# Kratom / 7-OH Chemistry, Metabolism, and Detection Reference **Working reference for the EusomniaMD 7-OH Resource Center** **Version:** 1.2 **Last reviewed:** August 8, 2026 **Scope:** Clinician-facing reference on pharmacologically active kratom alkaloids and metabolites, metabolic pathways, emerging semisynthetic analogues, and biological detection. > **Evidence rule used here:** A compound is called an **active metabolite** only when it is both a demonstrated metabolite of a kratom alkaloid and has experimental evidence of pharmacologic activity. Mere detection by mass spectrometry is not enough. Human-confirmed metabolism, ex-vivo human metabolism, preclinical pharmacology, and commercial-product chemistry are labeled separately. > **Critical interpretation rule:** "Detected in urine" does **not** mean "primarily eliminated unchanged in urine," and neither statement establishes a fixed clinical detection window. Likewise, a plasma half-life is not the same thing as duration of receptor occupancy, duration of intoxication, duration of withdrawal risk, or urine-test positivity. --- ## 1. Executive metabolic map ```text BOTANICAL KRATOM / MITRAGYNINE EXPOSURE Mitragynine (MG) | |-- CYP3A4 --> 7-hydroxymitragynine (7-OH; 7-HMG) | | | |-- rearrangement in human plasma ex vivo and liver-associated systems --> | | mitragynine pseudoindoxyl (MP) | | | '-- chemical degradation can yield 3-dehydromitragynine (3DM) | under simulated gastric conditions; clinical in-vivo importance unknown | |-- non-CYP, NADPH-independent oxidation demonstrated in human liver fractions --> | 3-dehydromitragynine (3DM; active/toxic in preclinical systems) | |-- CYP2C19 + CYP2D6 + CYP3A4 --> 9-O-demethylmitragynine | (= 9-hydroxycorynantheidine; 9OH) | | | '-- phase II --> 9OH glucuronide (9G) and sulfate conjugates | |-- CYP2D6 + CYP2C19 + CYP2C18 --> 16-carboxymitragynine | |-- CYP2C19 --> 9-O-demethyl-16-carboxymitragynine | '-- additional O-demethylation, ester hydrolysis, oxidation/reduction, and conjugation --> glucuronide/sulfate metabolites --> urine Speciogynine '-- O-demethylation --> 9-O-desmethylspeciogynine (5-HT1A agonist in functional assays) Paynantheine '-- O-demethylation --> 9-O-desmethylpaynantheine (5-HT1A agonist in functional assays) ``` **Important:** CYP assignments above come from recombinant human CYP experiments and, for the MG to 7-OH step, are supported by a controlled itraconazole interaction study in healthy volunteers. Whole-body metabolism can involve additional enzymes and nonenzymatic chemistry. [1-4] --- ## Master glossary: compounds most relevant to the 7-OH clinical problem This is the compact index for webpage implementation. **Metabolite** means formed biologically from another kratom alkaloid; **botanical alkaloid** means present in *M. speciosa*; **semisynthetic analogue** means deliberately chemically modified from a kratom scaffold. Several compounds occupy more than one category. | Compound | Also called | Category | Why it matters clinically | Human detection / timing status | |---|---|---|---|---| | **Mitragynine** | MG, MTG | Major botanical parent alkaloid | Main botanical exposure and precursor to multiple active metabolites, especially 7-OH | Plasma/urine/hair measurable by targeted MS. Botanical human t1/2 commonly ~40-70 h depending regimen; unchanged urinary recovery is very low. [1-7,29,30] | | **7-hydroxymitragynine** | 7-OH, 7-HMG, 7-OH-MTG | Trace botanical alkaloid; **active human MG metabolite**; semisynthetic retail drug | Potent opioid-active compound driving the current high-concentration product problem | Targeted plasma/urine/hair assays exist. After 2-g botanical tea, median terminal t1/2 ~5.67 h and urine remained analytically informative through the 120-h study collection; **direct purified high-dose human PK is unknown**. [1-7,29,30] | | **9-O-demethylmitragynine** | 9ODM, 9-O-desmethylmitragynine, **9-hydroxycorynantheidine**, 9OH | **Active MG metabolite** | MOR partial agonist; prominent phase-I urinary metabolite and potentially clinically relevant secondary opioid pathway | Identified in human urine by targeted MS; human plasma PK and validated urine window unknown. [3,8-10,33] | | **Mitragynine pseudoindoxyl** | MP | **Active downstream 7-OH/MG product**; directly manufactured semisynthetic drug | Potent opioid-active rearrangement product; may be ingested directly or form downstream from 7-OH | Targeted LC-HRMS/LC-QTOF can identify it. No validated human systemic half-life or urine/blood window; detection does not by itself prove direct ingestion. [2,11-14,18] | | **3-dehydromitragynine** | 3DM, 3DMTG, dehydromitragynine | Oxidative MG product; degradation/product constituent | Preclinical MOR partial agonism plus high-dose non-opioid toxicity signal; found in modern commercial products | Targeted HRMS/UPLC-MS/MS can identify it in research/product matrices; human in-vivo PK and biological window unknown. [34-36,40] | | **9-O-demethylmitragynine glucuronide** | 9G, glucuronyl-9OH | Phase-II 9OH conjugate | Weak MOR affinity reported, but clinically meaningful agonism not established | Detectable with conjugate-aware HRMS methods or after hydrolysis depending assay; timing unknown. [9,13,37] | | **16-carboxymitragynine** | 16-COOH-MG | MG metabolite / hydrolysis product | Important urinary/product marker; pharmacologic activity not established | Identified in human urine by targeted MS; no validated window. [3,9,10] | | **9-O-demethyl-16-carboxymitragynine** | 9ODM-16-COOH-MG | MG metabolite | Useful pathway marker; formed predominantly via CYP2C19 in recombinant studies | Human urine identification reported; no validated window. [3,9,10] | | **9-O-desmethylspeciogynine** | - | **Active speciogynine metabolite** | Functional 5-HT1A agonist in vitro, offering a plausible non-opioid pathway in botanical kratom pharmacology | Targeted metabolomics possible; human concentration-time profile and clinical window unknown. [15-17] | | **9-O-desmethylpaynantheine** | - | **Active paynantheine metabolite** | Functional 5-HT1A agonist in vitro | Targeted metabolomics possible; human concentration-time profile and clinical window unknown. [15-17] | | **MGM-15** | dihydro-7-OH, DH7OH; sometimes ambiguously called DHM | **Semisynthetic 