Trial Outcomes & Findings for Assessing the Pharmacokinetics and Drug Interaction Liability of Kratom, an Opioid-like Natural Product (NCT NCT04392011)
NCT ID: NCT04392011
Last Updated: 2023-12-20
Results Overview
Area under the plasma concentration time curve (AUC) of midazolam
Recruitment status
COMPLETED
Study phase
EARLY_PHASE1
Target enrollment
15 participants
Primary outcome timeframe
0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72 , 96, 120, and 144 hours
Results posted on
2023-12-20
Participant Flow
Participant milestones
| Measure |
Kratom Only(1 Day)-Washout(7 Days)-Drug Cocktail(1 Day)-Washout(7 Days)-Kratom+Drug Cocktail(1 Day)
Six non-naive\* subjects (3 males, 3 females) were administered a single low dose of a well-characterized kratom product (2 g) by mouth as a tea. Plasma and urine were collected from 0-120 hours. Subjects then underwent a washout period of at least 7 days before continuing the study. The same six subjects were then administered an oral probe drug cocktail of dextromethorphan HBr (2 x 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma and urine were collected from 0-24 hours. Subjects then underwent a washout period of at least 7 days.
The same 6 subjects were then administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
\*Non-naive subjects are defined as intermittent users who consume 2-8 g kratom at least once per month but no more than three times daily within the last six months prior to screening and are willing to abstain for several weeks.
|
Drug Cocktail (1 Day)-Washout(7 Days)-Kratom+Drug Cocktail(1 Day)
Seven non-naive\* subjects (4 males and 3 females) were administered an oral probe drug cocktail of dextromethorphan HBr (2 x 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma and urine were collected from 0-24 hours. Subjects then underwent a washout period of at least 7 days.
Six of those subjects were then administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
\*Non-naive subjects are defined as intermittent users who consume 2-8 g kratom at least once per month but no more than three times daily within the last six months prior to screening and are willing to abstain for several weeks.
|
|---|---|---|
|
Kratom Only
STARTED
|
8
|
0
|
|
Kratom Only
COMPLETED
|
6
|
0
|
|
Kratom Only
NOT COMPLETED
|
2
|
0
|
|
Washout
STARTED
|
6
|
7
|
|
Washout
COMPLETED
|
6
|
6
|
|
Washout
NOT COMPLETED
|
0
|
1
|
|
Drug Cocktail Only
STARTED
|
6
|
7
|
|
Drug Cocktail Only
COMPLETED
|
6
|
7
|
|
Drug Cocktail Only
NOT COMPLETED
|
0
|
0
|
|
Kratom + Drug Cocktail
STARTED
|
6
|
6
|
|
Kratom + Drug Cocktail
COMPLETED
|
6
|
6
|
|
Kratom + Drug Cocktail
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Assessing the Pharmacokinetics and Drug Interaction Liability of Kratom, an Opioid-like Natural Product
Baseline characteristics by cohort
| Measure |
Kratom Alone - Washout - Drug Cocktail - Washout - Kratom+Drug Cocktail
n=8 Participants
Six non-naive\* subjects (3 males, 3 females) were administered a single low dose of a well-characterized kratom product (2 g) by mouth as a tea. Plasma will be collected from 0-120 hours and during the washout period. Urine was collected from 0-120 hours. After a washout of at least 7 days, the subjects were then administered an oral probe drug cocktail of dextromethorphan HBr (2 x 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma and urine were collected from 0-24 hours. After a washout period of at least 7 days, they were then administered a combination of a well-characterized kratom product (2 g) by mouth as a tea with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Drug Cocktail - Washout - Kratom+Drug Cocktail
n=7 Participants
Seven non-naive\* subjects (4 males, 3 females) were administered an oral probe drug cocktail of dextromethorphan HBr (2 x 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma and urine were collected from 0-24 hours. After a washout period of at least 7 days, they were then administered a combination of a well-characterized kratom product (2 g) by mouth as a tea with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Total
n=15 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
8 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
15 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Sex: Female, Male
Female
|
5 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
9 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
3 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
White
|
4 Participants
n=5 Participants
|
6 Participants
n=7 Participants
|
10 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Asian
|
2 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Black
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
More than 1
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
8 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
15 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72 , 96, 120, and 144 hoursPopulation: Although 13 subjects completed the drug cocktail arm, only the 12 subjects that completed both that and the kratom + drug cocktail arm were analyzed, as the drug cocktail arm was intended as a baseline to which the kratom + drug cocktail arm would be compared.
Area under the plasma concentration time curve (AUC) of midazolam
Outcome measures
| Measure |
Drug Cocktail
n=12 Participants
Thirteen subjects were administered an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Kratom + Drug Cocktail
n=12 Participants
Twelve subjects were administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
|---|---|---|
|
Midazolam Area Under the Concentration vs. Time Curve (AUC)
|
58.3 nM * hr
Interval 48.5 to 70.2
|
80.8 nM * hr
Interval 64.2 to 102.0
|
SECONDARY outcome
Timeframe: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, 120, and 144 hoursPopulation: Although 13 subjects completed the drug cocktail arm, only the 12 subjects that completed both that and the kratom + drug cocktail arm were analyzed, as the drug cocktail arm was intended as a baseline to which the kratom + drug cocktail arm would be compared.
