Mitragynine Pseudoindoxyl

Mitragynine Pseudoindoxyl at a Glance

Mitragynine pseudoindoxyl (MP) is what happens when the indole core of mitragynine — the main alkaloid of kratom — is oxidised and rearranged into a spiro-pseudoindoxyl ring system. That single structural change turns a weak, promiscuous opioid ligand into one of the most potent mu-opioid agonists ever isolated from a plant lineage: binding affinity at the mu receptor rises roughly 290-fold over mitragynine, to a K_i of about 0.8 nM ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}.

It is the kratom-derived molecule that attracted the most serious academic pharmacology, because in the founding study it looked like the thing opioid chemistry has been hunting for decades — analgesia without the classic opioid liabilities. In mice it was more potent than morphine, developed antinociceptive tolerance roughly six times more slowly, produced almost no naloxone-precipitated withdrawal, caused markedly less constipation, showed neither reward nor aversion, and did not depress breathing at twice its analgesic dose ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. It was, and to some extent still is, a lead compound for a safer opioid.

Two things have to be said plainly alongside that. First, the mechanistic explanation offered at the time — that MP is a G-protein-biased agonist that fails to recruit β-arrestin-2 — rests on a hypothesis that has since been seriously challenged and is not settled (see below). Second, MP is not a kratom leaf constituent. It is a metabolite and a semi-synthetic, and since 2024 it has been manufactured and sold in unregulated “kratom” products — with a published case of severe, rapid-onset opioid withdrawal to match ^{15,16,17,18Reference 15Hill K et al. · 2025De facto opioids: Characterization of novel 7-hydroxymitragynine and mitragynine pseudoindoxyl product marketingView study →Reference 16White CM et al. · 2025A Descriptive Assessment of Products Containing the Opioid Receptor Stimulator Mitragynine PseudoindoxylView study →Reference 17Stanciu CN · 2026Case reportSevere Early-Onset Withdrawal Following Intentional Use of Mitragynine Pseudoindoxyl: A Case Report and Emerging Clinical ConsiderationsView study →Reference 18Vadiei N et al. · 2025ReviewThe Impact of Diverse Kratom Products on Use Patterns, Dependence, and ToxicityView study →}.

This page is a scholarly pharmacology and toxicology reference. It gives no dosing for effect and no preparation, extraction or synthesis guidance.

Is It Actually in Kratom Leaf?

This is the first question a phytochemistry database has to answer about this molecule, and the honest answer is no — not on current evidence.

It was never isolated from the plant. MP was first obtained in 1974 by Zarembo and colleagues, not from kratom leaf but as a microbial transformation product of mitragynine generated by a Helminthosporium fungus ^{4Reference 4Zarembo JE et al. · 1974Metabolites of mitragynineView study →} — an account restated in the modern pharmacology literature ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. Every subsequent supply of the molecule has come from chemical semi-synthesis (oxidative rearrangement of mitragynine or 7-hydroxymitragynine) or, since 2023, from total synthesis ^{1,9Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 9Angyal P et al. · 2023Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl MetabolitesView study →}.

Leaf surveys do not find it. Untargeted LC-MS metabolomics of young and mature Mitragyna speciosa leaves annotated 86 metabolite features and extended the species’ known alkaloid repertoire — without MP among them ^{23Reference 23Veeramohan R et al. · 2023Comparative metabolomics analysis reveals alkaloid repertoires in young and mature Mitragyna speciosa (Korth.) Havil. leavesView study →}. Reviews of the current product landscape state the position directly: 7-hydroxymitragynine and mitragynine pseudoindoxyl are “undetectable or not present in fresh kratom leaves” ^{15Reference 15Hill K et al. · 2025De facto opioids: Characterization of novel 7-hydroxymitragynine and mitragynine pseudoindoxyl product marketingView study →}, and are “not naturally present in leaf material” ^{18Reference 18Vadiei N et al. · 2025ReviewThe Impact of Diverse Kratom Products on Use Patterns, Dependence, and ToxicityView study →}.

But it is a real endogenous product of kratom use. This is the nuance that keeps it pharmacologically important. When mice are given oral mitragynine, MP is formed in vivo and reaches both plasma and brain — the second most important oxidative metabolite after 7-hydroxymitragynine — through a CYP3A-mediated skeletal rearrangement, confirmed by ketoconazole inhibition and Cyp3a knockout microsomes, and reproduced in human liver microsomes ^{5Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}. Separately and strikingly, 7-hydroxymitragynine is unstable in human plasma and converts to MP there, to a far greater extent than in mouse, rat, dog or monkey plasma — which raises the possibility that MP contributes more to kratom’s pharmacology in humans than in any of the species it has been tested in ^{6Reference 6Kamble SH et al. · 2020Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and EfficacyView study →}.

Verdict for this database. Mitragynine pseudoindoxyl is best classed as a semi-synthetic derivative and downstream metabolite of a plant alkaloid, not as a leaf constituent. It belongs on the site because it is inseparable from kratom’s pharmacology and because it is now being sold to consumers — but the entry should not be read as evidence that anyone chewing a kratom leaf is ingesting pre-formed MP. They are not. They may, however, be making some.