7-OH analogue, not a metabolite** | Higher hMOR/hDOR binding affinity than 7-OH in published in-vitro work; commercial human exposure documented, but no human PK studies | LC-MS/MS/LC-QTOF identification is feasible. No validated human half-life or biological detection window. GC analysis can create an MG identification artifact. [18,19,21] | | **MGM-16** | 9-fluoro-dihydro-7-hydroxymitragynine | **Synthetic/semisynthetic analogue, not a metabolite** | Potent preclinical mu/delta agonist; important because it sits immediately adjacent to MGM-15 in the emerging analogue market/regulatory response | No established clinical human PK or validated biological window. Targeted HRMS would require an appropriate standard. [18,20,22] | | **8-hydroxymitragynine / 11-hydroxymitragynine** | 8-OH-MG / 11-OH-MG | Related hydroxylated compounds | Emerging analytical/commercial relevance, but not established clinically important human metabolites | No validated human PK or testing window. | | **Speciogynine / paynantheine / speciociliatine / mitraciliatine / isopaynantheine** | minor botanical alkaloids | Botanical parent alkaloids | Contribute to the polypharmacology of botanical kratom and can have their own active metabolites/receptor activity | Several have controlled human plasma PK after botanical exposure; compound-specific clinical urine windows are not validated. [5,15-17,25-27] | | **Corynantheidine / corynoxines / speciofolines / rhynchophylline-family oxindoles / N-oxides** | various | Minor botanical alkaloids | Relevant to a complete kratom targetome, but not established principal 7-OH metabolic drivers | Detectable analytically when included in targeted methods; clinical PK/window data are sparse or absent. [25-27] | **Not shown as established human metabolites:** medicinal-chemistry compounds such as 7-hydroxypaynantheine, 7-hydroxyspeciogynine, paynantheine pseudoindoxyl, and speciogynine pseudoindoxyl. They are useful structure-activity probes but should not be presented as routine human metabolites without direct metabolic evidence. [24] --- ## 2. Active metabolites with the strongest evidence The table below includes compounds with **demonstrated pharmacologic activity** after formation from a kratom alkaloid. It deliberately distinguishes human-confirmed metabolites from metabolites demonstrated only in human liver systems or preclinical animals. | Compound | Parent / precursor | Formation pathway | Demonstrated pharmacology | Human metabolic evidence | Human half-life | Biological detectability | What remains unknown | |---|---|---|---|---|---|---|---| | **7-hydroxymitragynine (7-OH, 7-HMG, 7-OH-MTG)** | Mitragynine; also a trace botanical constituent and processing/oxidation product | Predominantly **CYP3A4-mediated oxidation of MG**. Human itraconazole pretreatment reduced 7-OH Cmax by about 56% and AUC0-72 by about 43%, supporting CYP3A4-mediated formation in vivo. | Potent opioid agonist, predominantly MOR; intrinsic efficacy is assay- and receptor-reserve-dependent. | **High.** Directly measured in human plasma after botanical/MG-rich exposure; metabolic formation demonstrated in a controlled human CYP3A interaction study. | **Direct purified 7-OH: unknown.** After botanical tea exposure, median terminal t1/2 was about **5.67 h** in one controlled study. Dried-leaf and extract studies show highly regimen-dependent terminal estimates because circulating 7-OH is being formed from MG. | Targeted LC-MS/MS, LC-HRMS, LC-QTOF, and CZE-MS/MS can measure 7-OH. In one controlled 2-g botanical tea study, 7-OH was quantifiable in plasma through about **24 h** and in urine through the study's **120-h collection** in completers. This is not a universal five-day window. | PK after direct high-dose commercial 7-OH, bioavailability by tablet/sublingual routes, intrinsic elimination, accumulation during q1-3h use, and validated clinical urine window. [1-7,29] | | **9-O-demethylmitragynine (9ODM; 9-hydroxycorynantheidine; 9OH)** | Mitragynine | O-demethylation. Recombinant human CYP studies implicate **CYP2C19, CYP3A4, and CYP2D6**; human liver S9 work identifies CYP3A as a major contributor. | **MOR partial agonist** activity demonstrated in functional pharmacology. | **Moderate-high.** A major MG metabolite in human liver systems and reported as the **most prevalent phase-I metabolite in urine** among kratom users in Basiliere/Kerrigan. | **Unknown in humans.** | Detectable in human urine with targeted LC-HRMS/LC-QTOF metabolite methods. No validated time-since-last-use window. | Plasma exposure, brain penetration, contribution to intoxication/dependence/withdrawal, and quantitative renal/fecal clearance. [3,8-10,33] | | **Mitragynine pseudoindoxyl (MP)** | Downstream of MG/7-OH; also manufactured and consumed directly | 7-OH undergoes oxidative/rearrangement chemistry to MP. Formation is demonstrated in **human plasma ex vivo** and liver systems; CYP3A-associated and nonenzymatic mechanisms both appear to contribute. | Potent opioid-active compound; strong MOR activity with DOR/KOR antagonism in several established assay systems. | **Moderate.** Formation in pooled human plasma ex vivo is directly demonstrated; MP is also found in commercial/forensic contexts. Controlled in-vivo human formation fraction is unknown. | **Unknown systemically in humans.** The 120-min plasma incubation experiment and 7-OH plasma instability are not systemic half-life measurements. | Targeted LC-HRMS/LC-QTOF can identify MP if chromatographic separation and reference standards are adequate. A positive result may reflect direct MP exposure, downstream formation, or both. | Human oral/sublingual PK, fraction formed from 7-OH in vivo, distribution, elimination, urine window, and whether analyte ratios distinguish direct from metabolic exposure. [2,11-14,18] | | **3-dehydromitragynine (3DM; 3DMTG; dehydromitragynine)** | Mitragynine; also described as a minor natural/product constituent | A **non-CYP, NADPH-independent oxidative pathway** was demonstrated in human liver microsomes/S9 and in mice. Separate 2026 chemistry work found that 7-OH can degrade to 3DM under simulated gastric conditions. | Preclinical MOR binding/partial agonism has been demonstrated; the 2021 study also identified **non-opioid toxicity at high doses in mice**. | **Limited for humans.