7-Hydroxymitragynine

The large majority of kratom-associated fatalities involve polysubstance use.supported

111 mitragynine-associated deaths (all with co-exposures). bkag017

Acute toxicity: 7-HMG produces naloxone-reversible respiratory depression as its primary acute lethal mechanism, with 4.5-fold greater potency than morphine in awake Sprague-Dawley rats (IV route)supported

7-HMG induced respiratory depression 4.5-fold more potent than morphine (rats, IV). Naloxone fully reversed 7-HMG respiratory depression. j.jpet.2025.103720

{{Warning}}Respiratory depression from 7-HMG is fully reversed by naloxonesupported

Naloxone fully reversed 7-HMG respiratory depression. j.jpet.2025.103720

The first published fatality with 7-HMG blood concentrations documented mitragynine at 1.06 mg/L and 7-HMG at 0.15 mg/L, with co-ingestants zopiclone, citalopram, and lamotrigine presentsupported

Fatal case: blood mitragynine 1.06 mg/L, 7-HMG 0.15 mg/L with zopiclone, citalopram, lamotrigine co-ingestants. j.forsciint.2014.10.025

An epidemiological study of 156 kratom-associated deaths found 80% were male (mean age 32.3 years), with polysubstance use in 87% of cases; mitragynine was the sole intoxicant in 23%supported

156 kratom-associated deaths: 80% male, mean age 32.3y, mitragynine alone in 23%, polysubstance use 87%. 0269881119862530

Two confirmed single-drug mitragynine fatalities had postmortem blood concentrations of 2,325 and 3,809 ng/mLsupported

Two single-substance fatalities. Blood mitragynine 2325 and 3809 ng/mL. bkac016

The largest case-control study (Florida) identified 38 mitragynine-induced fatalities (mean blood concentration 2,486 µg/L) versus 111 associated deaths with co-exposures (mean 179 µg/L); autopsy findings in induced fatalities included pulmonary edema (55.6%), hepatomegaly (47.4%), and cardiomegaly (47.4%).partially supported

38 mitragynine-induced fatalities (mean blood 2486 ug/L) vs 111 mitragynine-associated deaths (all with co-exposures). Higher rates of pulmonary edema, hepatomegaly, cardiomegaly in induced fatalities. bkag017

Documented patterns include intrahepatic cholestasis and severe cholestatic injury histologically mimicking primary biliary cholangitissupported

Case report of intrahepatic cholestasis following powdered kratom use. s13181-011-0155-5

Documented patterns include intrahepatic cholestasis and severe cholestatic injury histologically mimicking primary biliary cholangitissupported

Severe cholestatic liver injury from kratom use histologically mimicking primary biliary cholangitis. wjh.v12.i10.863

Hepatotoxicity patterns have been reviewed in the broader context of natural product liver injurysupported

Reviews hepatotoxicity of kratom including acute liver injury patterns; mechanisms remain unclear. ijms17040580

Rhabdomyolysis: Severe rhabdomyolysis requiring fasciotomy has been reported following kratom overdose, though confounded by coingestants.supported

Severe rhabdomyolysis and pressure necrosis requiring fasciotomy after kratom overdose; confounded by coingestants. adm.0000000000000873

Compulsive redosing — documented with semi-synthetic 7-HMG productssupported

SUD from 7-OH sublingual film. adm.0000000000001603

Compulsive redosing — documented with semi-synthetic 7-HMG productssupported

Inpatient withdrawal management for daily 7-OH use. adm.0000000000001558

Opioid use disorder — multiple case reports document DSM-5 OUD criteria met with 7-HMG productssupported

7-HMG use disorder case; buprenorphine treatment described. adm.0000000000001685

Dose escalation — progressive escalation from kratom to 7-HMG to mitragynine pseudoindoxyl documented clinically, suggesting rapid tolerance and increasing reinforcementsupported

Escalation: kratom → 7-HMG tablets → mitragynine pseudoindoxyl (9×20mg/day). cureus.105224

Tolerance: Tolerance to antinociceptive effects develops with chronic 7-HMG administration in mice, following the same pattern as morphine tolerance. Bidirectional cross-tolerance with morphine is established: mice tolerant to 7-HMG show cross-tolerance to morphine and vice versasupported

Tolerance to 7-HMG antinociception develops like morphine. Bidirectional cross-tolerance with morphine demonstrated. pmid:16169018

