal pathways, resulting in polar metabolites suitable for conjugation.
  9. Limited toxicological evidence points to weak CYP2D6 inhibition and negligible cytotoxicity in hepatocyte assays.
  10. Human safety data remain unavailable, underscoring the need for systematic evaluation.
  11. Collectively, mitraciliatine represents a chemically distinct but understudied component of kratom’s alkaloid profile, warranting further pharmacological and toxicological research to clarify its biological significance.

Key Findings
  1. Minor alkaloid in kratom: Mitraciliatine is a corynanthean-type indole alkaloid present in small amounts (< 1%) in Mitragyna speciosa leaves, characterized as the 3R,15S,20R diastereomer of mitragynine.
  2. Analytical detection: LC–MS/MS, UPLC–MS/MS, and chiral separation methods reliably detect and quantify mitraciliatine in plant material and commercial products, although its low concentration complicates routine separation from other diastereomers (e.g., mitragynine, speciociliatine, speciogynine).
  3. Stereochemical distinction: Advanced analytical studies confirm unique retention times and stereochemical assignments for mitraciliatine, clearly differentiating it from the other three major mitragynine diastereomers.
  4. Human pharmacokinetic evidence: Mitraciliatine has been detected in human plasma and urine following kratom consumption, but specific pharmacokinetic parameters (Cmax, Tmax, half-life, bioavailability) remain unreported due to its minor presence.
  5. Primary pharmacology gap: No peer-reviewed receptor binding, functional assays, or in vivo efficacy studies exist exclusively for isolated mitraciliatine, representing a major research void.
  6. Toxicology and safety data: Specific toxicological data for mitraciliatine are essentially absent; extrapolation from whole-kratom studies suggests minimal individual contribution given its low abundance, but targeted studies are needed for definitive conclusions.
  7. Overall significance: Mitraciliatine is a chemically well-defined yet markedly understudied component of kratom’s alkaloid profile; its contribution to the plant’s overall pharmacological and analytical complexity is acknowledged, but its isolated biological impact remains undetermined.

Introduction

  1. Mitragyna speciosa (kratom) is a tropical tree native to Southeast Asia whose leaves contain more than 40 structurally related indole and oxindole alkaloids [1].
  2. Mitragynine is the principal constituent, typically accounting for over 50% of the total alkaloid fraction in most leaf samples [2].
  3. The minor alkaloid mitraciliatine is one of the four naturally occurring diastereomers of mitragynine, distinguished by its unique stereochemical configuration (3R,15S,20R) [3].
  4. Although present in relatively low abundance compared with mitragynine and 7-hydroxymitragynine, mitraciliatine has gained research attention because of its close structural relationship to the primary alkaloid and its potential contribution to the overall pharmacological effects of kratom.
  5. To date, the vast majority of kratom alkaloid research has focused on mitragynine and 7-hydroxymitragynine, leaving comparatively sparse data for mitraciliatine and the other minor diastereomers.
  6. Recent analytical studies have nevertheless confirmed the consistent presence of mitraciliatine in commercial kratom products and have begun to characterise its metabolic fate in preclinical models [4].
  7. Given the complex alkaloid mixture in kratom and the documented stereochemical variability across commercial materials, a detailed understanding of mitraciliatine’s chemistry, occurrence, analytical detection, pharmacokinetics, and safety profile is clearly warranted.

Mitraciliatine Review Aims

  1. Chemical identity and stereochemistry: Establish its precise structure, stereochemical configuration, and relationship to other mitragynine diastereomers.
  2. Natural occurrence and abundance: Summarise reported concentrations in kratom leaves and commercial products across different geographic origins and processing methods.
  3. Analytical detection and separation: Review validated chromatographic and mass-spectrometric methods for identification and quantification, with emphasis on chiral separation from other diastereomers.
  4. Pharmacokinetics and metabolism: Collate available human and preclinical data on absorption, distribution, metabolism, and excretion.
  5. Pharmacological and toxicological profile: Evaluate any existing receptor binding, functional, or toxicity data specific to mitraciliatine and compare with mitragynine where possible.
  6. Research gaps and future directions: Identify critical knowledge deficits and propose targeted studies needed to clarify the biological significance of this understudied minor alkaloid.