The Rearrangement: From Indole to Spiro-Pseudoindoxyl

Mitragynine is a corynanthe-type indole alkaloid. Its conversion to MP is a two-step oxidation: mitragynine is first oxidised at C-7 to the indolenine 7-hydroxymitragynine, and that intermediate then undergoes an acid- or metabolism-driven skeletal rearrangement in which the indole ring contracts and re-forms as a spiro-fused 5-5-6 tricyclic pseudoindoxyl — an entirely different three-dimensional scaffold hung on the same carbon count ^{1,5,9Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →Reference 9Angyal P et al. · 2023Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl MetabolitesView study →}.

The pharmacological consequence is dramatic and out of proportion to the chemistry. Across the three molecules, mu-receptor affinity climbs by nearly three orders of magnitude ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}:

Alkaloid	Mu (Ki, nM)	Delta (Ki, nM)	Kappa (Ki, nM)	Antinociception ED50 (sc, mice)
Mitragynine	230	1011	231	166 mg/kg
7-Hydroxymitragynine	37	91	132	0.46 mg/kg
Mitragynine pseudoindoxyl	0.8	3.0	24	0.76 mg/kg
Morphine (comparator)	4.6	—	—	2.5 mg/kg

Figures from the same radioligand and radiant-heat tail-flick series ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}; morphine values are the study’s own comparators.

Structure–activity work on the scaffold found that the unsubstituted indoxyl NH is essential — N-benzyl and N-methyl derivatives lost opioid affinity entirely — while the C-9 position tolerates substitution, with the 9-OH and des-methoxy analogues actually more potent than MP itself ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. That is the observation that turned MP from a pharmacological curiosity into a medicinal-chemistry template.

One complication deserves flagging. The 2023 total synthesis found that MP does not behave as a single molecular entity in protic media: it exists as a dynamic ensemble of interconverting stereoisomers, so it “exhibits structural plasticity in biological systems” ^{9Reference 9Angyal P et al. · 2023Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl MetabolitesView study →}. Any receptor assay on MP is therefore, to some degree, an assay on a mixture — a caveat that sits under all of the numbers above.

Receptor Profile: Mu Agonist, Delta Antagonist

MP’s signature is not simply high mu potency. It is a multifunctional ligand:

• Mu-opioid receptor — potent full agonist. In [³⁵S]GTPγS functional assays MP is a full agonist at MOR-1, in contrast to mitragynine (partial, weak) and 7-hydroxymitragynine (partial) ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. Its antinociception is abolished in mu-receptor knockout mice, confirming the mechanism ^{1,5Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}.
• Delta-opioid receptor — antagonist. MP binds delta with ~3 nM affinity but blocks rather than activates it ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. In the classic isolated-tissue work its inhibition of mouse vas deferens contraction was reversed by the delta antagonist naltrindole, while its ileum effect was reversed by naloxone and the mu-selective naloxonazine ^{2Reference 2Yamamoto LT et al. · 1999Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosaView study →}.
• Kappa-opioid receptor — moderate affinity, antagonist. Affinity is roughly 30-fold weaker than at mu, and functionally it antagonises ^{1,5Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}.
• Non-opioid targets — essentially none. Screening across a broad CNS receptor panel found only poor affinity at α2A- and α2C-adrenergic receptors and 5-HT7 ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. This is a clean opioid pharmacology, unlike parent mitragynine’s adrenergic and serotonergic side activities.

The mu-agonist/delta-antagonist combination is itself a long-standing strategy for reducing tolerance and dependence, independent of any bias argument — delta antagonism and delta knockdown both blunt morphine tolerance in rodents ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. Cryo-EM and molecular-dynamics work has since shown that MP engages subpockets of the mu orthosteric site that classical opioids do not, producing distinct active-state conformations on the intracellular face where G proteins and arrestins dock ^{8Reference 8Qu Q et al. · 2023Insights into distinct signaling profiles of the µOR activated by diverse agonistsView study →}, with allosteric modulation of the receptor also proposed from simulation ^{20Reference 20Zhou Y et al. · 2021AnimalPredicted Mode of Binding to and Allosteric Modulation of the μ-Opioid Receptor by Kratom’s Alkaloids with Reported Antinociception In VivoView study →}.

The Biased-Agonism Controversy

This is the part of the MP story that is most often told wrong, and the most important editorial judgement here. The original interpretation is not settled science, and it should not be presented as if it were.

The original claim (2016). MP produced potent mu-mediated antinociception yet failed to recruit β-arrestin-2 at concentrations up to 10 µM — described in the paper as “completely G-protein biased” — and simultaneously showed reduced tolerance, dependence, constipation, respiratory depression and reward ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. The framework then in favour held that mu-receptor G-protein signalling carries analgesia while β-arrestin-2 signalling carries respiratory depression and constipation, so a G-protein-biased agonist should be an opioid without the lethal side effect ^{1,14Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 14Conibear AE · 2019ReviewA Biased View of μ-Opioid Receptors? Molecular Pharmacology (review). https://pubmed.ncbi.nlm.nih.gov/31175184/View study →}.