Tolerance: Tolerance to antinociceptive effects develops with chronic 7-HMG administration in mice, following the same pattern as morphine tolerance. Bidirectional cross-tolerance with morphine is established: mice tolerant to 7-HMG show cross-tolerance to morphine and vice versasupported

Tolerance to 7-HMG antinociception develops like morphine. Bidirectional cross-tolerance with morphine demonstrated. pmid:16169018

Clinical case reports describe rapid dose escalation, including one case documenting progression from powdered kratom to 7-HMG tablets to mitragynine pseudoindoxyl at doses of 9 × 20 mg daily including nocturnal use.partially supported

Escalation: kratom → 7-HMG tablets → mitragynine pseudoindoxyl (9×20mg/day). cureus.105224

In mice, naloxone-precipitated withdrawal signs were qualitatively and quantitatively similar to morphine withdrawalsupported

Naloxone-induced withdrawal signs equal to morphine in chronically treated mice. pmid:16169018

Inpatient medically managed withdrawal with documented COWS scoressupported

Inpatient withdrawal management for daily 7-OH use; COWS scores and medication treatment response documented. adm.0000000000001558

Acute withdrawal after high-dose chronic cessationsupported

Acute opioid withdrawal after abrupt cessation of high-dose 7-OH in patient who transitioned from kratom. j.japh.2026.103047

Severe early-onset withdrawal (COWS score 31) following escalation to mitragynine pseudoindoxylsupported

COWS 31. Severe withdrawal with hypertension, tachycardia. cureus.105224

Abuse liability: 7-HMG (but not mitragynine) substituted for morphine self-administration in a dose-dependent manner, and reinforcing effects were mediated by mu (µ₁) and delta receptorssupported

7-HMG substituted for morphine self-administration and engendered IV self-administration in rats. Reinforcing effects mediated by mu and delta receptors. adb.12639

Claim in safety — inconclusiveinconclusiveworking →

Treatment: Published treatment approaches include buprenorphine and methadonesupported

7-HMG use disorder case; buprenorphine treatment described. adm.0000000000001685

Treatment: Published treatment approaches include buprenorphine and methadonesupported

Low-dose sublingual buprenorphine led to complete abstinence from kratom (containing 7-HMG) within 3 weeks. bcr-2025-265834

Treatment: Published treatment approaches include buprenorphine and methadonesupported

Methadone used for kratom use disorder (including 7-HMG component); meets DSM-5 OUD criteria. adm.0000000000001666

Symptom management during acute withdrawal has employed clonidine, hydroxyzine, gabapentin, and loperamide.supported

Managed with clonidine, hydroxyzine, gabapentin, loperamide. cureus.105224

Claim in safety — inconclusiveinconclusiveworking →

In the only published human interaction study, itraconazole decreased 7-HMG Cmax by 56% when derived metabolically from oral kratomsupported

Itraconazole decreased 7-OH exposure by 56% Cmax, 43% AUC. acsptsci.3c00335

Claim in safety — inconclusiveinconclusiveworking →

The large majority of kratom-associated fatalities involve polysubstance use.supported

polysubstance use 87%. 0269881119862530

Cannabidiol: Co-administration increases mitragynine systemic exposure 2.8-fold in rats with delayed Tmax, attributed to CYP3A/2C9 inhibition.supported

CBD co-administration caused 2.8-fold increase in mitragynine exposure; delayed Tmax and increased psychoactive alkaloid systemic exposure. pharmaceutics16030318

CYP3A substrates (midazolam, many benzodiazepines, statins, calcium channel blockers): mitragynine increases midazolam exposure 2.2–2.7-fold in PBPK modeling, acting as a CYP3A4 perpetrator.supported

Mitragynine increases midazolam exposure 2.2-2.7x. acsptsci.5c00718

CYP2D6 substrates: Kratom alkaloids inhibit CYP2D6, potentially increasing exposure to CYP2D6-metabolized drugs.supported

Kratom/alkaloids inhibit CYP2D6, CYP3A, and P-glycoprotein. Could increase systemic exposure to co-consumed drugs. dmd.122.001005

P-glycoprotein substrates: Kratom alkaloids inhibit P-gp, potentially increasing CNS penetration of P-gp substrate drugs.supported

Kratom/alkaloids inhibit CYP2D6, CYP3A, and P-glycoprotein. Could increase systemic exposure to co-consumed drugs. dmd.122.001005

