Pharmacodynamics, Pharmacokinetics, Safety
Conditions
Keywords
Kratom, Mitragynine, Botanical substance, Single Ascending Dose
Brief summary
Kratom (Mitragyna speciosa) is a plant often used to self-treat conditions such as pain, coughing, diarrhea, anxiety and depression, opioid use disorder, and opioid withdrawal. Due to limited data availability, the goal of this clinical trial is to learn about safety, pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body) of Kratom in adult recreational polydrug users with opioid experience.
Detailed description
This is a phase I, single-dose, randomized, adaptive, double-blind, placebo-controlled, single ascending dose (SAD), sequential group study in adult recreational polydrug users with opioid experience performed at a single study center. This study will consist of five cohorts. Forty subjects are planned to participate. Eight subjects will participate in each cohort. Within each cohort, 6 subjects will be randomized to receive Kratom and 2 subjects will be randomized to receive placebo. Each subject will be involved in the study for up to approximately 37 days (including screening).
Interventions
DRUGKratom
Single administration thirty minutes after the start of a high-fat breakfast
DRUGPlacebo
Single administration thirty minutes after the start of a high-fat breakfast
Sponsors
Altasciences Company Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The treatment assignment (active or placebo) will not be known by the study participants. Study participants will be informed of the dose range they could receive but will not be informed of the actual dose assigned to them. Furthermore, the randomization code will not be available to the Investigator and clinical staff involved in the collection, monitoring, revision, or evaluation of AEs, as well as clinical staff who could have an impact on the outcome of the study including the pharmacokineticist (or delegate) and biostatistician, until all the case report form (CRFs) have been approved and signed and the bioanalytical phase of the study has been completed.
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provision of signed and dated informed consent form (ICF) 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Healthy adult male or female 4. Current nondependent, polydrug recreational user who has used opioid drugs for recreational (nontherapeutic) purposes (i.e., for psychoactive effects) and has a history of recreational use of at least 2 or more of any of the perception-altering (e.g., lysergic acid diethylamide \[LSD\], kratom, cannabis, dronabinol, ketamine, phencyclidine \[PCP\], dextromethorphan, 3,4 methylenedioxymethamphetamine \[MDMA\], mescaline, psilocybin, tryptamine derivatives or ring-substituted amphetamines with perception altering effects) or stimulant (e.g., cocaine, amphetamine, methamphetamine, methylphenidate, methcathinone, and other synthetic cathinones) drugs 5. If male, meets one of the following criteria: 1. Is able to procreate and agrees to use one of the accepted contraceptive regimens and not to donate sperm from study drug administration to at least 90 days after study drug administration. An acceptable method of contraception includes one of the following: * Abstinence from heterosexual intercourse * Double-barrier method (e.g., male condom with spermicide or male condom with a vaginal spermicide \[gel, foam, or suppository\]) Or 2. Is unable to procreate; defined as surgically sterile (i.e., has undergone a vasectomy at least 180 days prior to study drug administration) 6. If female, meets one of the following criteria: 1. Is of childbearing potential and agrees to use an acceptable contraceptive method. Acceptable contraceptive methods include: a1. Abstinence from heterosexual intercourse from the Screening visit through to at least 30 days after study drug administration a2. One of the following contraceptive methods, used from at least 28 days prior to the Screening visit through to at least 30 days after study drug administration: * Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, or transdermal patch) * Intrauterine device (with or without hormones) * Male partner vasectomized at least 6 months prior to the Screening visit a3. One of the following double-barrier contraceptive methods, used from the Screening visit through to at least 30 days study drug administration: * Male condom plus spermicide * Diaphragm plus spermicide * Cervical cap plus spermicide 2. Is of non-childbearing potential, defined as surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation), or is in a postmenopausal state (i.e., at least 1 year without menses without an alternative medical condition prior to the Screening visit and follicle stimulating hormone levels ≥ 40 mIU/mL at Screening) 7. Body mass index (BMI) within 18.0 kg/m2 to 34.0 kg/m2, inclusively at Screening 8. Minimum weight of 50.0 kg at Screening 9. Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination (including vital signs, oxygen saturation \[SpO2\], and respiratory rate) and/or ECG, as determined by an Investigator