** Formation is demonstrated in human liver fractions, but a controlled study confirming circulating 3DM as an in-vivo human metabolite has not been established. | **Unknown in humans; direct preclinical systemic half-life not adequately established for clinical use.** | Detectable by targeted high-resolution MS in products/research matrices; 3DM has been reported in recent commercial-product analyses. There is no validated clinical urine/blood window. | Human in-vivo formation, exposure after MG versus direct 7-OH, metabolism, clearance, clinical toxicity, and contribution to withdrawal. [34-36] | | **9-O-desmethylspeciogynine** | Speciogynine | O-demethylation; exact quantitative human enzyme contribution is not well defined. | Functional **5-HT1A agonist** in vitro; also inverse partial agonist activity at 5-HT2B was reported rather than 5-HT2B activation. | **Moderate pharmacology; limited human exposure data.** | **Unknown.** | Can be sought with targeted metabolomic/MS methods; no validated routine clinical assay or window. | Whether human concentrations reach clinically meaningful serotonergic exposure, and whether it contributes to mood/sleep/withdrawal phenomena. [15-17] | | **9-O-desmethylpaynantheine** | Paynantheine | O-demethylation; exact quantitative human enzyme contribution is not well defined. | Functional **5-HT1A agonist** in vitro; inverse partial agonist at 5-HT2B rather than agonist activity. | **Moderate pharmacology; limited human exposure data.** | **Unknown.** | Targeted MS is possible; no validated routine clinical window. | Human systemic exposure and clinical serotonergic contribution. [15-17] | | **9-O-demethylmitragynine glucuronide (9G; glucuronyl-9-hydroxycorynantheidine)** | 9OH / 9-O-demethylmitragynine | Phase-II **glucuronidation** downstream of 9OH. | **Weak MOR binding/affinity** has been reported preclinically. Functional agonist efficacy and clinical significance are not established, so this is best classified as an **interaction-positive conjugated metabolite**, not a proven clinically active opioid. | Phase-II formation is supported by metabolic-networking/earlier metabolite work; quantitative in-vivo human exposure is poorly defined. | **Unknown.** | Amenable to direct conjugate LC-HRMS or indirect detection after enzymatic hydrolysis, depending laboratory method. No validated window. | Whether meaningful concentrations reach systemic circulation/CNS and whether receptor binding has any clinical consequence. [9,10,13,37] | **Bottom line:** the best-established clinically relevant active-metabolite chain is **MG -> 7-OH -> MP**. **MG -> 9OH -> 9G** is a second pathway in which 9OH is clearly pharmacologically active and 9G has only weak receptor-binding evidence. **3DM** is an important oxidative product because it is pharmacologically active and potentially toxic in preclinical systems, but its in-vivo human contribution is not yet known. ### Key caution on 7-OH half-life Published human 7-OH half-lives are mostly measured after people ingest **botanical kratom or mitragynine-rich extract**, where much of the circulating 7-OH is being formed continuously from mitragynine. That means the observed terminal phase can be **formation-limited** rather than representing the intrinsic elimination of directly ingested purified 7-OH. It is therefore scientifically unsafe to take a botanical-kratom 7-OH half-life and use it as a fixed waiting-time rule for buprenorphine induction after high-dose commercial 7-OH use. [4-7] --- ## 3. Other identified mitragynine metabolites These compounds are important for forensic interpretation and for understanding total exposure, but **clinically meaningful pharmacologic activity has not been established for each one**. | Metabolite | Transformation | Human occurrence | Pharmacologic activity | Half-life | Detectability / elimination | |---|---|---|---|---|---| | **16-carboxymitragynine** | Ester hydrolysis / carboxylation pathway; CYP2D6, CYP2C19, CYP2C18 implicated in recombinant systems | Confirmed in human metabolite work | Not established as a clinically meaningful active metabolite | Unknown | Detected in urine by targeted MS; phase II conjugation reported. [3,9,10] | | **9-O-demethyl-16-carboxymitragynine** | Combined O-demethylation plus carboxylation; CYP2C19 prominent in recombinant systems | Confirmed in human metabolite work | Unknown | Unknown | Urinary metabolite/conjugate; targeted MS required. [3,9,10] | | **17-O-demethyl-16,17-dihydromitragynine** | O-demethylation plus reduction of the side-chain unsaturation | Identified in classic rat/human metabolite studies | Unknown | Unknown | Detected as unconjugated and/or conjugated metabolite depending species/sample; targeted MS. [9,10] | | **9,17-O-bisdemethyl-16,17-dihydromitragynine** | Additional O-demethylation plus reduction | Identified in classic metabolite studies | Unknown | Unknown | Urinary metabolite/conjugate reported; no clinical window. [9,10] | | **17-carboxy-16,17-dihydromitragynine** | Reduction plus carboxylation | Identified in classic metabolite studies | Unknown | Unknown | Targeted urine MS; no clinical window. [9,10] | | **9-O-demethyl-17-carboxy-16,17-dihydromitragynine** | O-demethylation plus reduction plus carboxylation | Identified in classic metabolite studies | Unknown | Unknown | Targeted urine MS; no clinical window. [9,10] | | **Glucuronide and sulfate conjugates of O-demethylated/carboxylated metabolites** | Phase II conjugation, mainly glucuronidation and sulfation | Confirmed in human urine | Generally treated as elimination metabolites; receptor activity not established | Unknown | Major urinary route for several phase I products; laboratories may require hydrolysis or direct conjugate measurement depending method. [9,10] | The older metabolic literature identified multiple phase I and phase II MG metabolites in rat and human urine, but the exact unconjugated/conjugated pattern differs by species. For the website, avoid implying that every metabolite identified in the combined rat/human work is quantitatively important in humans. [9,10] --- ## 4. Controlled human pharmacokinetics of major botanical kratom alkaloids The following values are