Alpha-2 adrenergic agonists: Antinociceptive synergism with 7-HMG documented in rats; human significance is unknown.supported

May produce antinociceptive synergism with alpha-2 agonists. jpet.122.001192

Serotonergic drugs: Serotonergic receptor activity has been noted for kratom alkaloids, but no case reports of serotonin syndrome with 7-HMG have been published.supported

Reviews kratom clinical pharmacology including opioid, adrenergic, serotonin receptor activities. 17512433.2024.2305798

Concurrent CNS depressant use (opioids, benzodiazepines, barbiturates, alcohol, z-drugs) — additive respiratory depression with established fatality risksupported

polysubstance use 87%. 0269881119862530

Concurrent CNS depressant use (opioids, benzodiazepines, barbiturates, alcohol, z-drugs) — additive respiratory depression with established fatality risksupported

111 mitragynine-associated deaths (all with co-exposures). bkag017

Severe hepatic impairment — 7-HMG is a CYP3A substrate; impaired clearance may produce unpredictable accumulation. Hepatotoxicity has been reported with kratom usesupported

Case report of intrahepatic cholestasis following powdered kratom use. s13181-011-0155-5

Severe hepatic impairment — 7-HMG is a CYP3A substrate; impaired clearance may produce unpredictable accumulation. Hepatotoxicity has been reported with kratom usesupported

Severe cholestatic liver injury from kratom use histologically mimicking primary biliary cholangitis. wjh.v12.i10.863

Severe respiratory disease — baseline respiratory compromise increases vulnerability to opioid-mediated respiratory depressionsupported

7-HMG induced respiratory depression 4.5-fold more potent than morphine (rats, IV). j.jpet.2025.103720

CYP3A4 inhibitor use — altered pharmacokinetic exposure with unpredictable net effectsupported

Itraconazole decreased 7-OH exposure by 56% Cmax, 43% AUC. acsptsci.3c00335

CYP3A4 inhibitor use — altered pharmacokinetic exposure with unpredictable net effectsupported

CYP3A inhibition increased mitragynine exposure by 120% and 7-HMG exposure by 130%. jpet.122.001525

Active substance use disorder — 7-HMG maintains self-administration and increases subsequent morphine intake in animal modelspartially supported

7-HMG substituted for morphine self-administration and engendered IV self-administration in rats. adb.12639

7-Hydroxymitragynine is a partial agonist at the mu-opioid receptor (MOR) and a competitive antagonist at kappa-opioid (KOR) and delta-opioid (DOR) receptorssupported

7-HMG is partial agonist at MOR and competitive antagonist at KOR/DOR. jacs.6b00360

Claim in pharmacology — inconclusiveinconclusiveworking →

In radioligand displacement assays, 7-HMG displays moderate binding affinity (Ki = 709 nM at human MOR), paradoxically lower than mitragynine (Ki = 77.9 nM) in the same assay systemsupported

MOR binding: mitragynine Ki=77.9 nM, 7-HMG Ki=709 nM. jpet.120.000189

The critical distinction is functional efficacy: in [³⁵S]GTPγS assays, mitragynine behaves as an antagonist while 7-HMG activates G-protein signaling with partial efficacy (Emax = 41.3%)partially supported

7-HMG partial agonist Emax=41.3%. jpet.120.000189

Claim in pharmacology — inconclusiveinconclusiveworking →

7-HMG is a G-protein-biased agonist — it activates G-protein-coupled signaling pathways without producing measurable β-arrestin recruitmentsupported

G-protein biased - does not recruit beta-arrestin. jacs.6b00360

This signaling bias was confirmed across 53 commercial kratom product samplessupported

Profiled 53 commercial kratom products. 7-HMG is partial agonist at human MOR with functional selectivity for G-protein signaling, no measurable beta-arrestin recruitment. s41598-020-76119-w

However, this hypothesis remains unresolved: 7-HMG produces respiratory depression 4.5-fold more potent than morphine in awake rats (IV administration), fully reversible by naloxonesupported

7-HMG induced respiratory depression 4.5-fold more potent than morphine (rats, IV). Naloxone fully reversed 7-HMG respiratory depression. j.jpet.2025.103720

Whether G-protein bias translates to a clinically meaningful safety advantage in humans is unknown.supported