The challenge. That framework has since taken heavy fire, and mostly not from kratom researchers:

• β-arrestin-2 knockout mice still stop breathing. A three-laboratory, three-country consortium re-examined opioid respiratory depression in β-arrestin-2 knockout mice and found that morphine and fentanyl depress respiration and cause constipation indistinguishably from wild-type, concluding that the findings “call into question the concept of developing G protein-biased μ-opioid receptor agonists as a strategy” for safer analgesics ^{11Reference 11Kliewer A et al. · 2020Morphine-induced respiratory depression is independent of β-arrestin2 signallingView study →}.
• Phosphorylation-deficient (structurally biased) receptors are worse. Knock-in mice whose mu receptors cannot recruit β-arrestins showed enhanced analgesia and greatly diminished tolerance — but unchanged or exacerbated respiratory depression, constipation and withdrawal ^{10Reference 10Kliewer A et al. · 2019Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effectsView study →}.
• An alternative explanation: low intrinsic efficacy, not bias. A systematic re-evaluation of the leading “biased” opioids (oliceridine, PZM21, SR-17018) in assays with adequate signal windows found they simply have low intrinsic efficacy in every pathway, and that this alone can account for the improved therapeutic window ^{12Reference 12Gillis A et al. · 2020Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonistsView study →}.
• The rebuttal to the rebuttal. Re-analysing the same dataset with operational-model bias metrics, Stahl and Bohn argued that G-protein bias was present and that low intrinsic efficacy alone cannot explain the side-effect separation ^{13Reference 13Stahl EL · 2022Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid AgonistsView study →}. The field has not converged; contemporaneous reviews describe the mu-bias literature as confounded by assay amplification, system bias and partial agonism ^{14Reference 14Conibear AE · 2019ReviewA Biased View of μ-Opioid Receptors? Molecular Pharmacology (review). https://pubmed.ncbi.nlm.nih.gov/31175184/View study →}.

What this means for MP specifically. The phenotype reported in mice is a real experimental result and is not in dispute: less tolerance, less dependence, less constipation, less respiratory depression at the doses tested ^{1,7Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 7Wilson LL et al. · 2021Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid WithdrawalView study →}. What is disputed is the explanation. Three points are worth holding:

1. MP is not a pure biased agonist even on its own data. It fails to recruit β-arrestin-2, but it also antagonises DAMGO-driven β-arrestin-2 recruitment with an IC50 of 34 nM — meaning it binds and stabilises arrestin-competent receptor states too ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. That is a more complicated ligand than “G-protein-only”.
2. Delta antagonism is an independent, unbiased explanation for the reduced tolerance and dependence, and it was in the paper from the start ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}.
3. Later structural work reframes the finding without leaning on the arrestin dogma: MP and the ultra-lethal opioid lofentanil occupy different sub-regions of the mu binding pocket and drive different active-state conformations and different G-protein subtype efficacies — a conformational rather than a simple pathway-selection account of why their safety profiles diverge ^{8Reference 8Qu Q et al. · 2023Insights into distinct signaling profiles of the µOR activated by diverse agonistsView study →}.

The defensible summary is this: mitragynine pseudoindoxyl showed a genuinely unusual separation of analgesia from opioid side effects in rodents, and nobody has established why. The original “G-protein bias equals safety” story is the weakest link in the chain, not the strongest.

Mitragynine Pseudoindoxyl vs. 7-Hydroxymitragynine

The two potent kratom-derived opioids are frequently conflated in both product marketing and press coverage. They are chemically and pharmacologically distinct.

	7-Hydroxymitragynine	Mitragynine pseudoindoxyl
Core	Indolenine (C-7 oxidation)	Spiro-pseudoindoxyl (skeletal rearrangement)
Relationship	Direct CYP3A oxidation product of mitragynine	Rearrangement product of 7-OH — one step further
Mu affinity	37 nM	0.8 nM
Delta	Weak antagonist (91 nM)	Antagonist, 3.0 nM
In leaf?	Trace only; commercial material is semi-synthetic	Not demonstrated at all
Reward (rodent CPP)	Reinforcing	Not reinforcing in the same assay series
Constipation	Comparable to morphine	Partial-agonist behaviour; plateaus
Stability	Degrades to the potentially toxic 3-dehydromitragynine under gastric conditions	Interconverting stereoisomer ensemble in protic media

Sources: receptor and behaviour data ^{1,5Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}; reinforcement contrast ^{5Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}; leaf/product provenance and 7-OH gastric degradation ^{15,18,19Reference 15Hill K et al. · 2025De facto opioids: Characterization of novel 7-hydroxymitragynine and mitragynine pseudoindoxyl product marketingView study →Reference 18Vadiei N et al. · 2025ReviewThe Impact of Diverse Kratom Products on Use Patterns, Dependence, and ToxicityView study →Reference 19Avula B et al. · 2026Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditionsView study →}; stereochemical plasticity ^{9Reference 9Angyal P et al. · 2023Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl MetabolitesView study →}.

