Kratom

COPD, sleep apnea, respiratory insufficiency

Kratom produces respiratory depression through MOR agonism. While G-protein-biased signaling reduces this risk compared to classical opioids at typical leaf doses, the risk is not eliminated — particularly with concentrated 7-OH products. Patients with pre-existing respiratory compromise face compounded risk. Class-level opioid contraindication.

Psychotic symptoms have been documented during withdrawal from concentrated 7-hydroxymitragynine products (Sharma 2025). This contraindication is most relevant for enriched 7-OH products rather than botanical leaf at moderate doses. Patients with psychosis history should avoid kratom, particularly concentrated preparations.

Comprehensive review of 26+ case reports with RUCAM causality assessment concluded kratom 'likely causes liver injury' (Schimmel & Dart 2020). Median latency ~20.6 days. Cholestatic pattern predominates. Patients with pre-existing hepatic impairment face compounded risk.

Mitragynine has a very large volume of distribution (38.04 ± 24.32 L/kg), indicating extensive tissue binding. Renal impairment was present in a fatal kratom-polydrug case (Gershman 2023). Altered accumulation dynamics with impaired renal clearance are pharmacokinetically plausible, though direct evidence is limited to a single case report.

Kratom acts as a partial μ-opioid receptor agonist. Neonatal abstinence syndrome has been documented in case reports of maternal kratom use during pregnancy (Chomchai 2019). Teratogenicity is unknown. The opioid-like mechanism warrants avoidance during pregnancy and lactation.

Concurrent use of kratom with other opioids produces additive MOR agonism. Fatal polydrug outcomes documented: hydromorphone + kratom fatality (femoral blood 79 ng/mL hydromorphone, 560 ng/mL mitragynine); Krypton deaths involved kratom + O-desmethyltramadol (9 fatalities). Pharmacodynamic synergy is the primary mechanism.

cyclosporine, tacrolimus, fentanyl, midazolam, alprazolam

A single 2 g dose of kratom tea increased the CYP3A probe midazolam AUC by 1.39× in 12 healthy adults (Tanna 2023). PBPK modeling predicts greater effects at higher kratom doses (Chiang 2026). Drugs with narrow therapeutic indices metabolized by CYP3A4 — including immunosuppressants, some opioids, and some benzodiazepines — may reach supratherapeutic levels.

alcohol, benzodiazepines, GHB, GBL, barbiturates

Combining kratom with CNS depressants carries pharmacodynamically plausible risk of synergistic respiratory depression and excessive sedation. While published case-confirmed fatalities specifically from kratom + alcohol, GHB/GBL, or ketamine were not identified, the mechanism is well-established from opioid pharmacology. Class-level opioid contraindication applied with editorial flag for interaction severity verification.