Comprehensive review of kratom medicinal chemistry and neuropharmacology; discusses biased agonism hypothesis and abuse potential of 7-HMG. j.neuropharm.2017.08.026

7-HMG shows high selectivity for MOR over other opioid receptor subtypes and demonstrates no significant binding at alpha-2 adrenergic receptors — unlike mitragynine, which possesses adrenergic activity.supported

7-HMG displays only MOR binding affinity (not alpha-2). jpet.122.001192

Claim in pharmacology — not_supportednot supportedworking →

Formation from mitragynine: Mitragynine undergoes CYP3A-mediated oxidation to 7-HMG in both mouse and human liver preparationssupported

Mitragynine is converted in vitro in mouse and human liver preparations to 7-HMG by CYP3A isoforms. acscentsci.9b00141

In healthy volunteers administered kratom tea (23.6 mg mitragynine), 7-HMG reached Cmax of 12.81 ± 3.39 ng/mL at Tmax 1.77 hours; 7-HMG area under the curve (AUC) was approximately 20% of mitragynine AUCpartially supported

7-OH Cmax 12.81 ng/mL at Tmax 1.77h. Metabolic ratio (7-OH/mitragynine AUC) = 13.25. acsptsci.3c00335

Co-administration of itraconazole (a potent CYP3A4 inhibitor) decreased 7-HMG Cmax by 56% and AUC by 43%, directly confirming CYP3A4-dependent formation in humans.supported

Itraconazole decreased 7-OH exposure by 56% Cmax, 43% AUC. acsptsci.3c00335

Claim in pharmacology — inconclusiveinconclusiveworking →

Claim in pharmacology — inconclusiveinconclusiveworking →

Conversion to mitragynine pseudoindoxyl: 7-HMG is unstable in human plasma, converting to mitragynine pseudoindoxyl — a compound with greater MOR potency and efficacy than either mitragynine or 7-HMGsupported

7-HMG is stable in rodent/monkey plasma but unstable in human plasma, converting to mitragynine pseudoindoxyl — an even more potent MOR agonist. acsptsci.0c00075

Preclinical studies with 7-HMG may therefore systematically underestimate pharmacological activity in humans.supported

This conversion occurs to much greater extent in humans than preclinical species. acsptsci.0c00075

CYP enzyme interactions: Both mitragynine and 7-HMG are CYP3A substratessupported

Both mitragynine and 7-HMG cleared via CYP3A. jpet.122.001525

CYP3A inhibition by ketoconazole (30 mg/kg oral in rats) increased mitragynine exposure by 120%, 7-HMG exposure by 130%, and amplified 7-HMG behavioral potency 9.7-foldpartially supported

CYP3A inhibition increased mitragynine exposure by 120% and 7-HMG exposure by 130%. jpet.122.001525

Kratom alkaloids also inhibit CYP2D6, CYP3A, and P-glycoprotein.supported

Kratom/alkaloids inhibit CYP2D6, CYP3A, and P-glycoprotein. dmd.122.001005

Kratom alkaloids also inhibit CYP2D6, CYP3A, and P-glycoprotein.partially supported

All three alkaloids inhibit CYP enzymes. s41598-020-76119-w

Route-of-administration effects: Semi-synthetic 7-HMG products formulated for sublingual or nasal delivery bypass hepatic first-pass metabolism, increasing bioavailability and accelerating onsetsupported

Semi-synthetic 7-OH via sublingual/nasal routes circumvents hepatic first-pass, increasing bioavailability and abuse risk. adm.0000000000001603

It demonstrates 13-fold greater antinociceptive potency than morphine in functional assays and occurs naturally as a trace constituent comprising less than 2% of total kratom alkaloid contentpartially supported

7-HMG 13x more potent than morphine in guinea pig ileum electrical stimulation assay. jm010576e

It demonstrates 13-fold greater antinociceptive potency than morphine in functional assays and occurs naturally as a trace constituent comprising less than 2% of total kratom alkaloid contentpartially supported

7-OH is a potent mu-opioid receptor agonist occurring at trace levels in leaf material but enriched in US market semi-synthetic products. 13880209.2025.2590311

Duration of opioid effects has not been characterized in controlled human studies; pharmacokinetic data indicate a single-dose elimination half-life of approximately 4.7 hours, extending to 24.7 hours at steady state.supported