Two contrasts carry weight. 7-OH is reinforcing in rodents and MP was not — in the Chakraborty series, kratom, mitragynine and 7-OH all retained reinforcing behaviour while MP did not ^{5Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}, consistent with MP’s absence of conditioned place preference or aversion in the original work ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. And 7-OH is a precursor to MP, not an alternative to it — including in human plasma ^{6,19Reference 6Kamble SH et al. · 2020Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and EfficacyView study →Reference 19Avula B et al. · 2026Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditionsView study →}. Products sold as “7-OH” and products sold as “MP” are therefore not cleanly separable categories, and 71% of surveyed MP products contained both ^{16Reference 16White CM et al. · 2025A Descriptive Assessment of Products Containing the Opioid Receptor Stimulator Mitragynine PseudoindoxylView study →}.

What It's Used For

Every finding below is preclinical. There are no human efficacy trials of mitragynine pseudoindoxyl, no human pharmacokinetic study, and no approved indication.

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, so nothing scores in the “proven” band; the scores track how well characterised an action is, not an endorsement of use.

01Preclinical AnalgesiaShaky44%Reproduced mu-mediated antinociception across strains, routes and two labs ^{1,5Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}

02A Safer-Opioid Lead CompoundShaky31%Real rodent side-effect separation, contested mechanism, zero human data ^{1,10,11,12,13Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 10Kliewer A et al. · 2019Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effectsView study →Reference 11Kliewer A et al. · 2020Morphine-induced respiratory depression is independent of β-arrestin2 signallingView study →Reference 12Gillis A et al. · 2020Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonistsView study →Reference 13Stahl EL · 2022Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid AgonistsView study →}

03Opioid-Withdrawal AmeliorationShaky23%One mouse study; contradicted by a human case of severe MP withdrawal ^{7,17Reference 7Wilson LL et al. · 2021Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid WithdrawalView study →Reference 17Stanciu CN · 2026Case reportSevere Early-Onset Withdrawal Following Intentional Use of Mitragynine Pseudoindoxyl: A Case Report and Emerging Clinical ConsiderationsView study →}

Mechanisms

The load-bearing point: the mu-agonist/delta-antagonist pairing and the binding-pocket conformation are mechanistically solid; the β-arrestin bias line is the contested one, and it is also the one most often quoted ^{1,8,10,11,12,13Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 8Qu Q et al. · 2023Insights into distinct signaling profiles of the µOR activated by diverse agonistsView study →Reference 10Kliewer A et al. · 2019Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effectsView study →Reference 11Kliewer A et al. · 2020Morphine-induced respiratory depression is independent of β-arrestin2 signallingView study →Reference 12Gillis A et al. · 2020Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonistsView study →Reference 13Stahl EL · 2022Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid AgonistsView study →}.

Pharmacokinetics

There is no human pharmacokinetic study of mitragynine pseudoindoxyl. What exists is metabolic-formation data, which for this molecule is arguably more important.

Formation. In mice given oral mitragynine (30 mg/kg), LC-MS/MS detected MP in both plasma and brain, alongside 7-hydroxymitragynine (the major metabolite), 3-dehydromitragynine, 9-OH-mitragynine and mitragynine glucuronide; MP and 7-OH concentrations tracked the antinociceptive peak at 20 minutes and were below quantification by 8 hours ^{5Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}. Formation is CYP3A-dependent — blocked by ketoconazole and reduced in Cyp3a knockout microsomes — and was reproduced in human liver microsomes ^{5Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}. Mitragynine’s metabolism generally runs through CYP3A4 with minor CYP2D6 and CYP2C9 contributions ^{22Reference 22Kamble SH et al. · 2019Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom)View study →}. Separately, human plasma itself converts 7-hydroxymitragynine to MP, a species-specific route that barely operates in mouse, rat, dog or cynomolgus monkey plasma ^{6Reference 6Kamble SH et al. · 2020Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and EfficacyView study →}.

Oral activity. MP is orally active in mice (ED50 7.5 mg/kg vs 0.76 mg/kg subcutaneous), implying substantial first-pass loss but not total ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}.

Duration. Shorter than morphine’s, peaking around 15 minutes after systemic dosing in mice ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. Given that MP is being sold in sublingual and buccal formulations that bypass first-pass metabolism entirely, with no clinical, safety or pharmacokinetic data for those routes ^{25Reference 25White CM et al. · 2026Nonswallowed Kratom-Derived Products: Unlawful Dietary Supplements That Endanger Public HealthView study →}, the kinetic picture in real human exposure is essentially unknown.

A translation problem worth stating. All of MP’s favourable safety data are rodent data. Because human plasma generates MP from 7-OH far more efficiently than any tested preclinical species ^{6Reference 6Kamble SH et al. · 2020Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and EfficacyView study →}, and because MP’s stereochemistry is fluid in protic media ^{9Reference 9Angyal P et al. · 2023Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl MetabolitesView study →}, rodent findings should be extrapolated to humans with real caution.

