Kratom (Mitragyna speciosa)
Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom
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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 (Cmax ; 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 Cmax (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 (KI , ~4 μM; kinact , ~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.
1 . kratom tea - midazolam interaction clinical NPDI study (id=NPDI-scab3g)
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Single dosing
Females
Healthy volunteers
Males
Asian
Black or African American
White
12
Participants were 6 males and 6 adult females. Females were non-pregnant.
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours
Drug or Natural Product Administration
Oral
cocktail
2.5mg
Single dose
Oral
Tea
2g
Single dose
Described as Yellow Indonesian Micro Powder - study ID K51
19.48±0.81, 3.18±0.13, 0.647±0.035, 5.12±0.26, 5.86±0.26, 0.512±0.010, and <0.124±0.0014 (below the limit of quantification) mg of mitragynine, speciogynine, mitraciliatine, speciociliatine, paynantheine, isopaynantheine, and 7-hydroxymitragynine, respectively, in each g of dried leaf powder.
2021
Characterization study: Tanna, R.S. et al. Clinical pharmacokinetic assessment of kratom (Mitragyna speciosa), a botanical product with opioid-like effects, in healthy adult participants. Pharmaceutics 14, 620 (2022).
Pharmacodynamics (PD) & Adverse Events
Due to the subtherapeutic dose of midazolam, pharmacodynamic changes were not measured.
The kratom tea and probe drugs were well tolerated by all 12 participants. No participants experienced severe adverse events. Five participtants experienced lightheadedness or headache during at least one arm that did not result in study discontinuation.
2 . kratom tea - dextromethorphan interaction clinical NPDI study (id=NPDI--fog0A)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
- CYP2D6 4173631
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Single dosing
Females
Healthy volunteers
Males
Asian
Black or African American
White
12
Participants were 6 males and 6 adult females. Females were non-pregnant.
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours
Drug or Natural Product Administration
Oral
cocktail
30mg
Single dose
Oral
Tea
2g
Single dose
Described as Yellow Indonesian Micro Powder - study ID K51
19.48±0.81, 3.18±0.13, 0.647±0.035, 5.12±0.26, 5.86±0.26, 0.512±0.010, and <0.124±0.0014 (below the limit of quantification) mg of mitragynine, speciogynine, mitraciliatine, speciociliatine, paynantheine, isopaynantheine, and 7-hydroxymitragynine, respectively, in each g of dried leaf powder.
2021
Characterization study: Tanna, R.S. et al. Clinical pharmacokinetic assessment of kratom (Mitragyna speciosa), a botanical product with opioid-like effects, in healthy adult participants. Pharmaceutics 14, 620 (2022).
Pharmacodynamics (PD) & Adverse Events
Due to the subtherapeutic dose of midazolam, pharmacodynamic changes were not measured.
The kratom tea and probe drugs were well tolerated by all 12 participants. No participants experienced severe adverse events. Five participtants experienced lightheadedness or headache during at least one arm that did not result in study discontinuation.