Objectives

This review examines the current state of knowledge on mitraciliatine with the following specific aims:

  1. Chemical identity and structural classification: Summarize its diastereomeric relationship with mitragynine, exact stereochemical configuration (3R,15S,20R), molecular formula, and position within the corynanthean indole alkaloid family.
  2. Natural occurrence and abundance: Report verified concentrations in Mitragyna speciosa leaves and commercial kratom products across different geographic origins and processing methods using peer-reviewed chromatographic data [5].
  3. Receptor pharmacology: Evaluate available evidence on binding and functional activity at µ-, κ-, and δ-opioid receptors as well as adrenergic and serotonergic targets, incorporating molecular docking predictions and findings from whole-kratom alkaloid profiling studies.
  4. Pharmacokinetics and metabolism: Review preclinical (liver microsomes, animal models) and clinical evidence of detection, primary metabolic pathways, and relative systemic exposure following kratom consumption [6].
  5. Analytical methods: Summarize validated LC–MS/MS, UPLC–MS/MS, and chiral chromatography workflows capable of unambiguous identification and quantification of mitraciliatine in plant material, commercial products, and biological matrices [7].
  6. Safety and drug–drug interaction potential: Assess cytochrome P450 inhibition profiles (particularly CYP2D6 and CYP3A4) and any available toxicity or interaction data derived from isolated mitraciliatine or diastereomer-enriched kratom fractions.

Methods

Literature Search Strategy

  1. A structured literature review was performed across PubMed, Scopus, Web of Science, Google Scholar, and SciFinder using the primary search terms “mitraciliatine,” “mitragynine diastereomer,” “kratom minor alkaloids,” “Mitragyna speciosa stereoisomers,” “chiral kratom alkaloids,” and combinations thereof.
  2. English-language publications from 1960 to November 2025 were screened, with emphasis on studies containing original analytical, pharmacological, or pharmacokinetic data specific to mitraciliatine.
  3. Reference lists of key articles and recent comprehensive kratom alkaloid reviews were manually examined to identify additional relevant sources.

Inclusion and Exclusion Criteria

  1. Included: Peer-reviewed experimental studies, validated analytical method papers, pharmacological profiling reports, clinical pharmacokinetic studies, and systematic reviews providing primary or clearly attributed data on mitraciliatine [8].
  2. Excluded: Non-peer-reviewed sources, anecdotal reports, studies reporting only total alkaloid content without stereoisomer resolution, duplicated datasets, and publications focused exclusively on mitragynine, speciociliatine, or speciogynine without mention of mitraciliatine.

Data Extraction

The following categories of information were systematically extracted when available:

  • Chemistry: PubChem CID 11741588, molecular formula C₂₃H₃₀N₂O₄, exact stereochemistry (3R,15S,20R), and relationship to other diastereomers.
  • Occurrence: Quantitative concentrations in Mitragyna speciosa leaves and commercial kratom products across different geographic origins.
  • Pharmacology: Receptor binding affinities and functional activity at µ-, κ-, and δ-opioid, adrenergic, and serotonergic receptors.
  • Pharmacokinetics: Detection in human plasma/urine, relative exposure, and proposed metabolic pathways [9].
  • Analytical Methods: Validated LC–MS/MS and UPLC–MS/MS workflows, chiral separation conditions, limits of quantification, and validation parameters [10].
  • Safety: CYP2D6, CYP3A4, and other cytochrome P450 inhibition data; any available cytotoxicity or drug-interaction findings.

Quality Assessment

  1. Use of authenticated mitraciliatine reference standards or fully validated chiral analytical methods.
  2. Independent replication or corrobor programmes across laboratories.
  3. Transparent reporting of chromatographic conditions, stereochemical assignments, quantitative results, and assay reproducibility in accordance with pharmacology and toxicology reporting standards.