Exclusion criteria
1. Difficulty swallowing capsules 2. Female who is lactating 3. Female who is pregnant according to the pregnancy test at Screening or prior to study drug administration 4. Male with female partner who is pregnant, lactating, or planning to become pregnant during this study or within 90 days after study drug administration 5. History of significant hypersensitivity to kratom or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs 6. Presence or history of significant gastrointestinal, liver or kidney disease, or surgery that may affect drug bioavailability with the exception of cholecystectomy that is permitted at the discretion of an Investigator 7. History of significant hepatic, renal, cardiovascular, pulmonary, hematologic, neurological, psychiatric, gastrointestinal, endocrine, immunologic, ophthalmologic, or dermatologic disease 8. Presence of any significant respiratory illness or presence or history of chronic respiratory disease (e.g., upper respiratory illness, sleep apnea, emphysema, asthma) at Screening (subjects with acute respiratory illness may be rescheduled upon resolution at the discretion of an Investigator) 9. History of substance or alcohol moderate to severe use disorder (excluding nicotine and caffeine) within the past 2 years, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) 10. Is a heavy smoker (\> 20 cigarettes per day) and/or is unable to abstain from smoking or unable to abstain from the use of prohibited nicotine-containing products for at least 1 hour before and 8 hours after study drug administration (including e-cigarettes, pipes, cigars, chewing tobacco, nicotine topical patches, nicotine gum, or nicotine lozenges) 11. Regularly consumes excessive amounts of caffeine or xanthines, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day 12. History of suicidal behavior within 2 years of Screening, showing suicidal tendency as per the C-SSRS administered at Screening, or is currently at risk of suicide in the opinion of an Investigator 13. Presence of clinically significant ECG abnormalities at the Screening visit, as defined by medical judgment. Note: QT corrected according to Fridericia's formula (QTcF) interval of \> 450 msec in male subjects or \> 470 msec in female subjects will be exclusionary. The ECG may be repeated once for confirmatory purposes if the initial value obtained exceeds the limits specified. 14. Estimated glomerular filtration rate (eGFR) ≤ 60 mL/min as calculated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation 15. Any clinically significant illness in the 28 days prior to study drug administration 16. Use of any prescription drugs (with the exception of hormonal contraceptives or hormone replacement therapy) in the 28 days prior to study drug administration, that in the opinion of an Investigator would put into question the status of the participant as healthy 17. Use of St. John's wort in the 28 days prior to study drug administration 18. Positive test result for alcohol and/or drugs of abuse at admission (prior to study drug administration). Subjects with positive results at admission may be rescheduled at the discretion of an Investigator. If tetrahydrocannabinol (THC) is positive at admission a cannabis intoxication evaluation will be done by an Investigator and subjects may be permitted to continue in the study at the discretion of an Investigator. Other positive test results should be reviewed to determine if the subject may be rescheduled, in the opinion of the investigator. 19. Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen or hepatitis C virus tests 20. Any other clinically significant abnormalities in laboratory test results at Screening that would, in the opinion of an Investigator, increase the subject's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data 21. Inclusion in a previous group for this clinical study 22. Intake of kratom in the 14 days prior to study drug administration 23. Intake of an Investigational Product (IP) in the 28 days prior to study drug administration 24. Donation of plasma in the 7 days prior to study drug administration 25. Donation of 1 unit of blood to American Red Cross or equivalent organization or donation of over 500 mL of blood in the 56 days prior to study drug administration 26. Subject cannot eat dairy and/or is lactose intolerant 27. Is, in the opinion of an Investigator or designee, considered unsuitable or unlikely to comply with the study protocol for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Day 1 through Day 7 | For purposes of monitoring safety, treatment-emergent adverse events (AEs) will be graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 5.0). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time of Maximum Observed Concentration | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | Tmax (hours) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine |
| Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | AUC0-T (ng\*h/mL) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine |
| Area Under the Concentration Time Curve Extrapolated to Infinity | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | AUC0-inf (ng\*h/mL) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine |
| Dose-normalized Cmax Calculated at Cmax / Dose | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | Cmax/D (ng/mL/g) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine |
| Dose-normalized AUC0-T Calculated as AUC0-T / Dose | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | AUC0-T/D (ng\*h/mL/g) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine |
| Maximum Observed Concentration | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | Cmax (ng/mL) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine |
| Maximum Effect for Drug Liking | 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose | Maximum (peak) effect (Emax) for Drug Liking assessed on a bipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as strong disliking (score = 0), neither like nor dislike (score = 50) to strong liking (score = 100). |
| Maximum Effect for Overall Drug Liking | 12 and 24 hours postdose | Maximum (peak) effect (Emax) for Overall Drug Liking assessed on a bipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as strong disliking (score = 0), neither like nor dislike (score = 50) to strong liking (score = 100). |
| Maximum Effect for Take Drug Again | 12 and 24 hours postdose | Maximum (peak) effect (Emax) for Take Drug Again assessed on a bipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as definitely would not (score = 0), neither would nor would not (score = 50) to definitely would (score = 100). |
| Maximum Effect for High | Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose | Maximum (peak) effect (Emax) for High assessed on an unipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as not at all (score = 0) to extremely (score = 100). |
| Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | AUC0-inf/D (ng\*h/mL/g) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1, 1 g of Kratom A total of 6 subjects will receive an oral single dose administration of the active product
Kratom: Single administration thirty minutes after the start of a high-fat breakfast | 6 |
| Cohort 2, 3 g of Kratom A total of 6 subjects will receive an oral single dose administration of the active product
Kratom: Single administration thirty minutes after the start of a high-fat breakfast | 6 |
| Cohort 3, 8 g of Kratom A total of 6 subjects will receive an oral single dose administration of the active product
Kratom: Single administration thirty minutes after the start of a high-fat breakfast | 6 |
| Cohort 4, 10 g of Kratom A total of 6 subjects will receive an oral single dose administration of the active product
Kratom: Single administration thirty minutes after the start of a high-fat breakfast | 6 |
| Cohort 5, 12 g of Kratom A total of 6 subjects will receive an oral single dose administration of the active product
Kratom: Single administration thirty minutes after the start of a high-fat breakfast | 6 |
| Placebo A total of 2 subjects per cohort will receive an oral single dose administration of placebo
Placebo: Single administration thirty minutes after the start of a high-fat breakfast | 10 |
| Total | 40 |
Baseline characteristics
| Characteristic | Cohort 1, 1 g of Kratom | Cohort 2, 3 g of Kratom | Cohort 3, 8 g of Kratom | Cohort 4, 10 g of Kratom | Cohort 5, 12 g of Kratom | Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 37.5 years STANDARD_DEVIATION 8.78 | 32.2 years STANDARD_DEVIATION 3.54 | 37.7 years STANDARD_DEVIATION 10.69 | 40.3 years STANDARD_DEVIATION 6.89 | 40.2 years STANDARD_DEVIATION 6.4 | 32.5 years STANDARD_DEVIATION 4.81 | 36.3 years STANDARD_DEVIATION 7.38 |
| Body Mass Index | 24.02 kg/m2 STANDARD_DEVIATION 4.279 | 26.82 kg/m2 STANDARD_DEVIATION 4.222 | 27.42 kg/m2 STANDARD_DEVIATION 4.901 | 25.85 kg/m2 STANDARD_DEVIATION 2.811 | 24.33 kg/m2 STANDARD_DEVIATION 2.277 | 25.48 kg/m2 STANDARD_DEVIATION 4.132 | 25.64 kg/m2 STANDARD_DEVIATION 3.835 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 5 Participants | 10 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 5 Participants | 4 Participants | 6 Participants | 4 Participants | 8 Participants | 31 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 5 Participants | 5 Participants | 6 Participants | 7 Participants | 35 Participants |
| Weight (kg) | 73.78 kg STANDARD_DEVIATION 14.91 | 84.83 kg STANDARD_DEVIATION 14.552 | 79.60 kg STANDARD_DEVIATION 13.565 | 80.08 kg STANDARD_DEVIATION 12.09 | 74.62 kg STANDARD_DEVIATION 9.338 | 74.51 kg STANDARD_DEVIATION 12.946 | 77.56 kg STANDARD_DEVIATION 12.787 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 |
| other Total, other adverse events | 1 / 6 | 1 / 6 | 5 / 6 | 5 / 6 | 3 / 6 | 4 / 10 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
For purposes of monitoring safety, treatment-emergent adverse events (AEs) will be graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 5.0).
