Kratom (Mitragyna speciosa)
Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants
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Increasing use of the botanical kratom to self-manage opioid withdrawal and pain has led to increased kratom-linked overdose deaths. Despite these serious safety concerns, rigorous fundamental pharmacokinetic knowledge of kratom in humans remains lacking. We assessed the pharmacokinetics of a single low dose (2 g) of a well-characterized kratom product administered orally to six healthy participants. Median concentration-time profiles for the kratom alkaloids examined were best described by a two-compartment model with central elimination. Pronounced pharmacokinetic differences between alkaloids with the 3S configuration (mitragynine, speciogynine, paynantheine) and alkaloids with the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) were attributed to differences in apparent intercompartmental distribution clearance, volumes of distribution, and clearance. Based on noncompartmental analysis of individual concentration-time profiles, the 3S alkaloids exhibited a shorter median time to maximum concentration (1-2 vs. 2.5-4.5 h), lower area under the plasma concentration-time curve (430-490 vs. 794-5120 nM × h), longer terminal half-life (24-45 vs. ~12-18 h), and higher apparent volume of distribution during the terminal phase (960-12,700 vs. ~46-130 L) compared to the 3R alkaloids. Follow-up mechanistic in vitro studies suggested differential hepatic/intestinal metabolism, plasma protein binding, blood-to-plasma partitioning, and/or distribution coefficients may explain the pharmacokinetic differences between the two alkaloid types. This first comprehensive pharmacokinetic characterization of kratom alkaloids in humans provides the foundation for further research to establish safety and effectiveness of this emerging botanical product.
1 . mitragynine (id=NPDI-PsV3FA)
In Vivo Pharmacokinetics Study
Results
Data from 5 healthy adults who completed the study (out of 7 enrolled) was used to calculate the compartmental model-derived pharmacokinetic estimates.
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Probe cocktail study
Healthy volunteers
More than one race
7
The six participants self-identified as White (one male and three females), Black (one male), or multiracial (one male). Participant age ranged from 26–40 years. None of the participants failed the drug toxicology screen, and all abstained from taking concomitant medications and botanical and other natural products during the entire study period. Except for the two discontinued female participants, the kratom tea was well tolerated, and none of the participants experienced any severe adverse events. Two participants experienced an adverse event during the study unrelated to kratom (lightheadedness upon placement of an intravenous catheter/first blood draw and mild headache, respectively) that did not result in study discontinuation.
Drug or Natural Product Administration
Oral
2 g
2 . speciogynine (id=NPDI-RfQQdQ)
In Vivo Pharmacokinetics Study
Results
Data from 5 healthy adults who completed the study (out of 7 enrolled) was used to calculate the results using compartmental model-derived pharmacokinetic estimates.
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Probe cocktail study
Healthy volunteers
More than one race
7
The six participants self-identified as White (one male and three females), Black (one male), or multiracial (one male). Participant age ranged from 26–40 years. None of the participants failed the drug toxicology screen, and all abstained from taking concomitant medications and botanical and other natural products during the entire study period. Except for the two discontinued female participants, the kratom tea was well tolerated, and none of the participants experienced any severe adverse events. Two participants experienced an adverse event during the study unrelated to kratom (lightheadedness upon placement of an intravenous catheter/first blood draw and mild headache, respectively) that did not result in study discontinuation.
Drug or Natural Product Administration
Oral
2 g
3 . mitraciliatine (id=NPDI-y7NNJA)
In Vivo Pharmacokinetics Study
Results
Data from 5 healthy adults who completed the study (out of 7 enrolled) was used to calculate the results using compartmental model-derived pharmacokinetic estimates .
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Probe cocktail study
Healthy volunteers
More than one race
7
The six participants self-identified as White (one male and three females), Black (one male), or multiracial (one male). Participant age ranged from 26–40 years. None of the participants failed the drug toxicology screen, and all abstained from taking concomitant medications and botanical and other natural products during the entire study period. Except for the two discontinued female participants, the kratom tea was well tolerated, and none of the participants experienced any severe adverse events. Two participants experienced an adverse event during the study unrelated to kratom (lightheadedness upon placement of an intravenous catheter/first blood draw and mild headache, respectively) that did not result in study discontinuation.