useful orientation numbers, **not** direct-purified-7-OH pharmacokinetics. In a controlled single-dose study of a standardized kratom product in healthy adults, median terminal half-lives were approximately: [5] | Alkaloid | Median terminal half-life | Comment | |---|---:|---| | **Mitragynine** | **45.3 h** | Major parent alkaloid; long terminal phase | | **Speciogynine** | **23.5 h** | Parent botanical alkaloid | | **Paynantheine** | **27.0 h** | Parent botanical alkaloid | | **Speciociliatine** | **12.3 h** | Parent botanical alkaloid | | **Mitraciliatine** | **17.8 h** | Parent botanical alkaloid | | **Isopaynantheine** | **14.4 h** | Parent botanical alkaloid | | **7-OH** | **5.67 h** | Mostly metabolically generated in this botanical-exposure context | A separate controlled dried-leaf study found mean MG half-lives around **43 h after single dosing** and **68 h after repeated dosing**, while mean 7-OH estimates were roughly **5 h single-dose** and **25 h repeated-dose** in that study. [6] A 2026 concentrated-mitragynine-extract study reported extremely variable 7-OH half-life estimates after repeated dosing, including much longer terminal estimates in the highest-dose cohort. The authors specifically cautioned that the high-dose estimates may reflect complex formation/elimination kinetics and possible saturation. This is another reason not to use a single fixed 7-OH half-life clinically. [7] ### Renal elimination Unchanged renal excretion differs substantially across alkaloids. **Mitragynine itself is only minimally recovered unchanged in urine**, while some minor alkaloids have materially higher unchanged urinary fractions. Most overall disposition therefore cannot be summarized as "the kidneys simply clear intact kratom alkaloids." Metabolism plus conjugation are important. [5] --- ## 5. Mitragynine pseudoindoxyl: metabolite and commercial drug **Mitragynine pseudoindoxyl (MP)** deserves its own category because it is simultaneously: 1. a downstream transformation product of 7-OH; 2. a potent opioid-active molecule in experimental pharmacology; and 3. an increasingly relevant semisynthetic/commercial compound in the 7-OH marketplace. [11-14,18] Kamble and colleagues demonstrated that 7-OH rearranged rapidly in human plasma ex vivo, with approximately **53.8% conversion to MP after 120 minutes** under their experimental conditions. MP itself remained comparatively stable during the experiment. Those are **ex-vivo plasma stability data**, not systemic human pharmacokinetics. [11,12] More recent metabolic-networking work supports both liver-associated and nonenzymatic contributions to MP formation. Human in-vivo fractional conversion, oral bioavailability, volume of distribution, systemic half-life, renal/fecal clearance, and clinical detection window have **not been established**. [13] For forensic interpretation, a positive MP result can be difficult to interpret without context because MP may represent **direct use of an MP-containing product, downstream formation after 7-OH exposure, or both**. Product analysis and analyte ratios may eventually help, but no universally validated clinical algorithm currently exists. --- ## 6. Emerging semisynthetic / synthetic analogues ### MGM-15 **Preferred descriptive name:** dihydro-7-hydroxymitragynine **Common labels:** MGM-15; DH7OH; some commercial material has used "DHM" terminology, which is chemically ambiguous. - MGM-15 is a **synthetic/semi-synthetic derivative of 7-OH**, produced by reduction/saturation of the relevant imine/double-bond system in the mitragynine scaffold. [19,20] - In receptor studies it shows strong opioid-receptor activity, including MOR and DOR activity. [19,20] - A 2025 analytical report identified commercial tablets averaging about **10.9 mg MGM-15 per tablet** in the products tested. [19] - The Center for Forensic Science Research and Education (CFSRE) reported first U.S. detection in 2025 and confirmed MGM-15 in drug material and toxicology specimens using **LC-QTOF-MS** with reference material. [21] - **GC-MS is problematic:** MGM-15 can undergo analytical conversion to mitragynine during GC analysis, creating a serious identification pitfall. High-quality LC-MS confirmation is preferable. [21] - **Human pharmacokinetics:** unknown. - **Human metabolism:** unknown. - **Human half-life:** unknown. - **Validated urine/blood detection window:** unknown. - **Clinical withdrawal/overdose literature:** essentially absent compared with 7-OH. ### MGM-16 **Description:** fluorinated dihydro-7-OH analogue. Position numbering varies depending on chemical nomenclature convention; the medicinal-chemistry literature describes it as a fluorinated analogue developed alongside MGM-15. [20,22] - Developed in preclinical medicinal chemistry as a potent dual mu/delta opioid agonist. [20,22] - Demonstrated antiallodynic/analgesic activity in animal models. [20,22] - DEA's 2026 scheduling record discusses MGM-16 as an emerging related compound but reported no established consumer-market/toxicology presence comparable to 7-OH or MGM-15 at the time of the notice. [18] - **Human use studies:** none established. - **Human metabolism:** unknown. - **Human half-life:** unknown. - **Urine/blood detection window:** unknown. - **Routine laboratory availability:** no standard clinical assay. ### 3-dehydromitragynine (3DM / 3DMTG) 3DM belongs in **two categories at once**: it is an oxidative MG product demonstrated in metabolic systems, and it can also occur as a minor natural/commercial-product constituent. The 2021 oxidative-metabolism study demonstrated formation from MG by a **non-CYP, NADPH-independent pathway** in human liver microsomes/S9 and in mice, and characterized MOR partial-agonist activity plus high-dose toxicity in mice through a mechanism not fully explained by opioid receptors. [34] A 2026 study additionally showed degradation of 7-OH to 3DM under **simulated gastric conditions**. That chemistry is relevant to oral products but does not establish the fraction of an oral 7-OH dose converted to 3DM in living humans. [35] - **Controlled human in-vivo confirmation:** not established. - **Human PK / half-life / clearance:** unknown. - **Routine toxicology detection:** not standard; targeted HRMS can identify