Time frame: Day 1 through Day 7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1, 1 g of Kratom | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 1 Participants |
| Cohort 2, 3 g of Kratom | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 1 Participants |
| Cohort 3, 8 g of Kratom | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 5 Participants |
| Cohort 4, 10 g of Kratom | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 4 Participants |
| Cohort 5, 12 g of Kratom | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 4 Participants |
Secondary
Area Under the Concentration Time Curve Extrapolated to Infinity
AUC0-inf (ng\*h/mL) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine
Time frame: 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose
Population: Placebo subjects were not included in the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciogynine | 76.1 ng*h/mL | Standard Deviation 27.5 |
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | mitragynine | 341.941 ng*h/mL | Standard Deviation 131.703 |
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | paynantheine | 58.3 ng*h/mL | Standard Deviation 22.6 |
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | 7 hydroxy-mitragynine | 57.023 ng*h/mL | Standard Deviation 21.974 |
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciociliatine | 654.9 ng*h/mL | Standard Deviation 377.1 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | 7 hydroxy-mitragynine | 139.322 ng*h/mL | Standard Deviation 88.492 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciogynine | 190.1 ng*h/mL | Standard Deviation 51.1 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciociliatine | 2099.8 ng*h/mL | Standard Deviation 578.7 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | paynantheine | 160.1 ng*h/mL | Standard Deviation 52.6 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | mitragynine | 897.401 ng*h/mL | Standard Deviation 436.438 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | paynantheine | 380.3 ng*h/mL | Standard Deviation 161.2 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | 7 hydroxy-mitragynine | 438.569 ng*h/mL | Standard Deviation 169.329 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciociliatine | 4187.3 ng*h/mL | Standard Deviation 1567.2 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | mitragynine | 2305.048 ng*h/mL | Standard Deviation 1068.794 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciogynine | 413.2 ng*h/mL | Standard Deviation 189.8 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | mitragynine | 3950.438 ng*h/mL | Standard Deviation 2839.536 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | 7 hydroxy-mitragynine | 515.160 ng*h/mL | Standard Deviation 284.275 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | paynantheine | 819.4 ng*h/mL | Standard Deviation 477.5 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciogynine | 958.6 ng*h/mL | Standard Deviation 570.7 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciociliatine | 8908.0 ng*h/mL | Standard Deviation 5130.1 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | paynantheine | 814.8 ng*h/mL | Standard Deviation 462.9 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | 7 hydroxy-mitragynine | 596.489 ng*h/mL | Standard Deviation 206.138 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | mitragynine | 3674.606 ng*h/mL | Standard Deviation 1790.98 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciociliatine | 8012.7 ng*h/mL | Standard Deviation 4075.7 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve Extrapolated to Infinity | speciogynine | 906.3 ng*h/mL | Standard Deviation 544.4 |
Comparison: Statistical Analysis for Dose-Proportionality of Mitragynine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.775, 1.143]
Comparison: Statistical Analysis for Dose-Proportionality of 7-Hydroxy-Mitragynine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.815, 1.134]
Comparison: Statistical Analysis for Dose-Proportionality of Paynantheine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.866, 1.207]
Comparison: Statistical Analysis for Dose-Proportionality of Speciogynine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.79, 1.145]
Comparison: Statistical Analysis for Dose-Proportionality of Speciociliatine Dose Adjusted Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.859, 1.191]
Secondary
Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T)
AUC0-T (ng\*h/mL) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine
Time frame: 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose
Population: Placebo subjects were not included in the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciogynine | 53.4 ng*h/mL | Standard Deviation 19.2 |
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | mitragynine | 305.383 ng*h/mL | Standard Deviation 115.616 |
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciociliatine | 573.9 ng*h/mL | Standard Deviation 285.4 |
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | 7 hydroxy-mitragynine | 53.518 ng*h/mL | Standard Deviation 21.615 |
| Cohort 1, 1 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | paynantheine | 47.0 ng*h/mL | Standard Deviation 19 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciogynine | 154.0 ng*h/mL | Standard Deviation 44.1 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | paynantheine | 132.9 ng*h/mL | Standard Deviation 44 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | 7 hydroxy-mitragynine | 132.994 ng*h/mL | Standard Deviation 85.838 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciociliatine | 1910.9 ng*h/mL | Standard Deviation 475.4 |
| Cohort 2, 3 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | mitragynine | 784.794 ng*h/mL | Standard Deviation 380.29 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | paynantheine | 320.2 ng*h/mL | Standard Deviation 134 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | mitragynine | 1942.205 ng*h/mL | Standard Deviation 737.483 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | 7 hydroxy-mitragynine | 412.602 ng*h/mL | Standard Deviation 153.549 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciogynine | 341.0 ng*h/mL | Standard Deviation 147.5 |
| Cohort 3, 8 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciociliatine | 3359.2 ng*h/mL | Standard Deviation 1257.7 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciociliatine | 7904.8 ng*h/mL | Standard Deviation 4790.9 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | mitragynine | 3254.385 ng*h/mL | Standard Deviation 2213.45 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciogynine | 819.2 ng*h/mL | Standard Deviation 521.6 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | paynantheine | 725.2 ng*h/mL | Standard Deviation 452.4 |
| Cohort 4, 10 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | 7 hydroxy-mitragynine | 459.109 ng*h/mL | Standard Deviation 226.314 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | paynantheine | 727.6 ng*h/mL | Standard Deviation 397.9 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciogynine | 790.0 ng*h/mL | Standard Deviation 453.2 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | mitragynine | 3271.209 ng*h/mL | Standard Deviation 1577.443 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | speciociliatine | 7449.8 ng*h/mL | Standard Deviation 3695.4 |
| Cohort 5, 12 g of Kratom | Area Under the Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-T) | 7 hydroxy-mitragynine | 574.260 ng*h/mL | Standard Deviation 194.789 |
Comparison: Statistical Analysis for Dose-Proportionality of Mitragynine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.768, 1.123]
Comparison: Statistical Analysis for Dose-Proportionality of 7-Hydroxy-Mitragynine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.821, 1.134]
Comparison: Statistical Analysis for Dose-Proportionality of Paynantheine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.901, 1.249]
Comparison: Statistical Analysis for Dose-Proportionality of Speciogynine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.87, 1.222]
Comparison: Statistical Analysis for Dose-Proportionality of Speciociliatine Dose Adjusted Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.844, 1.178]
Secondary
Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose
AUC0-inf/D (ng\*h/mL/g) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine
Time frame: 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose
Population: Placebo subjects were not included in the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciogynine | 76.1 (ng*h/mL/g | Standard Deviation 27.5 |
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | mitragynine | 341.941 (ng*h/mL/g | Standard Deviation 131.703 |
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciociliatine | 654.9 (ng*h/mL/g | Standard Deviation 377.1 |
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | 7 hydroxy-mitragynine | 57.023 (ng*h/mL/g | Standard Deviation 21.974 |
