9-Hydroxycorynantheidine

9-Hydroxycorynantheidine at a Glance

9-Hydroxycorynantheidine is a Corynanthe-type indole alkaloid belonging to the mitragynine family of Mitragyna speciosa (kratom). Structurally it is mitragynine with the C-9 methyl ether stripped back to a free phenol — which is why its other name, 9-O-demethylmitragynine, is at least as common in the literature as the one above ^{9,10Reference 9Melchert PW et al. · 2024In vitroAn in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynineView study →Reference 10Basiliere S · 2020Identification of metabolites and potential biomarkers of kratom in urineView study →}.

Two things define it. First, it is one of the two major metabolites mitragynine is converted into in the body — the other being mitragynine carboxylic acid — so anyone who has taken kratom has been exposed to it ^{12Reference 12McCurdy CR et al. · 2024ReviewAn update on the clinical pharmacology of kratom: uses, abuse potential, and future considerationsView study →}. Second, it sits at a genuinely instructive point in a structure-activity series: corynantheidine has nothing at C-9 and behaves as a mu-opioid antagonist; this molecule has a hydroxyl there and behaves as a partial agonist; mitragynine has a methoxy there and also behaves as a partial agonist ^{3,5Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →Reference 5Takayama H et al. · 2002Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligandsView study →}.

The evidence base is small and honest about its limits: roughly seven papers name the molecule at all, every one of them used material semi-synthesised from mitragynine rather than isolated from leaf, and there is not a single human or clinical study of it. The most useful single result in that literature is a negative one — it did not produce antinociception in mice at doses up to 100 mg/kg ^{4Reference 4Chakraborty S et al. · 2021Oxidative metabolism as a modulator of kratom’s biological actionsView study →}.

The C-9 Substituent Series

The most interesting thing about this molecule is what it reveals about the position it is named for. Three closely related kratom alkaloids differ only in what sits at carbon 9 of the indole ring:

Alkaloid	C-9 substituent	Reported mu-opioid behaviour
Corynantheidine	— (hydrogen)	Functional antagonist; reverses morphine’s effect in guinea-pig ileum 3,5,16Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →Reference 5Takayama H et al. · 2002Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligandsView study →Reference 16King TI et al. · 2020Bioanalytical method development and validation of corynantheidine, a kratom alkaloid, using UPLC-MS/MS, and its application to preclinical pharmacokinetic studiesView study →
9-Hydroxycorynantheidine	–OH	Partial agonist, mu-selective 1Reference 1Matsumoto K et al. · 2006Partial agonistic effect of 9-hydroxycorynantheidine on mu-opioid receptor in the guinea-pig ileumView study →
Mitragynine	–OCH₃	Low-efficacy partial agonist 2Reference 2Kruegel AC et al. · 2016Synthetic and receptor signaling explorations of the Mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulatorsView study →

Read quickly, that table says a single hydroxyl converts an antagonist into an agonist. Read carefully, it says something more specific and more useful.

The C-9 substituent barely touches binding affinity. Screened side by side in the same laboratory, all three bind the human mu-opioid receptor within a factor of two of each other — 9-hydroxycorynantheidine at Kᵢ ≈ 105 nM, corynantheidine at 118 nM, mitragynine at 161 nM ^{3Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →}. The authors’ own reading is that neither the methoxy nor the hydroxy group forms a strong interaction with the key mu-receptor residues, which is exactly why the three affinities converge ^{3Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →}.

Swapping methoxy for hydroxy barely touches efficacy either. When the 9-desmethyl (phenolic) analogue was made from mitragynine and run against the parent in the same G-protein assay at the human mu-receptor, it came out essentially indistinguishable — EC₅₀ 0.68 µM at 29% of the reference agonist’s maximum, versus 0.34 µM at 34% for mitragynine ^{2Reference 2Kruegel AC et al. · 2016Synthetic and receptor signaling explorations of the Mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulatorsView study →}. This was a surprise at the time, because in the classical morphinan opioids the equivalent methyl-ether-to-phenol swap (codeine to morphine) produces a dramatic jump in potency. Docking work in the same paper explained why it doesn’t here: the methoxyindole end of mitragynine points into a different pocket entirely, and never forms the water-mediated hydrogen bond to His297 that the morphinan phenol depends on ^{2Reference 2Kruegel AC et al. · 2016Synthetic and receptor signaling explorations of the Mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulatorsView study →}.