it with an appropriate standard. - **Validated urine/blood detection window:** unknown. - **Commercial relevance:** reported in contemporary product analyses, including products with complex/mislabeled alkaloid profiles. [36] ### 8-hydroxymitragynine and 11-hydroxymitragynine These names appear in emerging commercial/analytical literature. They should be listed as **related hydroxylated mitragynine compounds**, not as established clinically important human metabolites unless a specific human metabolic study demonstrates that pathway. Human pharmacology, PK, half-life, and detection windows remain poorly characterized. ### Research pseudoindoxyl / hydroxyl analogues Medicinal-chemistry literature includes compounds such as **7-hydroxypaynantheine, 7-hydroxyspeciogynine, paynantheine pseudoindoxyl, and speciogynine pseudoindoxyl**. These are useful for understanding structure-activity relationships but should **not** be presented to patients as established human metabolites or common retail exposures without direct evidence. [24] --- ## 7. Relevant parent botanical alkaloids: glossary Kratom contains dozens of indole and oxindole alkaloids. Modern analytical studies have structurally characterized more than forty, with counts varying by plant chemotype, analytical method, and what authors consider a distinct alkaloid. The following are the most relevant to a clinical 7-OH resource. [25,26] ### Mitragynine (MG) The predominant alkaloid in most kratom leaf products. Opioid-active itself but also functions as a **metabolic precursor to 7-OH**. It has a much longer terminal half-life than 7-OH in botanical exposure studies. Human MG metabolism is extensive; unchanged urinary excretion is low. [1-7] ### 7-hydroxymitragynine (7-OH) Minor naturally occurring alkaloid, human MG metabolite, oxidation/processing product, and now a high-dose commercial drug. Potent opioid pharmacology. Direct high-dose purified human PK remains a major evidence gap. [1-7,18] ### Mitragynine pseudoindoxyl (MP) Potent rearrangement product of 7-OH and also a directly manufactured commercial compound. Human systemic PK remains unknown. [11-14,18] ### Speciogynine Common minor alkaloid. Parent compound has serotonergic receptor binding; its **9-O-desmethyl metabolite** demonstrates functional 5-HT1A agonism. [15-17] ### Paynantheine Common minor alkaloid. Like speciogynine, it has serotonergic receptor interactions, while its **9-O-desmethyl metabolite** shows functional 5-HT1A agonism. [15-17] ### Speciociliatine Stereoisomer/related indole alkaloid with opioid-receptor activity. Human PK has been measured after botanical kratom exposure. [5,25,26] ### Mitraciliatine Minor alkaloid present in some chemotypes; has opioid-receptor activity in modern screening studies. Human PK has been measured after botanical exposure. [5,25,26] ### Isopaynantheine and epiallo-isopaynantheine Minor alkaloids found in botanical kratom. Opioid-receptor activity has been reported for some members of this subgroup, including KOR activity in modern functional screens. Clinical contribution is uncertain. [25-27] ### Corynantheidine Minor alkaloid with opioid-receptor binding/antagonist-like pharmacology reported in preclinical work. It is relevant to the broader kratom targetome but is not a principal 7-OH metabolite. ### Corynoxine A / corynoxine B / corynoxeine Oxindole alkaloids present in some kratom samples. They are pharmacologically interesting but far less clinically characterized than MG or 7-OH. [25,26] ### Speciofoline / isospeciofoline (and related spelling variants) Minor alkaloids identified in modern phytochemical profiling. Clinical activity remains incompletely characterized. [25,26] ### Rhynchophylline / 3-epirhynchophylline and related oxindoles Minor botanical constituents. They are part of the broader kratom alkaloid profile but should not be conflated with 7-OH or its metabolic pathway. [25,26] ### N-oxide alkaloids Mitragynine-N(4)-oxide, speciociliatine-N(4)-oxide, isopaynantheine-N(4)-oxide, and related N-oxides have been identified in botanical material. Their abundance can be affected by storage/oxidation and product processing. Clinical pharmacologic significance is incompletely defined. [25,26] --- ## 8. Biological detection: what can actually be tested ### Routine urine drug screens A routine "opiates" immunoassay is generally designed around morphine-like structures and **does not specifically identify mitragynine, 7-OH, MP, MGM-15, or MGM-16**. A negative routine opioid screen therefore does not exclude kratom-family exposure. Dedicated mitragynine immunoassays have been developed, but they are specialized assays and can cross-react with related alkaloids/metabolites. Confirmation by chromatography-mass spectrometry is preferred when compound-level identification matters. [28] ### Targeted urine testing Validated research/forensic methods include LC-MS/MS, LC-HRMS, LC-QTOF-MS, and capillary electrophoresis-MS/MS. A 2024 urine method reported analytical limits of detection of approximately **0.5 ng/mL for mitragynine** and **2 ng/mL for 7-OH**. These are analytical sensitivity limits, **not** clinical detection windows. [29] Controlled human botanical studies collected and quantified kratom alkaloids in urine for up to **120 hours** after dosing. This supports the proposition that targeted urine testing can remain informative for days in some exposure settings, especially for MG and metabolites. It does **not** establish a universal "five-day window" for every dose, product, metabolizer, or assay. [5] ### Plasma / blood Mitragynine, 7-OH, and several parent botanical alkaloids have been measured with validated LC-MS/MS methods in controlled human studies. The time to last quantifiable concentration varies dramatically by analyte, dose, repeated use, and assay sensitivity. [5-7] In the 2026 concentrated-mitragynine-extract study, 7-OH remained quantifiable much longer in some high-dose/repeated-dose participants than in low-dose participants, again demonstrating why a single blood "window" is not defensible. [7] ### Hair Mitragynine and 7-OH have been measured in hair using targeted LC-MS/MS forensic methods. Hair can support longer-term exposure assessment, but segment location, hair growth, cosmetic