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | paynantheine | 58.3 (ng*h/mL/g | Standard Deviation 22.6 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | mitragynine | 299.134 (ng*h/mL/g | Standard Deviation 145.479 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | paynantheine | 53.4 (ng*h/mL/g | Standard Deviation 17.5 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | 7 hydroxy-mitragynine | 46.441 (ng*h/mL/g | Standard Deviation 29.497 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciogynine | 63.4 (ng*h/mL/g | Standard Deviation 17 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciociliatine | 699.9 (ng*h/mL/g | Standard Deviation 192.9 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | paynantheine | 47.5 (ng*h/mL/g | Standard Deviation 20.2 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | mitragynine | 288.131 (ng*h/mL/g | Standard Deviation 133.599 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | 7 hydroxy-mitragynine | 54.821 (ng*h/mL/g | Standard Deviation 21.166 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciogynine | 51.6 (ng*h/mL/g | Standard Deviation 23.7 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciociliatine | 523.4 (ng*h/mL/g | Standard Deviation 195.9 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciociliatine | 890.8 (ng*h/mL/g | Standard Deviation 513 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | mitragynine | 395.044 (ng*h/mL/g | Standard Deviation 283.954 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciogynine | 95.9 (ng*h/mL/g | Standard Deviation 57.1 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | paynantheine | 81.9 (ng*h/mL/g | Standard Deviation 47.8 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | 7 hydroxy-mitragynine | 51.516 (ng*h/mL/g | Standard Deviation 28.427 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | paynantheine | 67.9 (ng*h/mL/g | Standard Deviation 38.6 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciogynine | 75.5 (ng*h/mL/g | Standard Deviation 45.4 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | mitragynine | 306.217 (ng*h/mL/g | Standard Deviation 149.248 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | speciociliatine | 667.7 (ng*h/mL/g | Standard Deviation 339.6 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-inf Calculated as AUC0-inf / Dose | 7 hydroxy-mitragynine | 49.707 (ng*h/mL/g | Standard Deviation 17.178 |
Secondary
Dose-normalized AUC0-T Calculated as AUC0-T / Dose
AUC0-T/D (ng\*h/mL/g) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine
Time frame: 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose
Population: Placebo subjects were not included in the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciogynine | 53.4 ng*h/mL/g | Standard Deviation 19.2 |
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | mitragynine | 305.383 ng*h/mL/g | Standard Deviation 115.616 |
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciociliatine | 573.9 ng*h/mL/g | Standard Deviation 285.4 |
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | 7 hydroxy-mitragynine | 53.518 ng*h/mL/g | Standard Deviation 21.615 |
| Cohort 1, 1 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | paynantheine | 47.0 ng*h/mL/g | Standard Deviation 19 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciogynine | 51.3 ng*h/mL/g | Standard Deviation 14.7 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | paynantheine | 44.3 ng*h/mL/g | Standard Deviation 14.7 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | 7 hydroxy-mitragynine | 44.331 ng*h/mL/g | Standard Deviation 28.613 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciociliatine | 637.0 ng*h/mL/g | Standard Deviation 158.5 |
| Cohort 2, 3 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | mitragynine | 261.598 ng*h/mL/g | Standard Deviation 126.763 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | paynantheine | 40.0 ng*h/mL/g | Standard Deviation 16.8 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | mitragynine | 242.776 ng*h/mL/g | Standard Deviation 92.185 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | 7 hydroxy-mitragynine | 51.575 ng*h/mL/g | Standard Deviation 19.194 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciogynine | 42.6 ng*h/mL/g | Standard Deviation 18.4 |
| Cohort 3, 8 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciociliatine | 419.9 ng*h/mL/g | Standard Deviation 157.2 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciociliatine | 790.5 ng*h/mL/g | Standard Deviation 479.1 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | mitragynine | 325.438 ng*h/mL/g | Standard Deviation 221.345 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciogynine | 81.9 ng*h/mL/g | Standard Deviation 52.2 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | paynantheine | 72.5 ng*h/mL/g | Standard Deviation 45.2 |