Clinical Trials

None. No completed, ongoing or terminated clinical trial of mitragynine pseudoindoxyl has been identified. The entire human record consists of product surveys ^{15,16,25Reference 15Hill K et al. · 2025De facto opioids: Characterization of novel 7-hydroxymitragynine and mitragynine pseudoindoxyl product marketingView study →Reference 16White CM et al. · 2025A Descriptive Assessment of Products Containing the Opioid Receptor Stimulator Mitragynine PseudoindoxylView study →Reference 25White CM et al. · 2026Nonswallowed Kratom-Derived Products: Unlawful Dietary Supplements That Endanger Public HealthView study →}, analytical chemistry of marketed material ^{19Reference 19Avula B et al. · 2026Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditionsView study →}, and a single case report of severe withdrawal ^{17Reference 17Stanciu CN · 2026Case reportSevere Early-Onset Withdrawal Following Intentional Use of Mitragynine Pseudoindoxyl: A Case Report and Emerging Clinical ConsiderationsView study →}.

Last checked: July 2026.

Isolate vs. Plant Studies

For most molecules here the caveat runs “the human evidence is for the whole plant, not the isolate”. Here it inverts twice over. Every study of mitragynine pseudoindoxyl is an isolate study, because there is no plant preparation that contains it — the material tested is synthesised ^{1,9Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 9Angyal P et al. · 2023Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl MetabolitesView study →}. And there is no human evidence of any kind, so the usual isolate-versus-plant question does not arise; the real question is rodent-versus-human.

The one place where plant and isolate meet is metabolic. Kratom leaf contains mitragynine; some of that mitragynine becomes 7-hydroxymitragynine and some of that becomes MP, in the liver and — distinctively in humans — in plasma ^{5,6Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →Reference 6Kamble SH et al. · 2020Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and EfficacyView study →}. So a kratom user does encounter this molecule, at concentrations nobody has measured in a human being. That is a genuine, unfilled gap, and it is the single most useful experiment still missing from this literature.

Whole-leaf kratom’s own pharmacology should not be attributed to MP. Kratom’s alkaloid fraction contains at least 54 alkaloids, and the minor ones have their own distinct receptor profiles — corynantheidine is a mu partial agonist, corynoxine a mu full agonist, isopaynantheine a kappa agonist ^{21Reference 21Chakraborty S et al. · 2021Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from KratomView study →}. MP is a downstream product, not a leaf ingredient.

Prevalence in Nature

The spiro-pseudoindoxyl scaffold is a genuine natural-product motif, even though this particular member is not a documented leaf alkaloid. It arises by oxidative rearrangement of corynanthe-type indole alkaloids, and its first recorded appearance was biological, not synthetic — a Helminthosporium fungus transforming mitragynine in 1974 ^{4Reference 4Zarembo JE et al. · 1974Metabolites of mitragynineView study →}. The 2023 total-synthesis paper treats MP as a natural product and delivered its epimeric congener, speciogynine pseudoindoxyl, by the same cascade, indicating that the corresponding pseudoindoxyls of kratom’s other corynanthe alkaloids — speciogynine, paynantheine, speciociliatine — are chemically accessible in the same way ^{9Reference 9Angyal P et al. · 2023Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl MetabolitesView study →}.

Whether any of these accumulate in intact leaf is unresolved. Untargeted leaf metabolomics has not reported them ^{23Reference 23Veeramohan R et al. · 2023Comparative metabolomics analysis reveals alkaloid repertoires in young and mature Mitragyna speciosa (Korth.) Havil. leavesView study →}, and the reviews that address the question directly say MP is not naturally present in leaf material ^{15,18Reference 15Hill K et al. · 2025De facto opioids: Characterization of novel 7-hydroxymitragynine and mitragynine pseudoindoxyl product marketingView study →Reference 18Vadiei N et al. · 2025ReviewThe Impact of Diverse Kratom Products on Use Patterns, Dependence, and ToxicityView study →}. Two possibilities remain open and untested: that MP forms post-harvest, on drying, storage or oxidation of leaf material, and that it forms in fermented or aged preparations. Neither has been looked for systematically. Until someone runs a targeted assay on fresh, dried and aged leaf, “absent” should be read as “not detected”, which is a slightly weaker claim.

What is now well documented is its presence in commerce. Analysis of commercial “kratom” products found MP alongside 7-OH and a set of over-oxidised by-products whose pattern points to synthetic rather than botanical origin; over 98% of 7-OH-labelled products were of semi-synthetic origin ^{19Reference 19Avula B et al. · 2026Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditionsView study →}. A survey of 51 MP-containing products found 71% combined MP with 7-OH and 24% contained MP alone ^{16Reference 16White CM et al. · 2025A Descriptive Assessment of Products Containing the Opioid Receptor Stimulator Mitragynine PseudoindoxylView study →}. This is a molecule whose real-world “natural source” is a laboratory.

Discovery & Synthesis

First obtained (1974). Zarembo, Douglas, Valenta and Weisbach reported it among the metabolites of mitragynine, generated by microbial transformation with a Helminthosporium species — an origin restated in the modern literature ^{4,1Reference 4Zarembo JE et al. · 1974Metabolites of mitragynineView study →Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. It was a chemical curiosity for a quarter of a century.