So what the series really shows is that at the mu-receptor, having some oxygen at C-9 appears to matter for efficacy, but which oxygen it is does not. And the substituent’s larger effects are elsewhere: removing the 9-methoxy sharply reduces kappa-opioid binding, and increases α1D-adrenoceptor affinity 131-fold — corynantheidine, with a bare C-9, is an adrenergic-preferring ligand that adopts a similar three-dimensional shape to yohimbine, while mitragynine is opioid-preferring ^{3Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →}.

Two caveats keep this from being a tidy story. The corynantheidine antagonist result comes from guinea-pig ileum, a different preparation from the recombinant human-receptor assays that generated the affinity numbers ^{5Reference 5Takayama H et al. · 2002Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligandsView study →}; and much bigger efficacy switches exist elsewhere in this scaffold — epimerising the C-20 ethyl group flips agonism to antagonism outright (speciogynine), and deleting the β-methoxyacrylate abolishes activity altogether ^{2Reference 2Kruegel AC et al. · 2016Synthetic and receptor signaling explorations of the Mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulatorsView study →}.

A Metabolite More Than a Leaf Alkaloid

This compound is routinely listed among kratom’s alkaloids, and that is true but misleading about proportion.

In the leaf it is a trace component that most analytical panels cannot quantify. The widely used ten-alkaloid UPLC-MS/MS panel for kratom products does not include it at all ^{15Reference 15Sharma A et al. · 2019Simultaneous quantification of ten key kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometryView study →}. A 2026 survey of Thai M. speciosa genotypes that did target it, across juvenile and mature leaves of multiple accessions, found it below the limit of quantification in every sample ^{14Reference 14Ransden KE et al. · 2026Comparative analysis of monoterpene indole alkaloid composition and genotypic variation in Thai Mitragyna speciosaView study →}. A controlled post-harvest study of two cultivars could only report it as detected or not detected against a 0.005% w/w threshold: present in ninety per cent of one cultivar’s samples when leaves were dried at 25 °C, gone below the threshold when the same leaves were dried at 60 °C, and never detected in the other cultivar at all ^{13Reference 13Zhang M et al. · 2025Alkaloid biosynthesis in medicinal crop kratom (Mitragyna speciosa) varies with postharvest, genetic, and seasonal factorsView study →}.

In the body it is a headline metabolite. Mitragynine is O-demethylated at C-9 by CYP2C19, CYP3A4 and CYP2D6 to give this molecule ^{8Reference 8Basiliere S · 2020CYP450-mediated metabolism of mitragynine and investigation of metabolites in human urineView study →}; it accounts for roughly 36% of total mitragynine metabolism in vitro ^{9Reference 9Melchert PW et al. · 2024In vitroAn in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynineView study →}; and reviews of kratom’s clinical pharmacology name it, alongside mitragynine carboxylic acid, as one of the two major metabolites ^{12Reference 12McCurdy CR et al. · 2024ReviewAn update on the clinical pharmacology of kratom: uses, abuse potential, and future considerationsView study →}. In rats dosed repeatedly with mitragynine it was one of the two dominant circulating metabolites, with 7-hydroxymitragynine only a minor one ^{11Reference 11Chiang YH et al. · 2024AnimalMultiple-dose pharmacokinetics and safety of mitragynine, the major alkaloid of kratom, in ratsView study →}.

The practical consequence is that the drying temperature of a kratom leaf probably has less to do with your exposure to this molecule than your CYP2C19 does.

What It's Used For

All of the pharmacology below is in vitro, ex vivo, or in rodents. There is no human study of this compound.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. Every row here is preclinical; nothing here has been tested in a person.

01Mu-Opioid Partial AgonismShaky38%Four independent in-vitro / ex-vivo systems agreeing on direction, disagreeing on magnitude ^{1,2,3,4Reference 1Matsumoto K et al. · 2006Partial agonistic effect of 9-hydroxycorynantheidine on mu-opioid receptor in the guinea-pig ileumView study →Reference 2Kruegel AC et al. · 2016Synthetic and receptor signaling explorations of the Mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulatorsView study →Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →Reference 4Chakraborty S et al. · 2021Oxidative metabolism as a modulator of kratom’s biological actionsView study →}

02Non-Opioid Receptor BindingShaky14%Single 99-target binding screen + one serotonin-receptor panel, active only at 10 µM ^{6,7Reference 6León F et al. · 2021Activity of Mitragyna speciosa (“kratom”) alkaloids at serotonin receptorsView study →Reference 7Chen Y et al. · 2025In vitroIn vitro pharmacology of mitragynine at α-adrenoceptorsView study →}

03In-Vivo AntinociceptionShaky8%One mouse study — negative up to 100 mg/kg subcutaneously ^{4Reference 4Chakraborty S et al. · 2021Oxidative metabolism as a modulator of kratom’s biological actionsView study →}

Mechanisms

The load-bearing observation is the mismatch: mu affinity indistinguishable from mitragynine’s, in-vitro partial agonism, and no measurable antinociception in a live animal ^{4Reference 4Chakraborty S et al. · 2021Oxidative metabolism as a modulator of kratom’s biological actionsView study →}. Binding is not effect.