Drug or Natural Product Administration
Oral
2 g
4 . speciociliatine (id=NPDI-p8vUgQ)
In Vivo Pharmacokinetics Study
Results
These values are based on the two-compartment model with elimination rate used to describe the median concentration-time profiles of all kratom alkaloids. Data from 5 healthy adults who completed the study (out of 7 enrolled) was used to calculate the results.
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Single dosing
Healthy volunteers
More than one race
7
Seven participants were enrolled. One participant was withdrawn immediately from the study due to nausea and vomiting within 20 minutes of tea consumption. The participant was replaced by another person who experienced nausea and vomiting within 2-3 hours of tea consumption. She continued on with the study, but was withdrawn after 48 hours due to abnormal appearing urine. The six participants identified as White (one male, three females), Black (one male), and multiracial (one male). Participant age ranged from 26-40. None of the participants failed the drug toxicology screening and all participants ceased to consume any concomitant medications, botanicals, and other natural product throughout the duration of the study.
Drug or Natural Product Administration
Oral
Tea
2 grams
Fasted
Fasted overnight prior to the study
<10 minutes
Pharmacodynamics (PD) & Adverse Events
Except for the two participants who were withdrawn from the study, none of the other participants experienced any severe adverse events. Two participants experienced adverse events (lightheadedness during blood draw and a mild headache) during the study that was unrelated to kratom use.
5 . paynantheine (id=NPDI-pX3CPg)
In Vivo Pharmacokinetics Study
Results
These values are based on the two-compartment model with elimination rate used to describe the median concentration-time profiles of all kratom alkaloids. Data from 5 healthy adults who completed the study (out of 7 enrolled) was used to calculate the results.
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Single dosing
Healthy volunteers
More than one race
7
Seven participants were enrolled. One participant was withdrawn immediately from the study due to nausea and vomiting within 20 minutes of tea consumption. The participant was replaced by another person who experienced nausea and vomiting within 2-3 hours of tea consumption. She continued on with the study, but was withdrawn after 48 hours due to abnormal appearing urine. The six participants identified as White (one male, three females), Black (one male), and multiracial (one male). Participant age ranged from 26-40. None of the participants failed the drug toxicology screening and all participants ceased to consume any concomitant medications, botanicals, and other natural product throughout the duration of the study.
Drug or Natural Product Administration
Oral
Tea
2 grams
Fasted
Fasted overnight prior to the study
<10 minutes
Pharmacodynamics (PD) & Adverse Events
Except for the two participants who were withdrawn from the study, none of the other participants experienced any severe adverse events. Two participants experienced adverse events (lightheadedness during blood draw and a mild headache) during the study that was unrelated to kratom use.
6 . isopaynantheine (id=NPDI-c1a6PQ)
In Vivo Pharmacokinetics Study
Results
These values are based on the two-compartment model with elimination rate used to describe the median concentration-time profiles of all kratom alkaloids. Data from 5 healthy adults who completed the study (out of 7 enrolled) was used to calculate the results.
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Single dosing
Healthy volunteers
More than one race
7
Seven participants were enrolled. One participant was withdrawn immediately from the study due to nausea and vomiting within 20 minutes of tea consumption. The participant was replaced by another person who experienced nausea and vomiting within 2-3 hours of tea consumption. She continued on with the study, but was withdrawn after 48 hours due to abnormal appearing urine. The six participants identified as White (one male, three females), Black (one male), and multiracial (one male). Participant age ranged from 26-40. None of the participants failed the drug toxicology screening and all participants ceased to consume any concomitant medications, botanicals, and other natural product throughout the duration of the study.
Drug or Natural Product Administration
Oral
Tea
2 grams
Fasted
Fasted overnight prior to study
<10 minutes
Pharmacodynamics (PD) & Adverse Events
Except for the two participants who were withdrawn from the study, none of the other participants experienced any severe adverse events. Two participants experienced adverse events (lightheadedness during blood draw and a mild headache) during the study that was unrelated to kratom use.