T1/2 4.7h single, 24.7h multiple. molecules29050984

First isolated in 1994 from Thai kratom leaf material. 7-HMG was reframed in 2019 as the primary active metabolite mediating mitragynine's analgesic effects, formed via hepatic CYP3A-catalyzed oxidationpartially supported

Mitragynine is converted in vitro in mouse and human liver preparations to 7-HMG by CYP3A isoforms. Brain concentrations of 7-HMG explain opioid-receptor-mediated analgesic activity of mitragynine. acscentsci.9b00141

A further metabolic transformation — conversion to mitragynine pseudoindoxyl in human plasma — may account for higher-than-predicted opioid potency in humans relative to animal modelssupported

7-HMG is stable in rodent/monkey plasma but unstable in human plasma, converting to mitragynine pseudoindoxyl — an even more potent MOR agonist. This conversion occurs to much greater extent in humans than preclinical species. acsptsci.0c00075

Since 2023, concentrated semi-synthetic 7-HMG products have proliferated in the consumer market, prompting the FDA to recommend DEA scheduling in July 2025.partially supported

SUD from 7-OH sublingual film. Semi-synthetic 7-OH via sublingual/nasal routes circumvents hepatic first-pass, increasing bioavailability and abuse risk. adm.0000000000001603

Since 2023, concentrated semi-synthetic 7-HMG products have proliferated in the consumer market, prompting the FDA to recommend DEA scheduling in July 2025.partially supported

Online sale of semi-synthetic 7-OH and mitragynine pseudoindoxyl products characterized; both are highly selective MOR agonists not present/detectable in fresh kratom; public health risks. j.drugalcdep.2025.112701

7-HMG binds MOR with moderate affinity (Ki = 709 nM) but activates G-protein signaling with partial efficacy (Emax = 41.3% in [³⁵S]GTPγS assay) while producing no measurable β-arrestin recruitmentpartially supported

MOR binding: mitragynine Ki=77.9 nM, 7-HMG Ki=709 nM. 7-HMG partial agonist Emax=41.3%. jpet.120.000189

7-HMG binds MOR with moderate affinity (Ki = 709 nM) but activates G-protein signaling with partial efficacy (Emax = 41.3% in [³⁵S]GTPγS assay) while producing no measurable β-arrestin recruitmentpartially supported

G-protein biased - does not recruit beta-arrestin. jacs.6b00360

Claim in summary — inconclusiveinconclusiveworking →

This G-protein-biased signaling profile distinguishes 7-HMG from classical opioids, though the clinical significance of biased agonism for respiratory depression risk remains unresolved.supported

7-HMG induced respiratory depression 4.5-fold more potent than morphine (rats, IV). Naloxone fully reversed 7-HMG respiratory depression. j.jpet.2025.103720

7-HMG produces naloxone-reversible respiratory depression 4.5-fold more potent than morphine in rats (IV route)supported

7-HMG induced respiratory depression 4.5-fold more potent than morphine (rats, IV). Naloxone fully reversed 7-HMG respiratory depression. j.jpet.2025.103720

No human LD₅₀ has been established; most kratom-associated fatalities involve polysubstance exposuresupported

polysubstance use 87%. 0269881119862530

Tolerance develops with chronic administration, cross-tolerance with morphine is bidirectional, and naloxone-precipitable withdrawal occurs in animal modelssupported

Tolerance to 7-HMG antinociception develops like morphine. Bidirectional cross-tolerance with morphine demonstrated. Naloxone-induced withdrawal signs equal to morphine in chronically treated mice. pmid:16169018

Multiple case reports now document opioid use disorder meeting DSM-5 criteria from semi-synthetic 7-HMG productssupported

SUD from 7-OH sublingual film. adm.0000000000001603

Multiple case reports now document opioid use disorder meeting DSM-5 criteria from semi-synthetic 7-HMG productssupported

7-HMG use disorder case; buprenorphine treatment described. adm.0000000000001685

The primary sources of controlled human data are the Huestis et al. dose-escalation study (500–4,000 mg dried kratom leaf) and the Mongar et al. drug interaction study (kratom tea with and without itraconazole)supported

Largest human RCT (500-4000mg kratom powder). molecules29050984

The primary sources of controlled human data are the Huestis et al. dose-escalation study (500–4,000 mg dried kratom leaf) and the Mongar et al. drug interaction study (kratom tea with and without itraconazole)supported

