Mitragyna speciosa · PhytoNexus

01 Identity and provenance

Accepted binomial: Mitragyna speciosa
Common names: Kratom
Family (APG IV): Rubiaceae
Part used: Leaf
Verification tier: Tier 2 · Verified Clinical columns reviewed and a source is on record.
Reviewer note (2026 audit): LiverTox NBK548231 | FDA 7-OH scientific assessment (2025) | VERIFIED 2026 (batch 2) - synthetic analogue, application, interactions, side effects and references populated from retrieved primary/regulatory sources. Interactions labelled CLINICAL vs THEORETICAL. Marketed-formulation column intentionally blank. | COMPOSITION

02 Constituent chemistry

Chemical class	Marker compound	Synthetic analogue in use
Indole alkaloids	Mitragynine Leaf	Opioid analgesics (FUNCTIONAL - mitragynine and 7-hydroxymitragynine are partial mu-opioid agonists with G-protein functional selectivity). Not structurally an opioid.

The analogue column is what makes the interaction reasoning tractable: where a constituent has a marketed structural counterpart, the counterpart's interaction profile is the starting hypothesis for the plant.

Looking up structures and physicochemical properties from PubChem…

03 Stated application

Reported activity: NOT APPROVED FOR ANY THERAPEUTIC USE. Self-administered for pain, opioid withdrawal, anxiety and diarrhoea. Stimulant at low dose, opioid-like at higher dose. A 2013 systematic review found no evidence supporting any clinical indication.
Reported adverse effects: Hepatotoxicity with a canalicular cholestatic pattern and perivenular necrosis on biopsy. Seizures, altered mental state, loss of consciousness; pulmonary, cardiovascular, renal and GI effects. Dependence and a defined withdrawal syndrome. In a 2025 review of 95 cases, mitragynine was confirmed in 55, of whom 35 were deceased. Products are variable and adulteration with synthetic 7-hydroxymitragynine is an escalating concern.

04 Interaction matrix

Source column, verbatim: CLINICAL RISK IS HIGH. Kratom alkaloids inhibit multiple CYP450 enzymes - mitragynine selectively inhibits CYP2D6 (IC50 2.2 microM) and moderately inhibits CYP3A4/5 (IC50 11.4 microM), so co-administered substrates can accumulate. Additive CNS and respiratory depression with opioids, benzodiazepines and alcohol. Most reported deaths involve polypharmacy.
Normalised onto 3 canonical drug classes below.

Curated from the reviewed source

Drug class	Severity	Mechanism type	Provenance	Expected effect
Opioid analgesics CNS	3Major	PD-additive + PK-CYP2D6/3A4	curated A	Respiratory depression, over-sedation, constipation, ileus; unpredictable…	why ▾
Class mechanism. Botanical mu-agonists and CNS depressants add to opioid respiratory and sedative effect; CYP2D6 and CYP3A4 modulation alters the conversion of codeine and tramadol to active metabolites. Expected Respiratory depression, over-sedation, constipation, ileus; unpredictable analgesia in CYP2D6 poor or ultrarapid metabolisers. Management Avoid concurrent botanical sedatives. Counsel on overdose signs and ensure naloxone availability where risk is high. Onset rapid Evidence A - human data with a cited source Matched on “opioids” Find evidence for this pair Map this mechanism
Sedatives, hypnotics and benzodiazepines CNS	3Major	PD-additive	curated A	Excess sedation, psychomotor and driving impairment, falls, respiratory d…	why ▾
Class mechanism. Valepotriate, kavalactone, apigenin, sesquiterpene and alkaloid constituents act at GABA-A, adenosine and histamine sites, summating with prescribed CNS depression. Some also inhibit CYP3A4 and raise benzodiazepine exposure. Expected Excess sedation, psychomotor and driving impairment, falls, respiratory depression when combined with opioids. Management Warn against driving and machine operation. Avoid triple combinations with opioids. Reduce hypnotic dose in older adults. Onset rapid Evidence A - human data with a cited source Matched on “benzodiazepines” Find evidence for this pair Map this mechanism
Alcohol CNS	2Moderate	PD-additive + organ toxicity	curated A	Excess sedation, impaired judgement, higher risk of botanical hepatotoxic…	why ▾
Class mechanism. Additive CNS depression plus shared hepatic injury pathways; alcohol also increases the extraction and absorption of lipophilic botanical constituents from tinctures. Expected Excess sedation, impaired judgement, higher risk of botanical hepatotoxicity. Management Advise abstinence with sedative or hepatotoxic botanicals; note the ethanol content of tinctures in recovering patients. Onset rapid Evidence A - human data with a cited source Matched on “alcohol” Find evidence for this pair Map this mechanism

