7-Hydroxymitragynine

opioids, benzodiazepines, barbiturates, alcohol, z-drugs

Co-administration of 7-HMG with any CNS depressant produces additive or synergistic respiratory depression. Epidemiological data show 87% of kratom-associated fatalities involve polysubstance use (Corkery et al. 2019). The Florida case-control study found mean mitragynine blood concentrations in co-exposure fatalities were 179 µg/L versus 2,486 µg/L in single-drug fatalities, indicating lethal synergism at lower kratom alkaloid levels.

severe COPD, severe asthma, respiratory failure, sleep apnea

7-HMG depresses respiratory drive via mu-opioid receptor activation in brainstem respiratory nuclei. In awake rats (IV), respiratory depression potency is 4.5-fold greater than morphine (Zuarth Gonzalez et al. 2025). Patients with compromised baseline respiratory function face disproportionate risk from any opioid-mediated respiratory suppression.

head injury with raised ICP, intracranial hypertension

All mu-opioid receptor agonists are contraindicated with raised intracranial pressure because opioid-induced respiratory depression elevates arterial CO2, causing cerebral vasodilation and further ICP elevation. This is a standard opioid-class contraindication applied by structural and pharmacological analogy.

opioid use disorder, active substance use disorder

Animal self-administration studies demonstrate that 7-HMG (but not mitragynine) substitutes for morphine in a dose-dependent manner. Prior 7-HMG exposure increased subsequent morphine intake, suggesting reward pathway sensitization (Hemby et al. 2019). Multiple human case reports document DSM-5 opioid use disorder criteria met with semi-synthetic 7-HMG products, including rapid dose escalation from kratom to 7-HMG to mitragynine pseudoindoxyl.

severe hepatic impairment, decompensated liver disease

7-HMG depends on CYP3A-mediated hepatic clearance. Severe liver impairment would reduce elimination, risking accumulation and prolonged opioid effects. Additionally, kratom use has been associated with cholestatic liver injury histologically mimicking primary biliary cholangitis (Gandhi et al. 2020) and intrahepatic cholestasis (Kapp et al. 2011). Whether 7-HMG per se or other kratom alkaloids drive hepatotoxicity is unknown.

moderate hepatic impairment

7-HMG elimination depends on CYP3A-mediated hepatic clearance. Even moderate hepatic impairment may reduce clearance sufficiently to produce accumulation, particularly with repeated dosing where elimination half-life already extends from 4.7h to 24.7h in healthy subjects.

pregnancy, breastfeeding

No published studies on neonatal opioid withdrawal syndrome from gestational 7-HMG exposure have been identified. Risk is inferred by structural and pharmacological analogy to other MOR agonists, all of which produce neonatal withdrawal with chronic gestational exposure. 7-HMG crosses the blood-brain barrier and would be expected to cross the placenta.

itraconazole, ketoconazole, ritonavir, clarithromycin, grapefruit juice

The interaction is pharmacokinetically complex: CYP3A4 inhibition decreases 7-HMG formation from mitragynine (56% Cmax reduction with itraconazole in humans) while simultaneously decreasing 7-HMG clearance. For users of pre-formed semi-synthetic 7-HMG products, the formation pathway is irrelevant and CYP3A4 inhibition would primarily reduce clearance — increasing exposure. In rats, ketoconazole increased 7-HMG behavioral potency 9.7-fold (Kamble et al. 2023).

paralytic ileus, gastrointestinal obstruction

All mu-opioid receptor agonists are contraindicated in paralytic ileus due to further reduction of gastrointestinal motility. This is a class-level contraindication extrapolated from morphine and other MOR agonists. No 7-HMG-specific GI motility data exist.