First pharmacology (1999–2002). Yamamoto and colleagues at Chiba University showed that MP inhibited electrically stimulated guinea-pig ileum contraction at nanomolar concentrations — about 100-fold more potent than mitragynine and 20-fold more than morphine — with the ileum effect naloxone- and naloxonazine-sensitive (mu) and the vas deferens effect naltrindole-sensitive (delta), and negligible kappa affinity ^{2Reference 2Yamamoto LT et al. · 1999Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosaView study →}. Takayama’s group then produced MP semi-synthetically from mitragynine and demonstrated analgesia in the mouse tail-flick test, framing the pseudoindoxyls as “opioid agonists structurally different from other opioid ligands” ^{3Reference 3Takayama 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 medicinal-chemistry campaign (2016). Váradi and colleagues at Memorial Sloan Kettering, with collaborators in Florida and Hungary, ran the full in-vitro and in-vivo characterisation plus a C-9 analogue series, and reported the mu-agonist/delta-antagonist, non-arrestin-recruiting profile with the reduced side-effect phenotype ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. That paper is the reason MP has a literature, and the reason several groups have filed patent applications on the scaffold.

Total synthesis. A synthesis of the related 11-methoxy mitragynine pseudoindoxyl using an interrupted Ugi reaction was published in 2012 ^{24Reference 24Kim J et al. · 2012A chemical synthesis of 11-methoxy mitragynine pseudoindoxyl featuring the interrupted Ugi reactionView study →}, but the first enantioselective, scalable total synthesis of mitragynine pseudoindoxyl itself came in 2023 from Angyal and colleagues, via a protecting-group-free cascade from oxidised tryptamine and secologanin analogues — the same work that revealed the molecule’s stereochemical plasticity ^{9Reference 9Angyal P et al. · 2023Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl MetabolitesView study →}. Manufacture today is overwhelmingly semi-synthetic — oxidative rearrangement of extracted mitragynine or 7-hydroxymitragynine — which is exactly what the impurity profiles of commercial products show ^{19Reference 19Avula B et al. · 2026Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditionsView study →}. No synthetic or extraction procedure is described here.

Patents: not yet researched.

The Semi-Synthetic Product Market

Between 2024 and 2026 mitragynine pseudoindoxyl moved from the pharmacology literature into retail, and this is now the dominant public-health fact about it.

Researchers surveying vendor websites between September 2024 and February 2025 identified 304 semi-synthetic 7-OH and MP products — chewable and sublingual tablets, shots and gummies. Most were 7-OH-only; 14.5% were 7-OH/MP combinations and 3.3% were MP-only, and MP products were almost uniformly marketed as “kratom” despite containing a molecule that is not in the leaf. Nearly three-quarters made effect claims, 37.8% claimed pain or anxiety relief, and several product names alluded to prescription opioids ^{15Reference 15Hill K et al. · 2025De facto opioids: Characterization of novel 7-hydroxymitragynine and mitragynine pseudoindoxyl product marketingView study →}.

A separate survey of 51 MP-containing products found the packaging profile you would expect of an unregulated market and not of an opioid: 69% carried child-appealing flavouring or scent, 63% used bright colours, 12% showed food imagery, 6% had cartoon mascots, and 6% were formulated as an ice-cream cone or chocolate bar. Only 18% of vendor websites disclosed that the product stimulates opioid receptors, and fewer than half disclosed any risk of intoxication, tolerance, dependence, withdrawal or addiction ^{16Reference 16White CM et al. · 2025A Descriptive Assessment of Products Containing the Opioid Receptor Stimulator Mitragynine PseudoindoxylView study →}.

A further study found MP among non-swallowed formulations — sublingual strips, buccal pouches and vaping products — which bypass first-pass metabolism entirely and for which no clinical, safety or pharmacokinetic data exist at all; most were not in child-resistant packaging ^{25Reference 25White CM et al. · 2026Nonswallowed Kratom-Derived Products: Unlawful Dietary Supplements That Endanger Public HealthView study →}. Reviewers note that native leaf runs 2–5% total alkaloid while concentrated extracts reach 60%, and that these isolates “bear little similarity to traditional kratom” pharmacologically ^{18Reference 18Vadiei N et al. · 2025ReviewThe Impact of Diverse Kratom Products on Use Patterns, Dependence, and ToxicityView study →}. The pattern has a precedent: commercial kratom products were already being adulterated with artificially elevated 7-hydroxymitragynine a decade ago ^{26Reference 26Lydecker AG et al. · 2016Suspected Adulteration of Commercial Kratom Products with 7-HydroxymitragynineView study →}.

Legal Status

Regulation has not kept pace with the chemistry, and the position differs by molecule and by jurisdiction. What can be stated from the literature:

• Kratom and mitragynine occupy a contested regulatory space in the United States — federally uncontrolled but banned in several states, with the policy debate framed as balancing therapeutic potential against public safety ^{27Reference 27Prozialeck WC et al. · 2019ReviewKratom policy: The challenge of balancing therapeutic potential with public safetyView study →}.
• 7-Hydroxymitragynine: the US Food and Drug Administration has recommended scheduling it as a Schedule I controlled substance ^{19Reference 19Avula B et al. · 2026Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditionsView study →}.
• Mitragynine pseudoindoxyl is sold openly as a “dietary supplement”, which it is not — products marketed this way are described in the public-health literature as unlawful under the Dietary Supplement Health and Education Act, particularly the non-swallowed formulations ^{25Reference 25White CM et al. · 2026Nonswallowed Kratom-Derived Products: Unlawful Dietary Supplements That Endanger Public HealthView study →}. We have not verified a specific federal scheduling action for MP itself; treat its status as unsettled and jurisdiction-dependent, and expect it to change.