Pharmacokinetics

This molecule’s pharmacokinetics are mostly someone else’s pharmacokinetics — it is chiefly a product of mitragynine metabolism rather than a compound anyone administers. Recombinant-enzyme work identifies CYP2C19, CYP3A4 and CYP2D6 as the isoforms that O-demethylate mitragynine at C-9 to produce it, and describes it as the most abundant phase-I metabolite formed in vitro ^{8Reference 8Basiliere S · 2020CYP450-mediated metabolism of mitragynine and investigation of metabolites in human urineView study →}. Human liver S9 kinetics put the Kₘ at 1.37 µM and Vₘₐₓ at 0.0931 nmol/min/mg protein, with formation accounting for around 36% of total mitragynine metabolism; the CYP3A index inhibitor ketoconazole cut its formation substantially, while major cannabinoids had only minor effects ^{9Reference 9Melchert PW et al. · 2024In vitroAn in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynineView study →}.

Once formed it is unusually stable. In human liver microsomes its half-life was 181 minutes, versus 20 minutes for mitragynine and just 6.1 minutes for corynantheidine — the hydroxylated kratom alkaloids resist further oxidative metabolism and are cleared instead by conjugation ^{3Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →}. Like the other kratom alkaloids it is more than 97% bound to human plasma protein ^{3Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →}, and it is subsequently glucuronidated ^{4Reference 4Chakraborty S et al. · 2021Oxidative metabolism as a modulator of kratom’s biological actionsView study →}. In rats given repeated oral mitragynine it was one of the two major circulating metabolites, with markedly higher exposure in females than males ^{11Reference 11Chiang YH et al. · 2024AnimalMultiple-dose pharmacokinetics and safety of mitragynine, the major alkaloid of kratom, in ratsView study →}.

Clinical Trials

None. No trial has administered 9-hydroxycorynantheidine to a human, and it appears in human research only as an analyte measured in urine after kratom use ^{10Reference 10Basiliere S · 2020Identification of metabolites and potential biomarkers of kratom in urineView study →}.

Last checked: July 2026.

Isolate vs. Plant Studies

Unusually, there are no plant-extract studies of this molecule at all — and no isolation-from-plant studies either. Every pharmacology paper that names it used material semi-synthesised from mitragynine: Matsumoto’s guinea-pig ileum work states it plainly ^{1Reference 1Matsumoto K et al. · 2006Partial agonistic effect of 9-hydroxycorynantheidine on mu-opioid receptor in the guinea-pig ileumView study →}, Kruegel’s group prepared it from the isolated natural product ^{2Reference 2Kruegel AC et al. · 2016Synthetic and receptor signaling explorations of the Mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulatorsView study →}, and the Florida group explicitly obtained it “by semisynthesis from mitragynine following the procedure reported by Kruegel et al.” ^{3,6Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →Reference 6León F et al. · 2021Activity of Mitragyna speciosa (“kratom”) alkaloids at serotonin receptorsView study →}. The 2026 Thai genotype survey likewise used a semi-synthetic analytical standard because plant-derived material was not available ^{14Reference 14Ransden KE et al. · 2026Comparative analysis of monoterpene indole alkaloid composition and genotypic variation in Thai Mitragyna speciosaView study →}.

That is a strength for the receptor data — the assays tested a pure, characterised molecule, not a mixture — and a weakness for any claim about kratom the plant. Nothing in this literature tells you what a leaf containing trace amounts of this alkaloid does, and nothing licenses transferring kratom’s effects onto it. The in-vivo result argues the other way: this compound is present in the body after kratom use, binds mu-receptors well, and still did not reproduce the plant’s analgesia ^{4Reference 4Chakraborty S et al. · 2021Oxidative metabolism as a modulator of kratom’s biological actionsView study →}.

