The patient is currently taking mitragynine
Interaction found with [quetiapine 50 mg oral tablet]
| CrCl Function (ml/Min) | ||||
| Kidney failure | Severely decreased | Moderately to severely decreased | Mildly to moderately decreased | Normal to high |
Monitor patient for QT prolongation and CNS depression. Consider discontituation of kratom or quetiapine if patient begins to experience adverse effects as a result of the interaction.
Quetiapine is a substrate of CYP3A4. Concomitant use with kratom in addition to other risk factors (e.g. hepatic impairment, myocardial infarction, heart failure) can lead to potential adverse events such as prolonged QTc prolongation. Concomitant use can also lead to additive CNS effects. The risk of a serious adverse event may be reduced by minimizing additional risk (e.g. QT prolonging agents, loop diuretics) or discontinuing the offending natural product.
Quetiapine is primarily eliminated through hepatic metabolism and more specifically by cytochrome P450 (CYP) 3A4.14 As a result, concomitant use of CYP3A4 inhibitors can lead to an increase in quetiapine concentrations that may require a dose reduction. In the context of its interaction with kratom, the natural product has the potential to inhibit the metabolism of CYP3A4. This interaction can lead to a significant adverse effect such as QTc prolongation due to increased quetiapine concentration.1,2,34,11,12 Hence, it is important to understand the supporting evidence for kratom NPDIs presented from metabolic studies and case reports in the literature.
A study published in 2020 investigated the effects of mitragynine on three major cytochrome P450s, specifically CYP2C9, CYP2D6, and CYP3A4. Mitragynine exhibited concentration-dependent inhibition of all three enzymes, with the most pronounced effect observed for CYP2D6.413 A 2021 study showed similar results, as mitragynine and three kratom extracts displayed concentration-dependent inhibition of CYP2C9, CYP2D6, and CYP3A in human liver microsomes (HLMs). At the minimum tested concentration (2 μg/mL), the kratom extracts inhibited CYP2D6, CYP2C9, and CYP3A by 44% to 64%, 24% to 29%, and 15% to 23%, respectively. Mitragynine at its lowest tested concentration (1 μM) inhibited the same three enzymes (CYP2D6, CYP2C9, and CYP3A) by 57%, 21%, and 26%, respectively. In addition to testing concentration inhibition in HLMs, the three kratom extracts along with mitragynine were also evaluated for their inhibition potential in human intestinal microsomes (HIMs). The study found the kratom extracts at their lowest tested concentrations inhibited CYP3A by 24-25% and 9%, respectively. Lastly, the study found two interesting results from IC50 shifts experiments they conducted. The first is that mitragynine was found to be a strong competitive inhibitor of CYP2D6; the second was that mitragynine showed time dependent inhibition of CYP3A activity. Hanapi et al. reported similar trends showing that mitragynine inhibited CYP2D6, CYP2C9, and CYP3A4, with IC50 values of 0.45±0.33 mM, 9.70±4.80 μM and 41.32±6.74 μM, respectively.514
There are two case reports that have been identified displaying the potential for kratom to inhibit CYP metabolism.6,715,16 The first case report details a 36-year-old Caucasian man who presented to the emergency department for dizziness. At the time, he only reported taking venlafaxine 150 mg daily and quetiapine 300 mg nightly; however, it was later discovered he had taken kratom as a way to treat his substance use disorder. At the time of the visit, evaluation was notable for high blood pressure (144/92 mm Hg), tachycardia (116 bpm), and elevated temperature (99.5 °F) and an electrocardiogram showing sinus tachycardia and a prolonged QTc (563 msec). The patient was advised to discontinue venlafaxine and quetiapine due to concern for serotonin syndrome and prolonged QTc.810 Proposed mechanisms as stated by the case report include inhibition of CYP2D6 and CYP3A causing supratherapeutic concentrations of venlafaxine and quetiapine since these drugs are substrates of CYP2D6 and CYP3A respectively in addition to potential pharmacodynamic interactions caused by kratom’s physiological effects.1,64,15 Additionally, a normal QTc interval is less than 450 ms for men and less than 460 ms for women indicating a prolonged QTc interval for this patient.92
Another case report involved a 27-year-old male, previously diagnosed with Asperger Syndrome, bipolar disorder, and a history of substance abuse, was found deceased in his residence. The decedent had multiple prescription medications in his residence at the time of death, and a postmortem forensic toxicology report indicated valproic acid was quantitatively positive at 8.8 mcg/mL, quetiapine was quantitatively positive at 12000 ng/mL, and mitragynine was qualitatively positive. The cause of death for the decedent was ruled as acute toxic effects of quetiapine complicated by mitragynine use, and the death was classified as an accident. This conclusion is consistent with the reference ranges for both quetiapine and valproic acid, which are 100 to 500 ng/mL and approximately 50 to 100 mcg/mL, respectively. Similar to the previous case report, a proposed mechanism was that quetiapine metabolism by CYP3A was inhibited by mitragynine.2,7,1011,16,17 The potential risk associated with QT prolongation involving quetiapine and kratom becomes more nuanced when considering the interaction with risk factors for QT prolongation. Tisdale et al. developed a risk score for determining the risk a patient has for developing QT prolongation. Some of the risk factors considered include sex and age of patient, presence of comorbidities such as MI or left ventricular dysfunction, and use of 2 or more QT prolonging agents.1118 The risk of using two or more QT prolonging agents becomes a interesting discussion point as recent studies have suggested that using more than one QT prolonging agent does cause a cumulative effect as one would expect. A recent 2022 study delving into the impact of hydroxychloroquine on the QTc interval, both in isolation and in combination with other QT-prolonging agents showed that the addition of a QT prolonging agent did not exert a significant influence on the patient’s QTc interval. Multiple studies have found similar results; however, further comprehensive studies are necessary to either substantiate or challenge this finding.1219 Based on the above case studies and in vitro studies, kratom/mitragynine should be used with caution for patients taking quetiapine.
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