First human evidence of CYP3A4-mediated conversion of mitragynine to 7-OH. Itraconazole decreased 7-OH exposure by 56% Cmax, 43% AUC. acsptsci.3c00335

Inpatient medically managed withdrawal with documented COWS scoressupported

Inpatient withdrawal management for daily 7-OH use; COWS scores and medication treatment response documented. adm.0000000000001558

Acute withdrawal after high-dose chronic 7-HMG cessationsupported

Acute opioid withdrawal after abrupt cessation of high-dose 7-OH in patient who transitioned from kratom. j.japh.2026.103047

Progressive escalation from kratom to 7-HMG to mitragynine pseudoindoxyl with severe withdrawal (COWS score 31)supported

Escalation: kratom → 7-HMG tablets → mitragynine pseudoindoxyl (9×20mg/day). COWS 31. cureus.105224

Kratom dependence treated with buprenorphine in context of comorbid OCDsupported

Low-dose sublingual buprenorphine led to complete abstinence from kratom (containing 7-HMG) within 3 weeks. bcr-2025-265834

A participant in this study's infrastructure was documented using concurrent semi-synthetic 7-HMG products alongside kratom.supported

7-OH is a highly selective mu opioid receptor agonist with binding affinity greater than morphine. Semi-synthetic products made by mono-oxidation of mitragynine. adm.0000000000001604

Clinical case reports document progressive escalation from kratom to 7-HMG tablets to mitragynine pseudoindoxyl at doses of 9 × 20 mg daily, with increasingly severe withdrawal upon cessation (COWS score 31).supported

Escalation: kratom → 7-HMG tablets → mitragynine pseudoindoxyl (9×20mg/day). COWS 31. cureus.105224

Mitragynine pseudoindoxyl, formed from 7-HMG in human plasma, is more potent and efficacious at MOR than 7-HMG itselfsupported

7-HMG... converting to mitragynine pseudoindoxyl — an even more potent MOR agonist. acsptsci.0c00075

Data from Obeng et al., Takayama et al., Zuarth Gonzalez et al., Kruegel et al., and Matsumoto et al..supported

MOR binding: mitragynine Ki=77.9 nM, 7-HMG Ki=709 nM. 7-HMG partial agonist Emax=41.3%. jpet.120.000189

Data from Obeng et al., Takayama et al., Zuarth Gonzalez et al., Kruegel et al., and Matsumoto et al..supported

7-HMG induced respiratory depression 4.5-fold more potent than morphine (rats, IV). j.jpet.2025.103720

Data from Obeng et al., Takayama et al., Zuarth Gonzalez et al., Kruegel et al., and Matsumoto et al..supported

Tolerance to 7-HMG antinociception develops like morphine. Bidirectional cross-tolerance with morphine demonstrated. pmid:16169018

Data from Obeng et al., Zuarth Gonzalez et al., Hemby et al., and Kruegel et al..supported

MOR binding: mitragynine Ki=77.9 nM, 7-HMG Ki=709 nM. 7-HMG partial agonist Emax=41.3%. jpet.120.000189

Data from Obeng et al., Zuarth Gonzalez et al., Hemby et al., and Kruegel et al..supported

7-HMG substituted for morphine self-administration and engendered IV self-administration in rats. Reinforcing effects mediated by mu and delta receptors. adb.12639

The most comprehensive human pharmacokinetic dataset comes from a randomized, between-subject, double-blind, placebo-controlled dose-escalation study of oral encapsulated dried kratom leaf powder (500–4,000 mg, corresponding to 6.65–53.2 mg mitragynine).supported

Largest human RCT (500-4000mg kratom powder). molecules29050984

In a separate healthy-volunteer study using kratom tea (23.6 mg mitragynine), mitragynine Cmax was 159.12 ± 8.68 ng/mL at Tmax 0.84 h, while 7-HMG Cmax was 12.81 ± 3.39 ng/mL at Tmax 1.77 hpartially supported

7-OH Cmax 12.81 ng/mL at Tmax 1.77h. acsptsci.3c00335

In rats, ketoconazole (30 mg/kg oral) increased mitragynine exposure by 120% and 7-HMG exposure by 130%, while amplifying 7-HMG behavioral potency 9.7-foldpartially supported

CYP3A inhibition increased mitragynine exposure by 120% and 7-HMG exposure by 130%. jpet.122.001525