treatment, external contamination, and incorporation kinetics complicate interpretation. Hair testing is unsuitable for determining a precise recent last-use time. [30] ### MGM-15 CFSRE has confirmed MGM-15 in toxicology specimens and drug materials using LC-QTOF-MS. No validated population detection window has been published. GC-MS can misidentify the compound because MGM-15 can convert to MG during analysis. [21] ### Mitragynine pseudoindoxyl MP can be measured with targeted modern LC-MS methods and has appeared in commercial/toxicology investigations. No validated blood or urine window exists. Because MP may arise downstream of 7-OH, detection alone may not prove direct MP ingestion. [11-14,18] ### MGM-16 No validated clinical biological detection window exists. As of DEA's July 2026 discussion, confirmed real-world consumer/toxicology exposure was not established to the same degree as 7-OH, MP, or MGM-15. [18] --- ## 9. Practical detection matrix | Analyte | Routine opiate screen? | Targeted LC-MS / HRMS? | Demonstrated biological detection | Defensible timing statement | |---|---|---|---|---| | **Mitragynine** | No specific detection | Yes | Plasma, urine, hair | Long terminal PK after botanical use; urine can remain detectable for days with sensitive targeted methods. No universal cutoff. [5-7,29,30] | | **7-OH** | No specific detection | Yes | Plasma, urine, hair | Detectable after botanical MG exposure and direct-product exposure; controlled botanical studies show hours-to-days depending dose/regimen. No validated window for high-dose purified 7-OH. [5-7,29,30] | | **9-O-demethylmitragynine** | No | Yes | Human urine | Prominent urinary MG metabolite; no validated time window. [3,9,10] | | **16-carboxymitragynine** | No | Yes | Human urine | Useful metabolite marker; no validated time window. [3,9,10] | | **Mitragynine pseudoindoxyl** | No | Yes, method-dependent | Commercial/treatment/toxicology contexts; formation demonstrated ex vivo | No validated window; direct ingestion cannot always be distinguished from downstream formation. [11-14,18] | | **MGM-15** | No | Yes; LC-QTOF confirmation preferred | Toxicology specimens and drug materials reported | No validated window. GC-MS transformation to MG is a known analytical trap. [21] | | **MGM-16** | No | In principle yes with reference standard and appropriate HRMS method | Real-world human biological prevalence not established | Unknown. [18,20,22] | | **Speciogynine / paynantheine and metabolites** | No | Yes | Parent alkaloids in plasma/urine; metabolites characterized | No clinically validated metabolite-specific window. [5,15-17] | --- ## 10. Interpretation traps for clinicians, toxicologists, and the website 1. **A positive 7-OH result does not automatically prove a person swallowed a commercial 7-OH product.** Mitragynine is metabolized to 7-OH. Product history and relative analyte concentrations matter. [1-4] 2. **A positive MP result does not automatically prove direct MP ingestion.** MP can form downstream from 7-OH. [11-14] 3. **A negative routine opioid screen does not rule out 7-OH intoxication or withdrawal.** Standard immunoassay design is the problem, not necessarily the patient's history. [28,29] 4. **Do not infer last-dose timing from a qualitative urine result.** Long MG kinetics, metabolite formation, repeated dosing, renal function, assay cutoff, and product composition make back-calculation unreliable. [5-7] 5. **Do not use ex-vivo plasma stability as a clinical half-life.** The approximately 99-minute 7-OH value from the pseudoindoxyl conversion experiment is a laboratory plasma-incubation observation, not a systemic human PK parameter. [11,12] 6. **Do not treat botanical-kratom 7-OH half-life as purified-7-OH PK.** Formation from MG can distort the apparent terminal phase. [4-7] 7. **Commercial labels are not dependable analytical records.** Multiple recent product surveys found large differences between labeled and measured alkaloids, semisynthetic profiles, undeclared active compounds, and oxidation products. [23,31,32] 8. **GC-MS can create identification artifacts for some emerging analogues.** MGM-15 is a particularly important example because it can transform to MG during GC analysis. [21] 9. **"Kratom" is chemically too broad for many clinical conclusions.** Botanical leaf, MG-rich extract, purified 7-OH, MP products, MGM-15 products, and mixtures should be documented separately whenever possible. --- ## 11. What is still genuinely unknown The most important unresolved questions for the current public-health crisis are: - Direct human PK of **purified high-dose 7-OH**, including Cmax, Tmax, oral/sublingual bioavailability, distribution, intrinsic elimination half-life, accumulation with frequent redosing, and active-metabolite contribution. - The fraction of direct 7-OH converted to **MP in vivo** in humans. - Human PK, metabolism, elimination, and toxicity of **MGM-15** and **MGM-16**. - Reliable biological detection windows for purified 7-OH, MP, MGM-15, MGM-16, and 3DMTG. - Whether analyte ratios can reliably distinguish botanical kratom use, MG extract use, purified 7-OH use, and direct MP use. - Quantitative contribution of **9-O-demethylmitragynine** to analgesia, intoxication, dependence, or withdrawal in humans. - Whether serotonergic active metabolites of speciogynine/paynantheine contribute materially to the distinctive affective or sleep features reported during botanical kratom withdrawal. - How hepatic impairment, renal impairment, CYP3A inhibition/induction, CYP2D6 phenotype, and polysubstance exposure alter direct 7-OH disposition. - Whether chronic high-frequency 7-OH dosing produces nonlinear kinetics or tissue redistribution that meaningfully changes buprenorphine induction timing. These gaps should be presented prominently. They are not weaknesses in the resource; they are the current state of the science. --- ## 12. Suggested terminology for the EusomniaMD website **Botanical kratom:** Leaf-derived *Mitragyna speciosa* material containing a mixture of naturally occurring alkaloids, usually dominated by mitragynine. **Mitragynine (MG):** Principal kratom alkaloid and metabolic precursor to 7-OH. **7-OH / 7-hydroxymitragynine:** Potent opioid-active alkaloid