Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom

Tanna, Rakshit S.; Nguyen, James; Hadi, Deena L.; Layton, Matthew E.; White, John R.; Cech, Nadja B.; Oberlies, Nicholas H.; Rettie, Allan E.; Thummel, Kenneth E.; Paine, Mary F.

doi:10.1002/cpt.2891

Cited by 14 publications

(10 citation statements)

References 38 publications

(111 reference statements)

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“…Sex differences have been reported in the pharmacokinetics of cannabidiol [ 45 , 46 ]. In addition, limited clinical data in humans indicated three female participants withdrew from study due to nausea and/or vomiting, which may indicate that females are more sensitive to kratom than males [ 8 , 10 ]. Future studies must investigate female pharmacokinetics to reveal any sex differences.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the multitude of receptor subtypes purported to be activated by kratom alkaloids and cannabidiol, both kratom and cannabidiol have also been implicated as having potential for pharmacokinetic interactions both in vitro and in vivo [ 6 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Both cannabidiol and mitragynine are potential inhibitors of cytochrome P450 (CYP) 2D6, and kratom was found to increase the exposure of midazolam (CYP3A substrate) when taken concomitantly with a 2 g dose of leaf kratom tea in humans [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Some of the central nervous system (CNS) receptor subtypes that are known targets of kratom alkaloids include µ-, δ-, and κ-opioid receptors, adrenergic receptors alpha1A and alpha2A, serotonergic receptors 5-HT1A and 5-HT2A, and dopamine D1 and D2 receptors [6]. In addition to the multitude of receptor subtypes purported to be activated by kratom alkaloids and cannabidiol, both kratom and cannabidiol have also been implicated as having potential for pharmacokinetic interactions both in vitro and in vivo [6,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Both cannabidiol and mitragynine are potential inhibitors of cytochrome P450 (CYP) 2D6, and kratom was found to increase the exposure of midazolam (CYP3A substrate) when taken concomitantly with a 2 g dose of leaf kratom tea in humans [10].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic Interaction of Kratom and Cannabidiol in Male Rats

Berthold,

Kamble,

Kanumuri

et al. 2024

Pharmaceutics

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Kratom and cannabidiol products are used to self-treat a variety of conditions, including anxiety and pain, and to elevate mood. Research into the individual pharmacokinetic properties of commercially available kratom and cannabidiol products has been performed, but there are no studies on coadministration of these products. Surveys of individuals with kratom use history indicate that cannabidiol use is one of the strongest predictors of both lifetime and past month kratom use. The purpose of this study was to determine if there are changes in pharmacokinetic properties when commercially available kratom and cannabidiol products are administered concomitantly. It was found that with concomitant administration of cannabidiol, there was a 2.8-fold increase in the exposure of the most abundant kratom alkaloid, mitragynine, and increases in the exposure of other minor alkaloids. The results of this work suggest that with cannabidiol coadministration, the effects of kratom may be both delayed and increased due to a delay in time to reach maximum plasma concentration and higher systemic exposure of the psychoactive alkaloids found in kratom.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic Interaction of Kratom and Cannabidiol in Male Rats

Berthold,

Kamble,

Kanumuri

et al. 2024

Pharmaceutics

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“…Practically, TDI of CYP3A by goldenseal would have long-lasting effects, akin to grapefruit juice, even after a single dose. Thus, patients taking medications that are extensively metabolized by intestinal CYP3A (e.g., some statins, immunosuppressants, and calcium channel blockers) ( Tanna et al, 2023 ) should be cautioned about consuming goldenseal. The integrated approach used in this study can be applied to other pharmacokinetic natural product-drug interactions to elucidate complex interactions between multiple phytoconstituents and varying mechanisms of enzyme inhibition.…”