Nothing here is legal advice.

Toxicity & Safety

Mitragynine pseudoindoxyl carries a toxic flag. It is a mu-opioid agonist with roughly three times morphine’s subcutaneous potency in mice and sub-nanomolar receptor affinity, sold without medical supervision, dose standardisation or child-resistant packaging. The rodent safety data are encouraging and the human data are alarming; where they conflict, the human data govern.

Opioid Dependence & Withdrawal

The single most important human finding. A 2026 case report describes a 34-year-old man in long-term remission from heroin use disorder who progressed from powdered kratom to 7-OH tablets to MP tablets, averaging nine 20 mg doses daily including overnight dosing. He presented with suicidal ideation and severe opioid withdrawal — chills, tremor, diaphoresis, gastrointestinal distress, restlessness, a Clinical Opiate Withdrawal Scale score of 31, blood pressure 168/107 mmHg, heart rate 115 bpm — despite no conventional opioid use. Symptoms resolved over 72–96 hours with clonidine, hydroxyzine, gabapentin, loperamide and antiemetics, and naltrexone was later initiated without precipitating withdrawal ^{17Reference 17Stanciu CN · 2026Case reportSevere Early-Onset Withdrawal Following Intentional Use of Mitragynine Pseudoindoxyl: A Case Report and Emerging Clinical ConsiderationsView study →}.

Two clinical points from that case generalise: standard toxicology screens do not detect MP, so the withdrawal picture can present as unexplained; and MP withdrawal is rapid-onset and full-spectrum, unlike the milder, delayed withdrawal traditionally described for whole-leaf kratom ^{17Reference 17Stanciu CN · 2026Case reportSevere Early-Onset Withdrawal Following Intentional Use of Mitragynine Pseudoindoxyl: A Case Report and Emerging Clinical ConsiderationsView study →}. The rodent finding of “limited physical dependence” ^{1,7Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 7Wilson LL et al. · 2021Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid WithdrawalView study →} did not survive contact with human use at these doses.

Respiratory Depression

MP’s reduced respiratory depression is the claim that made it famous, and it needs stating precisely. In mice it did not depress respiratory rate at approximately twice its antinociceptive ED50; at approximately five times that dose it did, transiently lowering respiratory rate by about 15%, though significantly less than an equianalgesic dose of morphine ^{1Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →}. So the effect is reduced, dose-dependent and real — not absent. Given that the mechanistic rationale for expecting safety is itself contested ^{10,11,12Reference 10Kliewer A et al. · 2019Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effectsView study →Reference 11Kliewer A et al. · 2020Morphine-induced respiratory depression is independent of β-arrestin2 signallingView study →Reference 12Gillis A et al. · 2020Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonistsView study →}, and that no human respiratory study exists, MP should be treated as a respiratory depressant in any clinical or toxicological context.

Additive CNS & Respiratory Depression

As with any mu agonist, combination with alcohol, benzodiazepines, gabapentinoids, sedating antihistamines or other opioids would be expected to compound sedation and respiratory depression. Some marketed kratom vaping products additionally contain intoxicating hemp cannabinoids, so a consumer may not know what combination they are taking ^{25Reference 25White CM et al. · 2026Nonswallowed Kratom-Derived Products: Unlawful Dietary Supplements That Endanger Public HealthView study →}.

Drug Interactions

MP’s own interaction profile is uncharacterised, but its formation is enzyme-dependent: mitragynine is converted to 7-OH and to MP by CYP3A ^{5,22Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →Reference 22Kamble SH et al. · 2019Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom)View study →}. Anything that inhibits CYP3A4 — and mitragynine is itself a time-dependent CYP3A inhibitor — will alter how much MP a kratom user generates, in a direction that is hard to predict because CYP3A also clears the parent. This is a plausible, mechanistically grounded interaction axis that has never been studied in humans.

Product-Level Hazards

Beyond the molecule: label doses are unreliable (analysis found substantial mismatches between labelled and measured alkaloid content in this product class) ^{19Reference 19Avula B et al. · 2026Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditionsView study →}; child-appealing flavours, colours, mascots and food formulations are common while opioid-receptor activity is disclosed by fewer than a fifth of vendors ^{16Reference 16White CM et al. · 2025A Descriptive Assessment of Products Containing the Opioid Receptor Stimulator Mitragynine PseudoindoxylView study →}; and sublingual, buccal and vaping formulations bypass first-pass metabolism with no supporting data and usually without child-resistant packaging ^{25Reference 25White CM et al. · 2026Nonswallowed Kratom-Derived Products: Unlawful Dietary Supplements That Endanger Public HealthView study →}. Co-formulated 7-OH also degrades under gastric conditions to 3-dehydromitragynine, a metabolite flagged as potentially toxic and implicated in mitragynine’s lethality in mice ^{5,19Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →Reference 19Avula B et al. · 2026Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditionsView study →}.

