Fatal combination of mitragynine and quetiapine – a case report with discussion of a potential herb-drug interaction

Hughes, Rhome L.

doi:10.1007/s12024-018-0049-9

Cited by 53 publications

(57 citation statements)

References 16 publications

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“…Widespread kratom use for self-treating opioid withdrawal symptoms and pain has raised concerns among US federal regulators, including the DEA and the FDA, regarding the safety of kratom, especially when combined with other drugs (U.S. Food & Drug Administration, 2018). The deaths associated with kratom have been hypothesized to be due to potential kratom-drug interactions (Hughes, 2019;Veltri and Grundmann, 2019). Kratom extracts and several isolated alkaloids have been reported to inhibit CYP activity in vitro, but these observations were deemed clinically irrelevant unless very high kratom doses are consumed with CYP2D6 substrates (Hanapi et al, 2010;Kong et al, 2011;Kamble et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Regardless of the mechanism, TDI of CYP3A in the liver and/or intestine could explain the attainment of toxic concentrations of the CYP3A substrate quetiapine described in a case report of a kratom-related death in which quetiapine overdose was not suspected (Hughes, 2019). The AUCR for quetiapine, which undergoes extensive first-pass metabolism in the liver, was predicted to be ~2.5-fold when taken with 2-g dose of kratom (Table 3), supporting the hypothesis that the kratom-related death could be due to TDI of CYP3A.…”

Section: Discussionmentioning

confidence: 99%

“…Using an in vitro to in vivo extrapolation (IVIVE) approach, mitragynine was predicted to precipitate clinical pharmacokinetic interactions with drugs cleared only by CYP2D6 (AUC ratio, 1.2-12) (Kamble et al, 2020). However, this observation does not explain the toxic concentrations of the antipsychotic and CYP3A substrate quetiapine detected in the postmortem blood evaluation of a young man who tested positive for mitragynine and who was believed not to have ingested excessive quantities of quetiapine based on pill count (Hughes, 2019). Because quetiapine undergoes extensive first-pass metabolism in at least the liver (Gjestad et al, 2017), these toxic concentrations could have involved time-dependent inhibition (TDI) of CYP3A.…”

Section: Introductionmentioning

confidence: 99%

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Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations

Tanna

Tian

Cech

et al. 2020

J Pharmacol Exp Ther

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Abbreviations: AUC, area under the plasma concentration-time curve; AUCR, ratio of AUC in presence to absence of inhibitor; CYP, cytochrome P450; DEA, Drug Enforcement Administration; f u,p , fraction unbound in human plasma; HIMs, human intestinal microsomes; HLMs, human liver microsomes; IVIVE, in vitro to in vivo extrapolation; k inact , maximum rate of inactivation; K I , time-dependent inhibition constant; K i , reversible inhibition constant; TDI, timedependent inhibition; UPLC-MS/MS, ultra-high performance liquid chromatography-tandem mass spectrometry This article has not been copyedited and formatted. The final version may differ from this version.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations

Tanna

Tian

Cech

et al. 2020

J Pharmacol Exp Ther

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“…Overall, there were 41 cases on kratom-associated adverse events or toxicities (Table 1). Kratom-associated adverse events were as follows: kratom-associated withdrawal symptoms (KAWS) in adults [41][42][43][44][45][46][47][48][49][50][51][52], kratom-associated neonatal abstinence syndrome (KANAS) [48,[52][53][54][55][56], hypothyroidism [43], hypogonadism [57], kratom-induced hepatoxicity (KIH) [58][59][60][61][62][63][64][65], CNS effects causing seizure and coma or posterior reversible encephalopathy syndrome (PRES) [39,66,67], acute respiratory distress syndrome (ARDS) [68,69], overdose toxidrome [70,71], and fatalities [72][73][74][75][76][77][78][79][80]. There were six case series of aggregated patient's data [48,…”

Section: Literature Case Reviewmentioning

confidence: 99%

“…Toxidromes and Fatalities [70][71][72][73][74][75][76][77][78][79][80] Kratom toxicity is presumed to resemble an opioid toxidrome: manifested by mydriasis, depressed respiratory function, altered mental status, hypotension, and hypothermia. Two recent case reports showed the role of naloxone reversal on the kratom toxidrome, although it was administered due to suspected co-intoxication with an opioid [70,71].…”

Section: Interventionmentioning

confidence: 99%

Kratom from Head to Toe—Case Reviews of Adverse Events and Toxicities

Alsarraf

Myers

Culbreth

et al. 2019

Curr Emerg Hosp Med Rep

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Purpose of Review This review describes case reports for patients with kratom-associated adverse events in order to assist clinicians with patient management. A stepwise approach is proposed for assessing active kratom users as well as considerations for the management of toxicities or withdrawal. Recent Findings Multiple in vitro and in vivo studies illustrate the pharmacologic and toxicologic effects of kratom extract. No randomized controlled trials in humans exist that assess the safety and efficacy of the substance. Cross-sectional surveys from active users and reports from poison control centers have shown acute and chronic physiological and psychological adverse events. Summary Reports of adverse effects associated with kratom use have demonstrated hypothyroidism, hypogonadism, hepatitis, acute respiratory distress syndrome, posterior reversible encephalopathy syndrome, seizure, and coma. Overdose toxidrome leads to respiratory failure, cardiac arrest, and fatalities. Adult and neonatal withdrawal symptoms have also occurred. Clinicians should be aware of the risks and benefits of kratom use.

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Clinical Pharmacology of the Dietary Supplement Kratom (Mitragyna speciosa)

Hartley

Bulloch

Penzak

2022

The Journal of Clinical Pharma

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Kratom (Mitragyna speciosa) consists of over 40 alkaloids, with 2 of them, mitragynine and 7-OH-mitragynine (7-OH-MG) being the main psychoactive compounds. Mitragynine and 7-OH-mitragynine each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the mu, delta, and kappa opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a "legal high," and numerous central nervous system disorders, including anxiety, depression, and posttraumatic stress disorder. Kratom induces analgesia and mild euphoria, with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence, with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects, including liver toxicity, seizures, and death. These risks are often compounded by polysubstance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P-glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes. In 2016, the US Drug Enforcement Administration took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other central nervous system conditions, kratom will likely remain available as a dietary supplement for the foreseeable future.

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Fatal combination of mitragynine and quetiapine – a case report with discussion of a potential herb-drug interaction

Cited by 53 publications

References 16 publications

Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations

Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations

Kratom from Head to Toe—Case Reviews of Adverse Events and Toxicities

Clinical Pharmacology of the Dietary Supplement Kratom (Mitragyna speciosa)

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