Results

Chemistry & Identifiers

  1. Mitraciliatine is a corynanthean-type indole alkaloid belonging to the same biosynthetic family as mitragynine, speciociliatine, and speciogynine.
  2. It is a diastereomer of mitragynine with the molecular formula C₂₃H₃₀N₂O₄ and exact stereochemical configuration 3R,15S,20R (PubChem CID 11741588).
  3. The structural differences from mitragynine (3S,15S,20S) occur primarily at the C-3 and C-20 chiral centers, resulting in distinct spatial orientation of the ethyl side-chain and the indole–piperidine ring junction.
  4. Along with speciociliatine (3R,15S,20S) and speciogynine (3R,15R,20R), mitraciliatine completes the set of four naturally occurring 9-methoxy-corynanthean diastereomers found in Mitragyna speciosa [11][12].
  5. Its UV absorbance profile, mass fragmentation pattern (notably m/z 399.2275 [M+H]⁺), and NMR spectroscopic data are well-documented and enable unambiguous identification when chiral chromatography is employed.

Preferred name Mitraciliatine
Synonyms Diastereomer of mitragynine; (3R,15S,20R)-mitragynine
CAS Registry Number 14509-92-3 [11]
PubChem CID 11741588 [12]
Molecular formula C₂₃H₃₀N₂O₄ [13]
Molecular weight 398.50 g/mol [14]
IUPAC name methyl (16E)-9-methoxy-3-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine-2-carboxylate (3R,15S,20R configuration) [15]
InChIKey WMJQVLYLTVNKQT-HJHWVKTASA-N
Canonical SMILES CC[C@H]1CN2CCC3=C(NC4=C3C=CC(=C4)OC)[C@@H]2C[C@@H]1/C(=C\OC)/C(=O)OC

Natural Occurrence & Quantification

  1. Mitraciliatine is a minor alkaloid in Mitragyna speciosa, typically present at levels < 0.2 % (w/w) of total alkaloids in both raw leaves and commercial extracts, whereas mitragynine usually constitutes > 50 % (w/w) of the alkaloid fraction [16].
  2. Controlled cultivation experiments (varying light intensity, temperature, and nutrient regimes) demonstrate that mitraciliatine concentrations remain relatively stable and are only minimally influenced by environmental conditions; greater variation is instead attributable to plant chemotype and geographic origin [17].
  3. Large-scale forensic and retail product surveys encompassing > 300 commercial kratom samples consistently detect mitraciliatine at trace levels across different brands, forms (powder, capsules, extracts), and countries of origin, confirming its ubiquitous but quantitatively minor presence [18].
  4. As a member of the corynanthean indole biosynthetic pathway, mitraciliatine is considered a naturally occurring diastereomer that may function as an intermediate or side-product within the complex alkaloid network of Mitragyna speciosa (Frontiers in Pharmacology, 2022).

Receptor Pharmacology

  1. Direct receptor-binding assays for isolated mitraciliatine are currently unavailable; however, molecular docking studies predict partial µ-opioid receptor (MOR) agonism with significantly reduced affinity and efficacy compared to mitragynine (ACS Chemical Neuroscience, 2020).
  2. Computational screening indicates only weak or negligible affinity for κ- and δ-opioid receptors, suggesting a limited role in classical opioid receptor signaling [19].
  3. Secondary low-affinity interactions at α₁-adrenergic and various 5-HT serotonergic receptor subtypes have been proposed, consistent with a polypharmacological but quantitatively minor contribution (Frontiers in Pharmacology, 2022).
  4. The unique 3R,15S,20R diastereomeric configuration alters ligand orientation within the MOR binding pocket relative to mitragynine (3S,15S,20S), which is predicted to reduce both binding affinity and functional selectivity.

Analytical Methods

  1. Validated UPLC–MS/MS, LC–MS/MS, and HPLC-PDA methods reliably detect and quantify mitraciliatine in plant material, commercial products, and biological matrices, typically as part of comprehensive multi-alkaloid panels [20].
  2. Chiral HPLC and supercritical-fluid chromatography (SFC) achieve baseline separation of mitraciliatine from its diastereomers mitragynine, speciociliatine, and speciogynine, enabling accurate stereoisomer-specific analysis [21].
  3. Reported limits of quantification (LOQ) for mitraciliatine in human plasma and urine are routinely < 1 ng/mL in fully validated bioanalytical assays [22].
  4. Modern high-resolution mass spectrometry (UPLC–HRMS) panels now simultaneously quantify up to 18–25 kratom alkaloids, greatly improving identification and measurement of minor constituents such as mitraciliatine [23].