Section: Discussionmentioning

confidence: 99%

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations

Nguyen

Tian

Tanna

et al. 2023

J Pharmacol Exp Ther

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The natural product goldenseal is a clinical inhibitor of CYP3A activity, as evidenced by a 40%–60% increase in midazolam area under the plasma concentration versus time curve (AUC) after coadministration with goldenseal. The predominant goldenseal alkaloids berberine and (−)- β -hydrastine were previously identified as time-dependent CYP3A inhibitors using human liver microsomes. Whether these alkaloids contribute to the clinical interaction, as well as the primary anatomic site (hepatic vs. intestinal) and mode of CYP3A inhibition (reversible vs. time-dependent), remain uncharacterized. The objective of this study was to mechanistically assess the pharmacokinetic goldenseal-midazolam interaction using an integrated in vitro–in vivo–in silico approach. Using human intestinal microsomes, (−)- β -hydrastine was a more potent time-dependent inhibitor of midazolam 1’-hydroxylation than berberine (K I and k inact : 8.48 μ M and 0.041 minutes −1 , respectively, vs. >250 μ M and ∼0.06 minutes −1 , respectively). Both the AUC and C max of midazolam increased by 40%–60% after acute (single 3-g dose) and chronic (1 g thrice daily × 6 days) goldenseal administration to healthy adults. These increases, coupled with a modest or no increase (≤23%) in half-life, suggested that goldenseal primarily inhibited intestinal CYP3A. A physiologically based pharmacokinetic interaction model incorporating berberine and (−)- β -hydrastine successfully predicted the goldenseal-midazolam interaction to within 20% of that observed after both chronic and acute goldenseal administration. Simulations implicated (−)- β -hydrastine as the major alkaloid precipitating the interaction, primarily via time-dependent inhibition of intestinal CYP3A, after chronic and acute goldenseal exposure. Results highlight the potential interplay between time-dependent and reversible inhibition of intestinal CYP3A as the mechanism underlying natural product-drug interactions, even after acute exposure to the precipitant. SIGNIFICANCE STATEMENT Natural products can alter the pharmacokinetics of an object drug, potentially resulting in increased off-target effects or decreased efficacy of the drug. The objective of this work was to evaluate fundamental mechanisms underlying the clinically observed goldenseal-midazolam interaction. Results support the use of an integrated approach involving established in vitro assays, clinical evaluation, and physiologically based pharmacokinetic modeling to elucidate the complex interplay between multiple phytoconstituents and various pharmacokinetic processes driving a drug interaction.

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“…While some adverse effects of this herb have been reported, the data is limited to case reports. Adverse effects include respiratory depression, seizures, and opioid-like withdrawal symptoms when a user stops kratom use abruptly [ 5 ]. The Drug Enforcement Administration lists kratom as a Drug and Chemical of Concern [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

The Great Imitator: A Case of Accidental Kratom Overdose

Ahmed¹,

Tran²,

McLean³

2023

Cureus

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Kratom ( Mitragyna speciosa ) is an herb that is sold over the counter in both pill and liquid forms. It contains opioid and stimulant properties and is used for relaxation as well as for weaning off opioid addictions. While a few adverse effects of kratom have been already reported, mainly with concerns around its toxicity, very little is known about it. We report a case of a female in her 40s presenting with signs of hypoxia reversed with naloxone administration, initially suspected to be a case of opioid overdose. Upon becoming alert and oriented, the patient and her husband reported that she consumed a large amount of kratom bought from the local gas station, and he later noticed that her lips were turning blue and she was becoming increasingly altered. Her urine toxicology was noted to be negative for opioids or any other substance use. The patient survived this accidental overdose due to the quick action of her husband, who rushed her to the emergency department (ED) upon realizing she appeared altered and very ill. It is important for emergency medicine practitioners to be aware of kratom overdose as a possible item on the differential diagnosis. This paper focuses on kratom overdose presentation and treatment.

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Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom

Cited by 14 publications

References 38 publications

Pharmacokinetic Interaction of Kratom and Cannabidiol in Male Rats

Pharmacokinetic Interaction of Kratom and Cannabidiol in Male Rats

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations

The Great Imitator: A Case of Accidental Kratom Overdose

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