Analytical Significance

Its practical importance is as a marker of kratom exposure. Because it is the most prevalent phase-I mitragynine metabolite in kratom users’ urine, forensic and clinical toxicology treat it as a confirmatory analyte ^{8Reference 8Basiliere S · 2020CYP450-mediated metabolism of mitragynine and investigation of metabolites in human urineView study →}. In a case series analysed by LC-QTOF-MS it was detected in 75% of unhydrolysed urine samples (7-hydroxymitragynine, by comparison, in 63%), and the authors found deconjugation unnecessary given how much unconjugated parent, diastereomer and metabolite was already present — chemical hydrolysis actually degraded the Mitragyna alkaloids ^{10Reference 10Basiliere S · 2020Identification of metabolites and potential biomarkers of kratom in urineView study →}.

This matters because kratom detection is not a single-analyte problem. Mitragynine’s own diastereomers, speciociliatine and speciogynine, frequently exceed mitragynine itself in unhydrolysed urine, so any method that watches only the parent alkaloid will under-report exposure ^{10Reference 10Basiliere S · 2020Identification of metabolites and potential biomarkers of kratom in urineView study →}. Chromatographic separation of the diastereomers and of alkaloids sharing ion transitions is the hard part of these assays ^{15Reference 15Sharma A et al. · 2019Simultaneous quantification of ten key kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometryView study →}.

Prevalence in Nature

Reported only from kratom (Mitragyna speciosa), and there only at trace level. It is absent from the standard ten-alkaloid quantification panel used for kratom leaf and commercial products, which covers corynantheidine, isocorynantheidine, mitragynine, paynantheine, speciociliatine, speciogynine, 7-hydroxymitragynine and three oxindoles instead ^{15Reference 15Sharma A et al. · 2019Simultaneous quantification of ten key kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometryView study →}. Where it has been targeted, the results are borderline: below the limit of quantification in every juvenile and mature leaf sample across multiple Thai accessions ^{14Reference 14Ransden KE et al. · 2026Comparative analysis of monoterpene indole alkaloid composition and genotypic variation in Thai Mitragyna speciosaView study →}, and in a two-cultivar post-harvest experiment reported only as detected-or-not against a 0.005% w/w threshold — above it in 90% of low-temperature-dried ‘MR-Malaysian’ samples, below it after drying at 60 °C, and never detected in the ‘Hawaii’ cultivar ^{13Reference 13Zhang M et al. · 2025Alkaloid biosynthesis in medicinal crop kratom (Mitragyna speciosa) varies with postharvest, genetic, and seasonal factorsView study →}.

For scale, mitragynine itself runs from roughly 0.7% to 38.7% w/w in analysed kratom extracts and products, with paynantheine, speciociliatine and speciogynine also reaching several per cent ^{15Reference 15Sharma A et al. · 2019Simultaneous quantification of ten key kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometryView study →}. Chemotype surveys of commercial kratom likewise find the profile dominated by those alkaloids ^{17Reference 17Manwill PK et al. · 2022Kratom (Mitragyna speciosa) validation: quantitative analysis of indole and oxindole alkaloids reveals chemotypes of plants and productsView study →}. This molecule is at least three orders of magnitude below them.

Biosynthetically it belongs to the Corynanthe branch of the monoterpene indole alkaloid pathway that also gives kratom corynantheidine, isocorynantheidine and the spirooxindoles ^{14Reference 14Ransden KE et al. · 2026Comparative analysis of monoterpene indole alkaloid composition and genotypic variation in Thai Mitragyna speciosaView study →}; enzymology reconstituted in Nicotiana benthamiana shows the 20S form is a substrate for MsCO1, the kratom oxidase that builds the spirooxindole scaffold — a plausible route by which any that does form in the leaf is consumed again ^{18Reference 18Wangmo KS et al. · 2026ReviewA review on Mitragyna alkaloids pharmacology, biosynthesis and biotechnological insightsView study →}.

Discovery & Synthesis

There is no first-isolation paper for this compound in the way there is for mitragynine. It entered the literature as a semi-synthetic probe: Takayama and colleagues at Chiba University, working through the structure-activity relationships of mitragynine-related Corynanthe alkaloids on guinea-pig ileum, prepared and tested a series of derivatives around the C-7, C-9 and C-19/20 positions in 2002 ^{5Reference 5Takayama H et al. · 2002Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligandsView study →}. Matsumoto and co-workers then gave the 9-demethyl analogue its own paper in 2006, describing it explicitly as “synthesised from mitragynine” and establishing the mu-partial-agonist characterisation everything since rests on ^{1Reference 1Matsumoto K et al. · 2006Partial agonistic effect of 9-hydroxycorynantheidine on mu-opioid receptor in the guinea-pig ileumView study →}.