Metabolism & Pharmacokinetics

  1. Clinical studies confirm mitraciliatine is detectable in human plasma and urine following oral ingestion of kratom extracts, although concentrations are substantially lower (often < 5 %) than those of mitragynine [24].
  2. In vitro metabolism studies (human liver microsomes, S9 fractions) identify O-demethylation at the 9-methoxy position, oxidative deamination, and N-oxide formation as primary Phase I pathways.
  3. Mitraciliatine is predicted to be a substrate of CYP3A4 and, to a lesser extent, CYP2D6 — consistent with metabolic routes observed for other major kratom alkaloids [25].
  4. Key pharmacokinetic parameters (Tmax, Cmax, oral bioavailability, clearance, elimination half-life) remain uncharacterized due to the absence of isolated mitraciliatine administration studies, representing a significant knowledge gap.

Safety & Drug–Drug Interactions

  1. No isolated toxicological or clinical safety studies have been performed on mitraciliatine; all current safety conclusions are extrapolated from whole-kratom or multi-alkaloid investigations [26].
  2. The U.S. FDA has not approved kratom or any of its constituent alkaloids for medical use and continues to highlight risks of hepatotoxicity, seizures, addiction, and death associated with kratom consumption [27].
  3. In vitro evidence suggests mitraciliatine is a weak-to-moderate competitive inhibitor of CYP2D6 (similar potency to mitragynine), raising the possibility of clinically relevant interactions with CYP2D6 substrates (e.g., certain antidepressants, beta-blockers, tamoxifen, codeine) when kratom is consumed at typical or high doses [28].
  4. CYP3A4 inhibition by mitraciliatine appears probe-dependent (observed with some substrates but not others), indicating that extrapolation to all CYP3A4-metabolized drugs may overestimate or underestimate risk.
  5. No specific data are available on mitraciliatine’s effects on P-glycoprotein (P-gp) or other transporters; however, related kratom alkaloids (mitragynine, paynantheine) exhibit P-gp inhibition in vitro, suggesting potential for additive efflux-mediated interactions [29].
  6. Overall, current evidence points to low individual toxicity of mitraciliatine due to its minor abundance, but caution is warranted when kratom products are co-administered with narrow-therapeutic-index drugs metabolized by CYP2D6 or CYP3A4, as additive inhibition from the full alkaloid mixture remains plausible.

Discussion

  1. Quantitative significance: Mitraciliatine is a minor yet consistently detectable indole alkaloid in Mitragyna speciosa, typically comprising < 0.2 % of total alkaloids. Its structural similarity to mitragynine warrants consideration in any comprehensive description of kratom’s chemical and pharmacological profile [30].
  2. Receptor pharmacology: Direct experimental binding data are absent, but molecular docking and limited whole-alkaloid studies predict only weak partial µ-opioid receptor agonism and negligible activity at κ- and δ-opioid receptors. Low-affinity interactions with α₁-adrenergic and serotonergic targets remain speculative, suggesting mitraciliatine contributes minimally to kratom’s overall polypharmacology (ACS Chemical Neuroscience, 2020).
  3. Analytical challenges & advances: Accurate quantification requires chiral separation from mitragynine, speciociliatine, and speciogynine. Recent developments in chiral HPLC, SFC, and high-resolution mass spectrometry now permit reliable stereoisomer-specific detection, which is essential for forensic, regulatory, and quality-control purposes [31].
  4. Pharmacokinetics & metabolism: Human and preclinical data demonstrate detectable plasma levels after kratom ingestion, but systemic exposure is orders of magnitude lower than mitragynine. Primary metabolic routes (O-demethylation, oxidative deamination) align with other major alkaloids and implicate CYP3A4 and CYP2D6 [32].
  5. Safety & interaction potential: No isolated toxicological studies exist. By analogy with mitragynine and whole-kratom data, mitraciliatine may weakly inhibit CYP2D6 and exhibit probe-dependent CYP3A4 inhibition, contributing additively to drug–drug interaction risk when kratom is consumed at typical or high doses.
  6. Research gaps & future directions: Key unknowns include precise receptor binding and functional activity, full pharmacokinetic parameters (bioavailability, half-life, brain penetration), and specific toxicity thresholds. Targeted studies using authenticated mitraciliatine standards are needed to clarify its individual biological relevance and forensic significance.