that exists in trace botanical quantities, is formed metabolically from MG, and is now sold in highly concentrated/semi-synthetic products. **Mitragynine pseudoindoxyl (MP):** Potent rearrangement product downstream of 7-OH that is also sold directly as a semisynthetic opioid-active compound. **MGM-15:** Dihydro-7-OH analogue now documented in commercial drug material and U.S. toxicology specimens; human PK and safety are essentially undefined. **MGM-16:** Fluorinated MGM-15/7-OH analogue from medicinal-chemistry research; potent opioid activity in animals, with human PK and safety undefined. **Active metabolite:** A metabolite with demonstrated pharmacologic activity, not merely a compound detectable after exposure. **Phase I metabolism:** Oxidation, reduction, hydrolysis, or demethylation that changes the parent molecular structure. **Phase II metabolism:** Conjugation, commonly glucuronidation or sulfation, usually increasing water solubility and facilitating elimination. **Detection window:** The interval during which a specified analyte can be detected above a specified assay cutoff in a specified biological matrix. It is assay- and dose-dependent and should not be treated as a universal property of the drug. **Formation-limited kinetics:** A situation in which the measured decline of a metabolite reflects how quickly it is still being produced from a longer-lived precursor, not simply how quickly the metabolite itself is eliminated. --- ## 13. Recommended evidence labels for web pages Use these labels directly beside claims when helpful: - **Human controlled data** - prospective human pharmacokinetic or interaction study. - **Human confirmed metabolite** - directly identified in human plasma, urine, or ex-vivo human biological systems. - **Clinical case evidence** - case report or small case series. - **Preclinical functional evidence** - receptor/cellular/animal pharmacology. - **Forensic/commercial evidence** - confirmed in marketed products, seized material, or toxicology testing. - **Clinical inference** - reasonable extrapolation from pharmacology plus direct clinical experience, but not established by controlled study. - **Unknown** - no adequate evidence currently available. This hierarchy is particularly important for withdrawal timelines and buprenorphine timing, where the current literature does not support false precision. --- ## 14. Author / source provenance for the eventual webpage For the professional biography associated with this resource, the public CSAM record independently confirms that **Brian Harris, MD** served as faculty for the **2025 California Society of Addiction Medicine Addiction Medicine Board Exam Preparation Course** and lists his board certifications in Addiction Medicine, Anesthesiology, and Sleep Medicine. [38] An archived August 2025 **Basic Sciences & Addiction - Addiction Medicine Board Review** deck identifies Brian Harris, MD as the presenter and contains a dedicated board-style kratom neuropharmacology question and explanation focused on mitragynine's opioid-receptor pharmacology. [41] This is useful contemporaneous evidence that kratom pharmacology was part of Dr. Harris's addiction-medicine teaching before the present 7-OH regulatory crisis. I did **not** find searchable text for “7-hydroxymitragynine” in the retrieved copy, so the stronger claim that this specific archived deck explicitly covered 7-OH should remain dependent on locating the relevant slide/version rather than being stated as independently verified. The website should describe prior teaching experience without implying that CSAM endorses the present EusomniaMD resource. --- ## 15. Selected primary and authoritative references 1. Kruegel AC, et al. **7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects.** *ACS Central Science.* 2019;5:992-1001. doi:10.1021/acscentsci.9b00141. 2. Kamble SH, et al. **Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy.** *ACS Pharmacology & Translational Science.* 2020;3:1063-1068. doi:10.1021/acsptsci.0c00075. PMID:33344889. 3. Basiliere S, Kerrigan S. **CYP450-Mediated Metabolism of Mitragynine and Investigation of Metabolites in Human Urine.** *Journal of Analytical Toxicology.* 2020;44:301-313. doi:10.1093/jat/bkz108. 4. Jaisi A, et al. **Effects of Itraconazole on Pharmacokinetics of Mitragynine and 7-Hydroxymitragynine in Healthy Volunteers.** *ACS Pharmacology & Translational Science.* 2024;7:823-833. doi:10.1021/acsptsci.3c00335. PMID:38481700. 5. Tanna RS, et al. **Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants.** *Pharmaceutics.* 2022;14:620. PMID:35335999. 6. Huestis MA, et al. **Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder.** *Molecules.* 2024;29:984. 7. Huestis MA, et al. **Mitragynine and 7-hydroxy-mitragynine plasma pharmacokinetics in humans after single and 15 multiple oral kratom extract doses.** *Journal of Analytical Toxicology.* 2026;50(6):bkag042. doi:10.1093/jat/bkag042. PMID:42266029. (Industry relationships disclosed by the authors.) 8. Matsumoto K, et al. **Partial agonistic effect of 9-hydroxycorynantheidine on mu-opioid receptor in the guinea-pig ileum.** *Life Sciences.* 2006;78:2265-2271. doi:10.1016/j.lfs.2005.09.030. PMID:16266723. 9. Philipp AA, et al. Classic LC-MS/GC-MS studies of **mitragynine phase-I and phase-II metabolites in rat and human urine.** *Journal of Mass Spectrometry.* 2009. 10. Basiliere/Kerrigan and related forensic metabolite studies documenting O-demethylated, carboxylated, glucuronidated, and sulfated MG metabolites in human urine. See ref. 3 and its cited metabolite literature. 11. Kamble SH, et al. Human-plasma ex-vivo conversion of 7-OH to MP. See ref. 2. In pooled human plasma, **53.8 +/- 1.6%** of incubated 7-OH was converted to MP by 120 min under the experiment's conditions; this is not a systemic human conversion fraction. 12. Zhou Y, et al. **Predicted Mode of Binding to and Allosteric Modulation of the Mu-Opioid Receptor by Kratom's Alkaloids with Reported Antinociception In Vivo.** *Biochemistry.* 2021;60:1420-1429. doi:10.1021/acs.biochem.0c00658. PMID:33274929. 13. Crandall WJ, et al. **Mixtures Biotransformation: Multilayer Molecular Networking of Kratom Liver Metabolites.** *Journal of Natural Products.