In mice, oral 7-HMG (5–10 mg/kg) produced potent antinociception while oral morphine at 20 mg/kg was only weakly active, suggesting superior oral bioavailability relative to morphine in rodentssupported

Oral 7-HMG (5-10 mg/kg) showed potent antinociception vs only weak oral morphine effect at 20 mg/kg. pmid:14969718

Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

CYP3A: Substrate and inhibitor. Mitragynine increases midazolam exposure 2.2–2.7-fold in physiologically based pharmacokinetic (PBPK) modeling.supported

PBPK model for mitragynine/7-HMG clinical translation. Mitragynine increases midazolam exposure 2.2-2.7x. acsptsci.5c00718

Cannabidiol interaction: Co-administration of CBD increases mitragynine exposure 2.8-fold in rats, with delayed Tmax, attributed to CYP3A/2C9 inhibition.supported

CBD co-administration caused 2.8-fold increase in mitragynine exposure; delayed Tmax. pharmaceutics16030318

In mice, subcutaneous 7-HMG (2.5–10 mg/kg) produced dose-dependent antinociception exceeding morphine in both tail-flick and hot-plate testssupported

7-HMG (2.5-10 mg/kg s.c.) dose-dependently produced antinociception in tail-flick and hot-plate tests; more potent than morphine. pmid:14969718

Oral 7-HMG (5–10 mg/kg) was potently antinociceptive while oral morphine at 20 mg/kg was only weakly active, establishing superior oral bioavailability in this species.supported

Oral 7-HMG (5-10 mg/kg) showed potent antinociception vs only weak oral morphine effect at 20 mg/kg. pmid:14969718

Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

The apparent paradox in 7-HMG's pharmacology — moderate binding affinity (Ki = 709 nM) yet high functional potency (13–17× morphine) — reflects the fundamental difference between equilibrium binding and in vivo efficacy. 7-HMG fully substituted for morphine in rat drug discrimination (99.7% morphine-lever responding) and produced complete antinociception, both reversed by naltrexonepartially supported

7-HMG potency 17x morphine at mu-opioid receptor. j.forsciint.2014.10.025

7-HMG activates MOR-coupled G-protein signaling without measurable β-arrestin-2 recruitmentsupported

G-protein biased - does not recruit beta-arrestin. jacs.6b00360

Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

All respiratory depression was fully reversed by naloxone, confirming mu-opioid receptor mediation. This respiratory depression potency ratio (IV, rat) has not been confirmed in humans.supported

Naloxone fully reversed 7-HMG respiratory depression. j.jpet.2025.103720

In 2004, Matsumoto and colleagues published the definitive in vivo antinociceptive characterization in mice, demonstrating that oral 7-HMG (5–10 mg/kg) produced robust analgesia while oral morphine at 20 mg/kg was only weakly active, establishing superior oral bioavailabilitysupported

Oral 7-HMG (5-10 mg/kg) showed potent antinociception vs only weak oral morphine effect at 20 mg/kg. pmid:14969718

By 2005, Matsumoto and colleagues had demonstrated that chronic 7-HMG administration produces tolerance, bidirectional cross-tolerance with morphine, and naloxone-precipitable withdrawal in mice — confirming a classical opioid dependence profile.supported

Tolerance to 7-HMG antinociception develops like morphine. Bidirectional cross-tolerance with morphine demonstrated. Naloxone-induced withdrawal signs equal to morphine in chronically treated mice. pmid:16169018

The compound attracted pharmacological attention in 2002 when Takayama and colleagues demonstrated that 7-HMG was 13-fold more potent than morphine in guinea pig ileum electrical stimulation assays — identifying it as structurally distinct from classical opioid ligands yet functionally comparable in analgesic potency.supported

7-HMG 13x more potent than morphine in guinea pig ileum electrical stimulation assay. Discovery of structurally unique opioid agonists based on mitragynine scaffold. jm010576e

Drug Enforcement Administration's listing of kratom as a "Drug and Chemical of Concern".supported

notes growing US/Europe availability and DEA Drugs of Concern listing. pmid:23212430

In 2019, Kruegel and colleagues published the finding that reshaped the field: mitragynine is converted to 7-HMG via CYP3A isoforms in both mouse and human liver preparations, and brain concentrations of 7-HMG in mice after oral mitragynine administration are sufficient to account for most or all opioid-mediated analgesic activitysupported