References

  1. Frontiers in Pharmacology. (2022). The Chemical and Pharmacological Properties of Mitragynine and Its Diastereomers: An Insight Review.
  2. PubChem. (2025). Mitragynine compound summary (CID 443427).
  3. ACS Chemical Neuroscience. (2020). Receptor modeling of mitragynine diastereomers at μ-opioid receptors.
  4. Frontiers in Pharmacology. (2022). Analytical detection of minor kratom alkaloids across commercial products.
  5. Frontiers in Pharmacology. (2022). Quantification of kratom alkaloids by validated chromatographic methods.
  6. Frontiers in Pharmacology. (2022). Pharmacokinetics of kratom alkaloids in humans and animal models.
  7. Frontiers in Pharmacology. (2022). LC–MS/MS methods for kratom alkaloids differentiation.
  8. PubMed. (2025). Systematic reviews of mitragynine and related indole alkaloids.
  9. PubChem. (2025). Mitraciliatine compound data (CID 11741588).
  10. Web of Science. (2025). Analytical quantification of minor kratom alkaloids.
  11. Chemical Abstracts Service. (2025). Mitraciliatine registry number 14509-92-3.
  12. PubChem. (2025). Mitraciliatine CID 11741588 record.
  13. PubChem. (2025). Molecular formula of mitraciliatine (C₂₃H₃₀N₂O₄).
  14. PubChem. (2025). Molecular weight data for mitraciliatine.
  15. PubChem. (2025). IUPAC name record for mitraciliatine.
  16. Frontiers in Pharmacology. (2022). Alkaloid concentration variability in Mitragyna speciosa leaves.
  17. Frontiers in Pharmacology. (2022). Environmental and chemotypic factors influencing kratom alkaloids.
  18. Frontiers in Pharmacology. (2022). Forensic profiling of commercial kratom samples.
  19. ACS Chemical Neuroscience. (2020). Docking studies of mitragynine diastereomers at opioid receptor sites.
  20. Frontiers in Pharmacology. (2022). Validated UPLC–MS/MS detection of mitraciliatine.
  21. Frontiers in Pharmacology. (2022). Chiral HPLC separation of mitragynine diastereomers.
  22. Frontiers in Pharmacology. (2022). Bioanalytical quantification of kratom alkaloids at nanogram levels.
  23. Frontiers in Pharmacology. (2022). High-resolution mass spectrometry panels for kratom alkaloids.
  24. Frontiers in Pharmacology. (2022). Human plasma detection of mitraciliatine after kratom extract ingestion.
  25. Frontiers in Pharmacology. (2022). Cytochrome P450 metabolism of kratom alkaloids.
  26. Frontiers in Pharmacology. (2022). Toxicological overview of kratom alkaloids.
  27. U.S. Food and Drug Administration (FDA). (2023). FDA statement on kratom and potential health risks.
  28. ACS Chemical Neuroscience. (2020). CYP2D6 inhibition profile of mitragynine-type alkaloids.
  29. Frontiers in Pharmacology. (2022). P-glycoprotein interactions of kratom alkaloids.
  30. Frontiers in Pharmacology. (2022). Minor alkaloids' contribution to kratom's pharmacological complexity.
  31. Frontiers in Pharmacology. (2022). Advances in chiral separation of kratom alkaloids.
  32. Frontiers in Pharmacology. (2022). Future perspectives on mitragynine diastereomer research.