Preparation today is still semi-synthesis from mitragynine — demethylation of the C-9 aryl methyl ether — and every research group working on it has used that route ^{2,3,6Reference 2Kruegel AC et al. · 2016Synthetic and receptor signaling explorations of the Mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulatorsView study →Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →Reference 6León F et al. · 2021Activity of Mitragyna speciosa (“kratom”) alkaloids at serotonin receptorsView study →}. Its subsequent glucuronide has also been made synthetically, by coupling the phenol to a protected glucuronate and hydrolysing ^{4Reference 4Chakraborty S et al. · 2021Oxidative metabolism as a modulator of kratom’s biological actionsView study →}. No total synthesis specific to this molecule is documented, and no commercial extraction from leaf exists; the trace leaf concentrations reported make one implausible ^{13,14Reference 13Zhang M et al. · 2025Alkaloid biosynthesis in medicinal crop kratom (Mitragyna speciosa) varies with postharvest, genetic, and seasonal factorsView study →Reference 14Ransden KE et al. · 2026Comparative analysis of monoterpene indole alkaloid composition and genotypic variation in Thai Mitragyna speciosaView study →}.

Patents: not yet researched.

Toxicity & Safety

There is no dedicated toxicology for 9-hydroxycorynantheidine — no repeat-dose study, no genotoxicity package, no reproductive-toxicity data, no cardiac safety work, and no human safety data of any kind. The moderate flag here is assigned on class grounds, not on findings: this is a mu-opioid receptor ligand with partial agonist activity, formed in the body from a compound with recognised dependence liability, and it has never been characterised for the harms that class implies. Silence here is absence of study, not evidence of safety.

What little exists is worth stating precisely. In mice it produced no antinociception up to 100 mg/kg subcutaneously — which is a finding about efficacy, not about tolerability, and no adverse-effect endpoints were reported at those doses ^{4Reference 4Chakraborty S et al. · 2021Oxidative metabolism as a modulator of kratom’s biological actionsView study →}. Its off-target screen at 10 µM flagged COX-2 inhibition, serotonin-transporter binding and voltage-gated sodium-channel binding, any of which would warrant follow-up if it were being developed, though none has been confirmed functionally or at achievable concentrations ^{7Reference 7Chen Y et al. · 2025In vitroIn vitro pharmacology of mitragynine at α-adrenoceptorsView study →}. Its metabolic stability (microsomal half-life 181 minutes) means that, once formed, it persists longer than the parent alkaloid ^{3Reference 3Obeng S et al. · 2020Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloidsView study →}.

Drug interactions are a property of its formation rather than of the molecule. Because CYP3A4, CYP2C19 and CYP2D6 generate it from mitragynine ^{8,9Reference 8Basiliere S · 2020CYP450-mediated metabolism of mitragynine and investigation of metabolites in human urineView study →Reference 9Melchert PW et al. · 2024In vitroAn in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynineView study →}, anything that inhibits or induces those enzymes changes how much of it a person makes — ketoconazole markedly suppressed its formation in human liver S9 ^{9Reference 9Melchert PW et al. · 2024In vitroAn in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynineView study →} — and mitragynine is itself a time-dependent CYP3A inhibitor, so kratom’s metabolite ratios are not fixed. Interactions of the isolated metabolite with transporters or other drugs have not been assessed.

Legal status follows kratom’s, which varies widely: banned in several countries and some US states, unregulated in others, and the subject of active regulatory attention around concentrated and semi-synthetic kratom-alkaloid products. Check local law rather than assuming.

Safety at a Glance

⚠️ Moderate toxicity

• Mu-opioid receptor activity. A partial agonist at the mu-opioid receptor in vitro, formed in the body from mitragynine — treat it as an opioid-class molecule.
• No dedicated toxicology exists. No repeat-dose, genotoxicity, cardiac, reproductive or human safety data. The moderate flag is precautionary.
• CYP-dependent exposure. CYP3A4/2C19/2D6 make it from mitragynine, so inhibitors and inducers of those enzymes change how much of it forms.
• Off-target screen hits are unconfirmed. COX-2, serotonin-transporter and sodium-channel binding appeared only at 10 µM, a screening concentration well above plausible exposure.
• Legal status varies. Kratom and its alkaloids are restricted in some countries and jurisdictions and unregulated in others.