Predicted from constituent chemistry

These edges are not clinical findings. Each one is a rule inference: a constituent class in this plant is known to act on a target that the drug class also acts on. They are shown because a blank cell reads as “safe”, and for a Tier 1 entry a blank cell only means “not yet looked at”. Treat them as a literature-search agenda, not as a warning.

Drug class	Severity	Mechanism type	Provenance	Expected effect
Antidepressants (SSRI, SNRI, TCA) CNS	4Contraindicated	PD-additive serotonergic + PK-CYP2D6	predicted D	Serotonin syndrome (agitation, clonus, hyperthermia, autonomic instabilit…	why ▾
Chemistry of this pair. Indole and beta-carboline alkaloids act on monoamine storage, reuptake and oxidation, and several are tubulin poisons. Class mechanism. Hypericin- and hyperforin-type constituents inhibit monoamine reuptake and induce CYP3A4/2C19 and P-glycoprotein; others inhibit CYP2D6, raising tricyclic and SSRI concentrations. Expected Serotonin syndrome (agitation, clonus, hyperthermia, autonomic instability) or loss of antidepressant effect on withdrawal of an inducer. Management Screen for serotonergic burden before adding. Taper rather than stop abruptly. Consider therapeutic drug monitoring for tricyclics. Onset rapid Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism
Antihypertensives Cardiovascular	4Contraindicated	PD-additive	predicted D	Orthostatic hypotension, dizziness, syncope and falls; or loss of blood-p…	why ▾
Chemistry of this pair. Indole and beta-carboline alkaloids act on monoamine storage, reuptake and oxidation, and several are tubulin poisons. Class mechanism. Vasodilator, diuretic, ACE-inhibitory and calcium-antagonist activity in botanical extracts adds to prescribed blood-pressure lowering. A minority (ephedrine-, glycyrrhizin- and caffeine-bearing) act in the opposite direction and antagonise control. Expected Orthostatic hypotension, dizziness, syncope and falls; or loss of blood-pressure control with pressor botanicals. Management Home BP log for 2 weeks after any change. Warn about postural symptoms; review in the elderly and in those on multiple agents. Onset rapid Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism
Cytotoxic and targeted anticancer drugs Oncology	4Contraindicated	PK-CYP3A4/UGT + PD-antagonistic	predicted D	Neutropenic sepsis and severe diarrhoea from over-exposure, or reduced an…	why ▾
Chemistry of this pair. Indole and beta-carboline alkaloids act on monoamine storage, reuptake and oxidation, and several are tubulin poisons. Class mechanism. Botanical CYP3A4 and UGT1A1 modulation alters exposure to irinotecan, taxanes, vinca alkaloids and kinase inhibitors. High-dose antioxidant botanicals may also oppose the oxidative mechanism of some cytotoxics and of proteasome inhibitors. Expected Neutropenic sepsis and severe diarrhoea from over-exposure, or reduced antitumour effect; boronic-acid proteasome inhibitors are directly antagonised by polyphenols. Management No botanical should be taken during active cytotoxic therapy without oncology sign-off. Record all supplements in the chemotherapy chart. Onset unspecified Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism
Monoamine oxidase inhibitors CNS	4Contraindicated	PD-additive	predicted D	Hypertensive crisis, hyperpyrexia, serotonin syndrome, intracranial haemo…	why ▾
Chemistry of this pair. Indole and beta-carboline alkaloids act on monoamine storage, reuptake and oxidation, and several are tubulin poisons. Class mechanism. Beta-carboline (harmine, harmaline) and related botanical alkaloids are themselves reversible MAO-A inhibitors. Combined with a prescribed MAOI, or with tyramine-rich food or sympathomimetics, the pressor and serotonergic reserve is abolished. Expected Hypertensive crisis, hyperpyrexia, serotonin syndrome, intracranial haemorrhage. Management Absolute contraindication. Apply the full MAOI dietary and drug restriction list to the botanical as well. Onset rapid Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism
Narrow-therapeutic-index CYP3A4 substrates Pharmacokinetic	4Contraindicated	PK-CYP3A4	predicted D	Toxic accumulation or subtherapeutic failure of the co-prescribed drug, s…	why ▾
Chemistry of this pair. Alkaloidal bases have pH-dependent absorption and commonly interact with hepatic CYP isoenzymes and efflux transporters. Class mechanism. Furanocoumarins, bergamottin, piperine, glabridin and berberine inhibit CYP3A4; hyperforin, andrographolide and several diterpenes induce it through PXR. Because CYP3A4 handles roughly half of marketed drugs, the affected list is broad and the direction is product-specific. Expected Toxic accumulation or subtherapeutic failure of the co-prescribed drug, sometimes fatal for antiarrhythmics, immunosuppressants and oncology agents. Management Screen the full regimen for 3A4 substrates. Where the substrate has a narrow index, avoid rather than monitor. Onset unspecified Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism
Antacids, PPIs and H2 blockers Gastrointestinal	2Moderate	PK-absorption	predicted D	Reduced or erratic absorption of alkaloids; heartburn and reflux from pre…	why ▾
Chemistry of this pair. Alkaloidal bases have pH-dependent absorption and commonly interact with hepatic CYP isoenzymes and efflux transporters. Class mechanism. Gastric pH elevation alters the dissolution and ionisation of alkaloidal and enteric-coated botanical products; menthol- and peppermint-oil products lose their enteric protection at high pH and can be released prematurely. Expected Reduced or erratic absorption of alkaloids; heartburn and reflux from premature release of volatile-oil preparations. Management Separate administration by 2 hours. Avoid non-enteric peppermint oil in reflux disease. Onset unspecified Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism

05 Hazard register

product variability - unregulated potency and adulteration with

06 Confusable material

No same-genus or shared-common-name entry in the corpus.

07 Mechanism map

Chemistry sorts to the left, pharmacology to the right. Dashed edges are predicted. Drag nodes, scroll to zoom, export at 3× for a figure.

species

chemical class

marker compound

drug class

expected effect

hazard

08 Open literature

Abstract-scoped query built from this binomial, its common names and its marker compounds, run live against Europe PMC, PubMed and OpenAlex, then ranked locally against an evidence hierarchy.

Checking openFDA spontaneous reports…

09 Isomechanistic neighbours

Species whose interaction profile overlaps this one, ranked by shared severity weight rather than by count — a shared contraindication counts for more than a shared minor signal. Practical use: these are the plants you should not stack with this one, because the mechanisms summate.

Species	Family	Shared classes	Jaccard
Strychnos nux-vomica Nux Vomica	Loganiaceae	7	0.64
Peganum harmala Syrian Rue	Nitrariaceae	7	0.70
Rauvolfia serpentina Sarpagandha	Apocynaceae	6	0.67
Catharanthus roseus Periwinkle	Apocynaceae	6	0.67
Alstonia scholaris Saptaparna	Apocynaceae	6	0.67
Physostigma venenosum Calabar Bean	Fabaceae	6	0.55

10 References and notes

Source column: Smallets S et al. Front Pharmacol 2025;16:1620601. doi:10.3389/fphar.2025.1620601

Smallets S et al. Front Pharmacol 2025

Narrative review Smallets S et al. Front Pharmacol 2025 manual

16:1620601. doi:10.3389/fphar.2025.1620601

2025 doi:10.3389/fphar.2025.1620601 manual

BibTeX for all 2 records

@article{SmalletsSe2025,
  title = {Smallets S et al. Front Pharmacol 2025},
  author = {Smallets S et al.},
  journal = {Front Pharmacol},
  year = {2025},
}

@article{anon2025,
  title = {16:1620601. doi:10.3389/fphar.2025.1620601},
  year = {2025},
  doi = {10.3389/fphar.2025.1620601},
}

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