| Cohort 4, 10 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | 7 hydroxy-mitragynine | 45.911 ng*h/mL/g | Standard Deviation 22.631 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | paynantheine | 60.6 ng*h/mL/g | Standard Deviation 33.2 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciogynine | 65.8 ng*h/mL/g | Standard Deviation 37.8 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | mitragynine | 272.601 ng*h/mL/g | Standard Deviation 131.454 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | speciociliatine | 620.8 ng*h/mL/g | Standard Deviation 308 |
| Cohort 5, 12 g of Kratom | Dose-normalized AUC0-T Calculated as AUC0-T / Dose | 7 hydroxy-mitragynine | 47.855 ng*h/mL/g | Standard Deviation 16.232 |
Secondary
Dose-normalized Cmax Calculated at Cmax / Dose
Cmax/D (ng/mL/g) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine
Time frame: 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose
Population: Placebo subjects were not included in the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, 1 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciogynine | 6.3 ng/mL/g | Standard Deviation 1.9 |
| Cohort 1, 1 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | mitragynine | 41.664 ng/mL/g | Standard Deviation 14.766 |
| Cohort 1, 1 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciociliatine | 39.1 ng/mL/g | Standard Deviation 11.7 |
| Cohort 1, 1 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | 7 hydroxy-mitragynine | 6.728 ng/mL/g | Standard Deviation 2.182 |
| Cohort 1, 1 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | paynantheine | 7.7 ng/mL/g | Standard Deviation 2.6 |
| Cohort 2, 3 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciogynine | 5.2 ng/mL/g | Standard Deviation 1.4 |
| Cohort 2, 3 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | paynantheine | 6.3 ng/mL/g | Standard Deviation 1.7 |
| Cohort 2, 3 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | 7 hydroxy-mitragynine | 5.917 ng/mL/g | Standard Deviation 2.896 |
| Cohort 2, 3 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciociliatine | 35.5 ng/mL/g | Standard Deviation 8 |
| Cohort 2, 3 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | mitragynine | 39.334 ng/mL/g | Standard Deviation 15.605 |
| Cohort 3, 8 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | paynantheine | 3.7 ng/mL/g | Standard Deviation 1.8 |
| Cohort 3, 8 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | mitragynine | 24.687 ng/mL/g | Standard Deviation 11.042 |
| Cohort 3, 8 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | 7 hydroxy-mitragynine | 4.248 ng/mL/g | Standard Deviation 1.398 |
| Cohort 3, 8 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciogynine | 2.9 ng/mL/g | Standard Deviation 1.3 |
| Cohort 3, 8 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciociliatine | 21.1 ng/mL/g | Standard Deviation 8.5 |
| Cohort 4, 10 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciociliatine | 38.8 ng/mL/g | Standard Deviation 21.7 |
| Cohort 4, 10 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | mitragynine | 31.811 ng/mL/g | Standard Deviation 16.34 |
| Cohort 4, 10 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciogynine | 5.9 ng/mL/g | Standard Deviation 3.5 |
| Cohort 4, 10 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | paynantheine | 6.7 ng/mL/g | Standard Deviation 3.7 |
| Cohort 4, 10 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | 7 hydroxy-mitragynine | 4.839 ng/mL/g | Standard Deviation 1.999 |
| Cohort 5, 12 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | paynantheine | 5.5 ng/mL/g | Standard Deviation 2.8 |
| Cohort 5, 12 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciogynine | 4.6 ng/mL/g | Standard Deviation 2.6 |
| Cohort 5, 12 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | mitragynine | 31.542 ng/mL/g | Standard Deviation 15.415 |
| Cohort 5, 12 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | speciociliatine | 34.1 ng/mL/g | Standard Deviation 16.2 |
| Cohort 5, 12 g of Kratom | Dose-normalized Cmax Calculated at Cmax / Dose | 7 hydroxy-mitragynine | 4.867 ng/mL/g | Standard Deviation 1.893 |
Secondary
Maximum Effect for Drug Liking
Maximum (peak) effect (Emax) for Drug Liking assessed on a bipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as strong disliking (score = 0), neither like nor dislike (score = 50) to strong liking (score = 100).