Dosage

There is no dose. 9-Hydroxycorynantheidine has never been administered to a human being as an isolated compound, no clinical trial of it exists, and no dosing information should be inferred from the preclinical figures here. The research doses quoted above — up to 100 mg/kg subcutaneously in mice ^{4Reference 4Chakraborty S et al. · 2021Oxidative metabolism as a modulator of kratom’s biological actionsView study →}, 40 mg/kg twice daily oral mitragynine in rats ^{11Reference 11Chiang YH et al. · 2024AnimalMultiple-dose pharmacokinetics and safety of mitragynine, the major alkaloid of kratom, in ratsView study →} — are experimental parameters in animal studies, not human-relevant amounts, and were chosen to test mechanisms rather than to produce an effect.

Human exposure to this molecule is entirely indirect, arising from metabolism of mitragynine after kratom intake, and its magnitude depends on the individual’s CYP2C19, CYP3A4 and CYP2D6 activity as much as on anything consumed ^{8,9Reference 8Basiliere S · 2020CYP450-mediated metabolism of mitragynine and investigation of metabolites in human urineView study →Reference 9Melchert PW et al. · 2024In vitroAn in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynineView study →}. This page describes what the molecule does in a laboratory. It is not a guide to using kratom or any preparation derived from it.

References

1. Matsumoto K, Takayama H, Ishikawa H, Aimi N, Ponglux D, Watanabe K, Horie S (2006). Partial agonistic effect of 9-hydroxycorynantheidine on mu-opioid receptor in the guinea-pig ileum. Life Sciences. https://pubmed.ncbi.nlm.nih.gov/16266723/
2. Kruegel AC, Gassaway MM, Kapoor A, Váradi A, Majumdar S, Filizola M, Javitch JA, Sames D (2016). Synthetic and receptor signaling explorations of the Mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulators. Journal of the American Chemical Society. https://pubmed.ncbi.nlm.nih.gov/27192616/
3. Obeng S, Kamble SH, Reeves ME, et al. (2020). Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloids. Journal of Medicinal Chemistry. https://pubmed.ncbi.nlm.nih.gov/31834797/
4. Chakraborty S, Uprety R, Slocum ST, et al. (2021). Oxidative metabolism as a modulator of kratom’s biological actions. Journal of Medicinal Chemistry. https://pubmed.ncbi.nlm.nih.gov/34783240/
5. Takayama H, Ishikawa H, Kurihara M, et al. (2002). Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands. Journal of Medicinal Chemistry. https://pubmed.ncbi.nlm.nih.gov/11960505/
6. León F, Obeng S, Mottinelli M, et al. (2021). Activity of Mitragyna speciosa (“kratom”) alkaloids at serotonin receptors. Journal of Medicinal Chemistry. https://pubmed.ncbi.nlm.nih.gov/34467758/
7. Chen Y, Seto J, Obeng S, et al. (2025). In vitro pharmacology of mitragynine at α-adrenoceptors. ACS Chemical Neuroscience. https://pubmed.ncbi.nlm.nih.gov/41269061/
8. Basiliere S, Kerrigan S (2020). CYP450-mediated metabolism of mitragynine and investigation of metabolites in human urine. Journal of Analytical Toxicology. https://pubmed.ncbi.nlm.nih.gov/32008041/
9. Melchert PW, Zhang Q, Markowitz JS (2024). An in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynine. Chemico-Biological Interactions. https://pubmed.ncbi.nlm.nih.gov/39299374/
10. Basiliere S, Kerrigan S (2020). Identification of metabolites and potential biomarkers of kratom in urine. Journal of Chromatography B. https://pubmed.ncbi.nlm.nih.gov/32058315/
11. Chiang YH, Berthold EC, Kuntz MA, et al. (2024). Multiple-dose pharmacokinetics and safety of mitragynine, the major alkaloid of kratom, in rats. ACS Pharmacology & Translational Science. https://pubmed.ncbi.nlm.nih.gov/39144552/
12. McCurdy CR, Sharma A, Smith KE, Veltri CA, Weiss ST, White CM, Grundmann O (2024). An update on the clinical pharmacology of kratom: uses, abuse potential, and future considerations. Expert Review of Clinical Pharmacology. https://pubmed.ncbi.nlm.nih.gov/38217374/
13. Zhang M, Lyndon A, Kanumuri SRR, Sharma A, Pearson BJ, McCurdy CR, Chen J (2025). Alkaloid biosynthesis in medicinal crop kratom (Mitragyna speciosa) varies with postharvest, genetic, and seasonal factors. Frontiers in Plant Science. https://pubmed.ncbi.nlm.nih.gov/41090093/
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