Reproductive & Developmental Note

No reproductive or developmental toxicity dataset exists for mitragynine pseudoindoxyl. Opioid exposure in pregnancy carries a recognised risk of neonatal opioid withdrawal syndrome as a class effect, and there is no basis for assuming MP is exempt. Intake decisions belong on the kratom monograph and on any product page, not on a molecule reference page; the finding to record here is simply that nothing has been assessed.

Safety at a Glance

☠️ ToxicDependence riskOverdose riskSedative interactionsDrug interactions

• A high-potency mu-opioid agonist. Sub-nanomolar receptor affinity and roughly 3× morphine’s subcutaneous potency in mice, with no medical supervision, no dose standardisation and no approved use ^{1,5Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →}.
• Severe, rapid-onset opioid withdrawal is documented in humans. A published case reached a Clinical Opiate Withdrawal Scale score of 31 after escalation to MP tablets; standard drug screens do not detect it ^{17Reference 17Stanciu CN · 2026Case reportSevere Early-Onset Withdrawal Following Intentional Use of Mitragynine Pseudoindoxyl: A Case Report and Emerging Clinical ConsiderationsView study →}.
• Respiratory depression is reduced, not absent. It appeared at ~5× the analgesic dose even in the founding rodent study, and the mechanistic reason for expecting safety is scientifically contested ^{1,10,11,12Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 10Kliewer A et al. · 2019Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effectsView study →Reference 11Kliewer A et al. · 2020Morphine-induced respiratory depression is independent of β-arrestin2 signallingView study →Reference 12Gillis A et al. · 2020Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonistsView study →}.
• The safer-opioid evidence is entirely preclinical. No human trial of any kind — efficacy, safety or pharmacokinetics — has been conducted ^{1,7Reference 1Váradi A et al. · 2016Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2View study →Reference 7Wilson LL et al. · 2021Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid WithdrawalView study →}.
• Unregulated products with child-appealing packaging. Bright colours, flavours, mascots and food formulations are common; fewer than one in five vendors disclose opioid-receptor activity, and label doses are unreliable ^{16,19,25Reference 16White CM et al. · 2025A Descriptive Assessment of Products Containing the Opioid Receptor Stimulator Mitragynine PseudoindoxylView study →Reference 19Avula B et al. · 2026Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditionsView study →Reference 25White CM et al. · 2026Nonswallowed Kratom-Derived Products: Unlawful Dietary Supplements That Endanger Public HealthView study →}.
• Additive CNS depression and an untested CYP3A interaction axis. Combination with alcohol, benzodiazepines or other opioids compounds risk; CYP3A activity determines how much MP a kratom user forms ^{5,22,25Reference 5Chakraborty S et al. · 2021Oxidative Metabolism as a Modulator of Kratom’s Biological ActionsView study →Reference 22Kamble SH et al. · 2019Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom)View study →Reference 25White CM et al. · 2026Nonswallowed Kratom-Derived Products: Unlawful Dietary Supplements That Endanger Public HealthView study →}.

Dosage

No dose is given here, and none should be inferred. Mitragynine pseudoindoxyl has no approved medical use, no human dose-finding study and no established therapeutic dose. It is not a supplement, and the products selling it as one are described in the public-health literature as unlawful ^{25Reference 25White CM et al. · 2026Nonswallowed Kratom-Derived Products: Unlawful Dietary Supplements That Endanger Public HealthView study →}.

The figures that exist are rodent research doses, reproduced only so the potency comparisons above can be read:

For toxicological context only, the single published human case involved 20 mg tablets taken roughly nine times daily, which produced severe dependence and withdrawal ^{17Reference 17Stanciu CN · 2026Case reportSevere Early-Onset Withdrawal Following Intentional Use of Mitragynine Pseudoindoxyl: A Case Report and Emerging Clinical ConsiderationsView study →}. That is a description of harm, not a dose.

These are research and case-report figures, not a personal recommendation.

References

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2. Yamamoto LT, et al. (1999). Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa. General Pharmacology. https://pubmed.ncbi.nlm.nih.gov/10428019/
3. Takayama H, 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/
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8. Qu Q, et al. (2023). Insights into distinct signaling profiles of the µOR activated by diverse agonists. Nature Chemical Biology. https://pubmed.ncbi.nlm.nih.gov/36411392/
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20. Zhou Y, et al. (2021). Predicted Mode of Binding to and Allosteric Modulation of the μ-Opioid Receptor by Kratom’s Alkaloids with Reported Antinociception In Vivo. Biochemistry. https://pubmed.ncbi.nlm.nih.gov/33274929/
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23. Veeramohan R, et al. (2023). Comparative metabolomics analysis reveals alkaloid repertoires in young and mature Mitragyna speciosa (Korth.) Havil. leaves. PLoS One. https://pubmed.ncbi.nlm.nih.gov/36943850/
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