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

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011–2017, one-third of which reported c...

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Autores principales: Tanna, Rakshit S., Nguyen, James T., Hadi, Deena L., Layton, Matthew E., White, John R., Cech, Nadja B., Oberlies, Nicholas H., Rettie, Allan E., Thummel, Kenneth E., Paine, Mary F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198846/
https://www.ncbi.nlm.nih.gov/pubmed/36924284
http://dx.doi.org/10.1002/cpt.2891
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author Tanna, Rakshit S.
Nguyen, James T.
Hadi, Deena L.
Layton, Matthew E.
White, John R.
Cech, Nadja B.
Oberlies, Nicholas H.
Rettie, Allan E.
Thummel, Kenneth E.
Paine, Mary F.
author_facet Tanna, Rakshit S.
Nguyen, James T.
Hadi, Deena L.
Layton, Matthew E.
White, John R.
Cech, Nadja B.
Oberlies, Nicholas H.
Rettie, Allan E.
Thummel, Kenneth E.
Paine, Mary F.
author_sort Tanna, Rakshit S.
collection PubMed
description Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011–2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (C(max); geometric mean ratio (90% confidence interval) 0.99 (0.83–1.19) and 0.96 (0.78–1.19), respectively) but a modest increase in midazolam AUC and C(max) (1.39 (1.23–1.57) and 1.50 (1.32–1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98–1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (K(I), ~4 μM; k(inact), ~0.07 min(−1)). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.
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spelling pubmed-101988462023-06-01 Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom Tanna, Rakshit S. Nguyen, James T. Hadi, Deena L. Layton, Matthew E. White, John R. Cech, Nadja B. Oberlies, Nicholas H. Rettie, Allan E. Thummel, Kenneth E. Paine, Mary F. Clin Pharmacol Ther Article Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011–2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (C(max); geometric mean ratio (90% confidence interval) 0.99 (0.83–1.19) and 0.96 (0.78–1.19), respectively) but a modest increase in midazolam AUC and C(max) (1.39 (1.23–1.57) and 1.50 (1.32–1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98–1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (K(I), ~4 μM; k(inact), ~0.07 min(−1)). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns. 2023-06 2023-03-28 /pmc/articles/PMC10198846/ /pubmed/36924284 http://dx.doi.org/10.1002/cpt.2891 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Article
Tanna, Rakshit S.
Nguyen, James T.
Hadi, Deena L.
Layton, Matthew E.
White, John R.
Cech, Nadja B.
Oberlies, Nicholas H.
Rettie, Allan E.
Thummel, Kenneth E.
Paine, Mary F.
Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom
title Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom
title_full Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom
title_fullStr Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom
title_full_unstemmed Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom
title_short Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom
title_sort clinical assessment of the drug interaction potential of the psychotropic natural product kratom
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198846/
https://www.ncbi.nlm.nih.gov/pubmed/36924284
http://dx.doi.org/10.1002/cpt.2891
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