generation run 2026-05-08
92 min completedmodel pipeline-v5plan not recordedrun/aeafc8d3…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- taper_unassessed
- sparse_evidence
- note_for_reviewer
Reproduce
- inputs
- 45 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
24 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | ClinicalTrials.gov | 7-hydroxymitragynine kratom mitragynine | 4 | 3 | Selected trials most relevant to 7-HMG PK and clinical pharmacology |
| 2 | PubMed | 7-hydroxymitragynine toxicity overdose death case report | 1 | 1 | Key safety/toxicology case report |
| 3 | PubMed | 7-hydroxymitragynine dependence withdrawal addiction abuse potential | 4 | 4 | Hemby 2019 critical for abuse/dependence data; dopamine study for reward mechanisms |
| 4 | OpenAlex | 7-hydroxymitragynine kratom opioid | 15 | 8 | Selected all highly cited papers with direct relevance to 7-HMG pharmacology, discovery, and safety |
| 5 | PubMed | 7-hydroxymitragynine pharmacology opioid receptor | 15 | 8 | Selected highly relevant primary studies and reviews on 7-HMG pharmacology and safety |
| 6 | PubMed | 7-hydroxymitragynine mu opioid binding potency morphine comparison | 1 | 1 | Critical primary source for binding affinity data |
| 7 | PubChem | 7-Hydroxymitragynine | 1 | 1 | Only result, confirms chemical identity |
| 8 | OpenAlex | 7-hydroxymitragynine synthesis discovery isolation Mitragyna speciosa | 8 | 4 | Biosynthesis, chemical composition, and G-protein bias confirmation papers |
| 9 | PubMed | mitragynine 7-hydroxymitragynine beta-arrestin biased agonism G protein | 1 | 1 | Key mechanistic paper establishing biased agonism of 7-HMG at MOR |
| 10 | PubMed | kratom withdrawal opioid use disorder treatment | 8 | 6 | Emerging clinical evidence for 7-HMG dependence, withdrawal management with buprenorphine |
| 11 | PubMed | 7-hydroxymitragynine human pharmacokinetics clinical study dose | 1 | 1 | Critical: only large human PK study with 7-HMG plasma concentration data |
| 12 | PubMed | kratom death fatality medical examiner postmortem | 4 | 4 | Safety-critical fatality data; postmortem concentrations inform toxicity thresholds |
| 13 | PubMed | kratom hepatotoxicity liver injury case report | 1 | 1 | Documents hepatotoxic potential relevant to safety profile |
| 14 | PubMed | kratom intracranial self-stimulation reward reinforcement | 1 | 1 | Reward/reinforcement data for abuse liability profile |
| 15 | PubMed | kratom 7-hydroxymitragynine NCT pharmacokinetics drug interaction results | 6 | 4 | Drug interaction data critical for safety/harm reduction section |
| 16 | WebSearch | 7-hydroxymitragynine legal status UK Australia Canada Thailand scheduled banned | 10 | 1 | International legal status information |
| 17 | WebSearch | 7-hydroxymitragynine legal status scheduled United States DEA 2024 2025 | 10 | 2 | Critical regulatory context for legal status section |
| 18 | FDA.gov | — | 1 | 1 | Primary regulatory source |
| 19 | WebSearch | Takayama 2002 7-hydroxymitragynine first isolation 1994 Ponglux CAS number discovery paper | 10 | 2 | Establishes discovery timeline and CAS number |
| 20 | Multiple API sources | Final citation compilation and research output writing | 60 | 1 | Final output compilation |
| 21 | DOI Verification | verify_doi 10.1021/acscentsci.9b00141 and 10.1248/cpb.52.916 | 2 | 2 | API verification of landmark papers |
| 22 | PubMed | 7-hydroxymitragynine semi-synthetic production mono-oxidation mitragynine manufacturing | 1 | 1 | Confirms semi-synthetic production route |
| 23 | WebSearch/WebFetch | 7-hydroxymitragynine first isolation 1994 Ponglux CAS 174418-82-7 discovery | 10 | 2 | Discovery history and CAS number |
| 24 | Wikipedia/Web | — | 1 | 1 | International legal status overview |
131 claims by section — every cited sentence, checked against its source
safety46 · 43 ok
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
pharmacology23 · 18 ok
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
summary16 · 15 ok
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
clinical-evidence7 · 7 ok
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
comparative-pharmacology7 · 7 ok
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
pharmacokinetic-detail7 · 6 ok
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
receptor-pharmacology7 · 5 ok
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
history6 · 6 ok
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
neuroscience6 · 6 ok
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
alkaloid-profile2 · 2 ok
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
botanical-overview2 · 2 ok
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
chemistry2 · 1 ok
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