Mitragynine is converted in vitro in mouse and human liver preparations to 7-HMG by CYP3A isoforms. Brain concentrations of 7-HMG explain opioid-receptor-mediated analgesic activity of mitragynine. acscentsci.9b00141

Between 2023 and 2025, concentrated semi-synthetic 7-HMG products proliferated in gas stations, smoke shops, and online retailers, marketed as dietary supplementspartially supported

Online sale of semi-synthetic 7-OH and mitragynine pseudoindoxyl products characterized. j.drugalcdep.2025.112701

In mice, subcutaneous 7-HMG (2.5–10 mg/kg) produced dose-dependent antinociception in both tail-flick (spinal reflex) and hot-plate (supraspinal) tests, indicating engagement of both spinal and supraspinal analgesic circuits.supported

7-HMG (2.5-10 mg/kg s.c.) dose-dependently produced antinociception in tail-flick and hot-plate tests. pmid:14969718

Reward circuitry: 7-HMG at low doses increased dopamine release in the nucleus accumbens while high doses decreased it, as measured by fixed-potential amperometry in micesupported

7-HMG low dose increased dopamine release, high dose decreased dopamine release in nucleus accumbens. j.neulet.2025.138153

Respiratory control: 7-HMG depresses respiratory drive with 4.5-fold greater potency than morphine, acting on brainstem respiratory nuclei including the pre-Bötzinger complexpartially supported

7-HMG induced respiratory depression 4.5-fold more potent than morphine (rats, IV). j.jpet.2025.103720

Reinforcement mechanisms: Self-administration of 7-HMG is mediated by both mu (µ₁) and delta opioid receptors, as demonstrated by reduction in self-administration following administration of naloxonazine (mu₁-selective antagonist) and naltrindole (delta-selective antagonist).supported

Reinforcing effects mediated by mu and delta receptors. adb.12639

Animal data challenge this prediction for respiratory depression (4.5× morphine potency) but may still be relevant to tolerance kinetics and gastrointestinal effectssupported

7-HMG induced respiratory depression 4.5-fold more potent than morphine (rats, IV). j.jpet.2025.103720

Active metabolite paradigm: The discovery that mitragynine's analgesic effects are mediated by its metabolite 7-HMG, which itself converts to the more potent mitragynine pseudoindoxyl in human plasma, establishes a multi-step prodrug activation chain that complicates pharmacodynamic modeling and species translation of preclinical data.supported

7-HMG is stable in rodent/monkey plasma but unstable in human plasma, converting to mitragynine pseudoindoxyl — an even more potent MOR agonist. This conversion occurs to much greater extent in humans than preclinical species. acsptsci.0c00075

Step 1 — Mitragynine: The dominant kratom alkaloid (40–66% of total alkaloid content), absorbed from the gastrointestinal tract after oral kratom ingestion. Mitragynine itself behaves as an antagonist at MOR in [³⁵S]GTPγS assays despite having higher binding affinity (Ki = 77.9 nM) than 7-HMG.partially supported

MOR binding: mitragynine Ki=77.9 nM, 7-HMG Ki=709 nM. jpet.120.000189

Step 3 — Mitragynine pseudoindoxyl: Formed from 7-HMG by non-enzymatic conversion in human plasma. More potent and efficacious at MOR than either parent compound.supported

7-HMG is stable in rodent/monkey plasma but unstable in human plasma, converting to mitragynine pseudoindoxyl — an even more potent MOR agonist. acsptsci.0c00075

Known colloquially as kratom, the tree has been used in traditional medicine for centuries, primarily as a stimulant at low doses and an analgesic at higher doses.supported

Reviews kratom pharmacology including mitragynine and 7-HMG; notes growing US/Europe availability and DEA Drugs of Concern listing. pmid:23212430

Contemporary market products labeled as "7-OH" or "7-hydroxymitragynine" are predominantly manufactured by mono-oxidation of mitragynine extracted from kratom leaf — a semi-synthetic process distinct from traditional plant preparationsupported

Semi-synthetic products made by mono-oxidation of mitragynine. Formulations include sublingual tablets, powders, liquid shots. adm.0000000000001604

Claim in chemistry — inconclusiveinconclusiveworking →

7-HMG occurs in trace quantities in Mitragyna speciosa leaves, typically comprising less than 2% of total alkaloid content in conventional kratom preparationssupported

7-OH is a potent mu-opioid receptor agonist occurring at trace levels in leaf material. 13880209.2025.2590311