Area under the plasma concentration time curve (AUC) of dextromethorphan
Outcome measures
| Measure |
Drug Cocktail
n=12 Participants
Thirteen subjects were administered an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Kratom + Drug Cocktail
n=12 Participants
Twelve subjects were administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
|---|---|---|
|
Dextromethorphan Area Under the Concentration vs. Time Curve (AUC)
|
46.5 nM*h
Interval 19.4 to 112.0
|
46.2 nM*h
Interval 19.2 to 112.0
|
SECONDARY outcome
Timeframe: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, and 120 hoursArea under the concentration vs. time curve (AUC) of mitragynine.
Outcome measures
| Measure |
Drug Cocktail
n=6 Participants
Thirteen subjects were administered an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Kratom + Drug Cocktail
Twelve subjects were administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
|---|---|---|
|
Mitragynine Area Under the Concentration vs. Time Curve (AUC)
|
388 nM x h
Interval 300.0 to 1240.0
|
—
|
SECONDARY outcome
Timeframe: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96,120, and 144 hoursPopulation: Although 13 subjects completed the drug cocktail arm, only the 12 subjects that completed both that and the kratom + drug cocktail arm were analyzed, as the drug cocktail arm was intended as a baseline to which the kratom + drug cocktail arm would be compared.
Maximum concentration (Cmax) of midazolam and dextromethorphan
Outcome measures
| Measure |
Drug Cocktail
n=12 Participants
Thirteen subjects were administered an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Kratom + Drug Cocktail
n=12 Participants
Twelve subjects were administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
|---|---|---|
|
Midazolam and Dextromethorphan Cmax
midazolam
|
21.1 nM
Interval 17.2 to 26.0
|
31.6 nM
Interval 26.4 to 38.0
|
|
Midazolam and Dextromethorphan Cmax
dextromethorphan
|
4.57 nM
Interval 2.07 to 10.1
|
4.30 nM
Interval 2.06 to 9.28
|
SECONDARY outcome
Timeframe: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, and 120 hoursMaximum plasma concentration of mitragynine.
Outcome measures
| Measure |
Drug Cocktail
n=6 Participants
Thirteen subjects were administered an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Kratom + Drug Cocktail
Twelve subjects were administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
|---|---|---|
|
Mitragynine Cmax
|
81.9 nM
Interval 50.1 to 177.0
|
—
|
SECONDARY outcome
Timeframe: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96,120, and 144 hoursPopulation: Although 13 subjects completed the drug cocktail arm, only the 12 subjects that completed both that and the kratom + drug cocktail arm were analyzed, as the drug cocktail arm was intended as a baseline to which the kratom + drug cocktail arm would be compared.
Time to reach one-half of the concentration of midazolam and dextromethorphan
Outcome measures
| Measure |
Drug Cocktail
n=12 Participants
Thirteen subjects were administered an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Kratom + Drug Cocktail
n=12 Participants
Twelve subjects were administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
|---|---|---|
|
Midazolam and Dextromethorphan Half-life
midazolam
|
3.85 h
Interval 3.25 to 4.56
|
4.12 h
Interval 3.45 to 4.92
|
|
Midazolam and Dextromethorphan Half-life
dextromethorphan
|
6.87 h
Interval 5.85 to 8.06
|
6.84 h
Interval 5.62 to 8.34
|
SECONDARY outcome
Timeframe: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, and 120 hoursTime to reach one-half of the concentration of mitragynine.
Outcome measures
| Measure |
Drug Cocktail
n=6 Participants
Thirteen subjects were administered an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Kratom + Drug Cocktail
Twelve subjects were administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
|---|---|---|
|
Mitragynine Half Life
|
45.3 h
Interval 31.9 to 50.2
|
—
|
Adverse Events
Kratom Alone
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Drug Cocktail
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Kratom + Drug Cocktail
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Kratom Alone
n=8 participants at risk
Six non-naive\* subjects were administered a single low dose of a well-characterized kratom product (2 g) by mouth as a tea. Plasma and urine were collected from 0-120 hours. Subjects then underwent a washout period of at least 7 days before continuing the study.
|
Drug Cocktail
n=13 participants at risk
Thirteen subjects were administered an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
Kratom + Drug Cocktail
n=12 participants at risk
Twelve subjects were administered kratom (2 g) with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma was collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine was collected from 0-24 hours.
|
|---|---|---|---|
|
Nervous system disorders
headache/lightheadedness
|
12.5%
1/8 • Number of events 3 • 3 months
|
7.7%
1/13 • Number of events 1 • 3 months
|
8.3%
1/12 • Number of events 3 • 3 months
|
|
Nervous system disorders
nausea/vomiting
|
12.5%
1/8 • Number of events 1 • 3 months
|
0.00%
0/13 • 3 months
|
8.3%
1/12 • Number of events 1 • 3 months
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place