* 2026. doi:10.1021/acs.jnatprod.5c01235. 14. Contemporary forensic/commercial analyses of mitragynine pseudoindoxyl and related semisynthetic kratom-opioid products; interpret biological detection with route and product chemistry in mind. 15. Leon F, et al. **Activity of Mitragyna speciosa (Kratom) Alkaloids at Serotonin Receptors.** *Journal of Medicinal Chemistry.* 2021;64:13510-13523. doi:10.1021/acs.jmedchem.1c00726. 16. Leon et al. supporting information and metabolic experiments for 9-O-desmethylspeciogynine. See ref. 15. 17. Leon et al. supporting information and metabolic experiments for 9-O-desmethylpaynantheine. See ref. 15. 18. U.S. Drug Enforcement Administration. **Schedules of Controlled Substances: Temporary Placement of Mitragynine Pseudoindoxyl, MGM-15, and MGM-16 in Schedule I - Notice of Intent.** *Federal Register.* July 6, 2026; Docket DEA-1644. 19. Gour A, et al. **From Kratom to Semi-Synthetic Opioids: The Rise and Risks of MGM-15.** *Drug Testing and Analysis.* 2025;17:2384-2389. doi:10.1002/dta.3952. PMID:40936282. 20. Matsumoto K, et al. **Orally active opioid mu/delta dual agonist MGM-16, a derivative of the indole alkaloid mitragynine, exhibits potent antiallodynic effect on neuropathic pain in mice.** *Journal of Pharmacology and Experimental Therapeutics.* 2014;348:383-392. PMID:24345467. 21. Center for Forensic Science Research and Education (CFSRE), NPS Discovery. **MGM-15 analytical monograph / public alert.** 2025-2026. Use the specific monograph version cited by the website when discussing analytical artifacts. 22. Medicinal-chemistry studies of MGM-15/MGM-16 and fluorinated 7-OH analogues; see ref. 20 and later structure-activity work. 23. Contemporary 2025-2026 market/product analyses of semisynthetic 7-OH-related alkaloids and label-content discrepancies. 24. Bhowmik S, et al. and related medicinal-chemistry studies of hydroxylated/pseudoindoxyl analogues derived from Mitragyna scaffolds. 25. Flores-Bocanegra L, et al. **The Chemistry of Kratom [Mitragyna speciosa]: Updated Characterization Data and Methods to Elucidate Indole and Oxindole Alkaloids.** *Journal of Natural Products.* 2020. 26. Manwill PK, et al. Modern LC-MS/NMR characterization of kratom alkaloid chemotypes and minor constituents. 2022. 27. Chakraborty S, et al. **Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom.** *ACS Chemical Neuroscience.* 2021;12:2661-2678. doi:10.1021/acschemneuro.1c00149. PMID:34213886. 28. Dedicated **mitragynine immunoassays** have been developed, but they are not equivalent to routine hospital opiate screens and require assay-specific interpretation/cross-reactivity review. 29. Targeted urine methods for MG/7-OH include validated LC-MS/MS and later CZE-MS/MS approaches. A 2015 LC-MS/MS method demonstrated sub-ng/mL analytical sensitivity; analytical LOD is not the same as a clinical cutoff or detection window. 30. 2024 *Journal of Analytical Toxicology* LC-MS/MS hair method for mitragynine and 7-OH; hair establishes historical exposure, not acute timing. 31. Brown et al. 2026 *Journal of AOAC International* analysis of high-7-OH products showing alkaloid concentrations/profiles inconsistent with authentic botanical leaf. 32. 2026 quantitative commercial-product analyses documenting label disagreement, oxidation products, and semisynthetic chemical signatures. 33. **An in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynine.** Human liver S9 study reporting 9ODM formation as a major MG pathway and supporting CYP3A contribution. 2024. 34. Chakraborty S, et al. **Oxidative Metabolism as a Modulator of Kratom's Biological Actions.** *Journal of Medicinal Chemistry.* 2021;64:16553-16572. doi:10.1021/acs.jmedchem.1c01111. Establishes preclinical formation/activity of 7-OH, MP, and 3DM, including non-CYP 3DM formation. 35. Avula B, et al. **Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditions.** *Phytochemistry.* 2026. PMID: 41825819. Reports degradation of 7-OH to 3DM under simulated gastric conditions; treat this as product/GI chemistry until human in-vivo conversion is quantified. 36. Gour A, et al. **Mislabeling and Status of Semisynthetic Kratom-Derived Products in the US Market.** *Drug Testing and Analysis.* 2026. doi:10.1002/dta.70122. PMID:42448619. Reports frequent label-content disagreement and pharmacologically/toxicologically relevant compounds including 7-OH and 3DM. 37. Metabolic literature identifying **9-O-demethylmitragynine glucuronide (9-hydroxycorynantheidine glucuronide)** and reporting weak MOR affinity; clinical activity is unproven. See refs. 9, 13 and cited pharmacology therein. 38. California Society of Addiction Medicine. **2025 Addiction Medicine Board Exam Preparation Course.** Official CSAM Education Center faculty listing: Brian Harris, MD. 39. Reissig CJ, et al. **A Pilot, Dose-Finding, Pharmacodynamic and Pharmacokinetic Study of Orally Administered Botanical Kratom.** *J Clin Psychopharmacol.* 2026;46:386-398. doi:10.1097/JCP.0000000000002158. PMID:41837407. 40. Gour A, et al. *Drug Testing and Analysis* 2026 commercial-product study; see ref. 36. 41. Harris B. **Basic Sciences & Addiction - Addiction Medicine Board Review.** August 2025 archived presentation deck. Contains a board-style kratom pharmacology item discussing mitragynine as a partial mu-opioid agonist and kappa-opioid antagonist. Internal source archive; distinguish this from formal CSAM endorsement. --- ## 16. Web-publication note For the public-facing resource, prefer wording such as: > "In a controlled study, targeted testing remained informative through the study's 120-hour urine collection period. This should not be interpreted as a universal five-day detection window." rather than: > "7-OH stays in urine for five days." Likewise, prefer: > "Published botanical-kratom studies report 7-OH half-lives ranging from several hours to much longer terminal estimates after repeated high-dose exposure, but direct purified-7-OH human pharmacokinetics have not been adequately characterized." rather than assigning a single half-life to the commercial drug. The scientifically useful message is not that every number is known. It is that **we now know enough to identify the pharmacologically important pathway, and we know exactly where the evidence stops.**