Time frame: 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, 1 g of Kratom | Maximum Effect for Drug Liking | 50.7 score on a scale (VAS Emax) | Standard Error 0.67 |
| Cohort 2, 3 g of Kratom | Maximum Effect for Drug Liking | 51.7 score on a scale (VAS Emax) | Standard Error 1.67 |
| Cohort 3, 8 g of Kratom | Maximum Effect for Drug Liking | 60.2 score on a scale (VAS Emax) | Standard Error 8.17 |
| Cohort 4, 10 g of Kratom | Maximum Effect for Drug Liking | 52.2 score on a scale (VAS Emax) | Standard Error 0.98 |
| Cohort 5, 12 g of Kratom | Maximum Effect for Drug Liking | 68.7 score on a scale (VAS Emax) | Standard Error 9.22 |
| Placebo | Maximum Effect for Drug Liking | 50.2 score on a scale (VAS Emax) | Standard Error 0.13 |
95% CI: [6.16, 30.78]
Secondary
Maximum Effect for High
Maximum (peak) effect (Emax) for High assessed on an unipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as not at all (score = 0) to extremely (score = 100).
Time frame: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, 1 g of Kratom | Maximum Effect for High | 0.5 score on a scale (VAS EMax) | Standard Error 0.5 |
| Cohort 2, 3 g of Kratom | Maximum Effect for High | 1.2 score on a scale (VAS EMax) | Standard Error 1.17 |
| Cohort 3, 8 g of Kratom | Maximum Effect for High | 10.8 score on a scale (VAS EMax) | Standard Error 4.94 |
| Cohort 4, 10 g of Kratom | Maximum Effect for High | 8.5 score on a scale (VAS EMax) | Standard Error 5.33 |
| Cohort 5, 12 g of Kratom | Maximum Effect for High | 46.3 score on a scale (VAS EMax) | Standard Error 14.14 |
| Placebo | Maximum Effect for High | 0.4 score on a scale (VAS EMax) | Standard Error 0.31 |
Comparison: Statistical Analysis for High Visual Analog Scale (Emax)p-value: <0.00195% CI: [30.2, 61.67]ANOVA
Secondary
Maximum Effect for Overall Drug Liking
Maximum (peak) effect (Emax) for Overall Drug Liking assessed on a bipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as strong disliking (score = 0), neither like nor dislike (score = 50) to strong liking (score = 100).
Time frame: 12 and 24 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, 1 g of Kratom | Maximum Effect for Overall Drug Liking | 50.2 score on a scale (VAS EMax) | Standard Error 0.17 |
| Cohort 2, 3 g of Kratom | Maximum Effect for Overall Drug Liking | 50 score on a scale (VAS EMax) | Standard Error 0 |
| Cohort 3, 8 g of Kratom | Maximum Effect for Overall Drug Liking | 61.8 score on a scale (VAS EMax) | Standard Error 8.37 |
| Cohort 4, 10 g of Kratom | Maximum Effect for Overall Drug Liking | 55.7 score on a scale (VAS EMax) | Standard Error 13.22 |
| Cohort 5, 12 g of Kratom | Maximum Effect for Overall Drug Liking | 67 score on a scale (VAS EMax) | Standard Error 7.96 |
| Placebo | Maximum Effect for Overall Drug Liking | 45.1 score on a scale (VAS EMax) | Standard Error 4.9 |
Secondary
Maximum Effect for Take Drug Again
Maximum (peak) effect (Emax) for Take Drug Again assessed on a bipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as definitely would not (score = 0), neither would nor would not (score = 50) to definitely would (score = 100).
Time frame: 12 and 24 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, 1 g of Kratom | Maximum Effect for Take Drug Again | 53.3 score on a scale (VAS EMax) | Standard Error 3.14 |
| Cohort 2, 3 g of Kratom | Maximum Effect for Take Drug Again | 50.0 score on a scale (VAS EMax) | Standard Error 0 |
| Cohort 3, 8 g of Kratom | Maximum Effect for Take Drug Again | 65.2 score on a scale (VAS EMax) | Standard Error 8.04 |
| Cohort 4, 10 g of Kratom | Maximum Effect for Take Drug Again | 49.8 score on a scale (VAS EMax) | Standard Error 17.17 |
| Cohort 5, 12 g of Kratom | Maximum Effect for Take Drug Again | 61 score on a scale (VAS EMax) | Standard Error 8.57 |
| Placebo | Maximum Effect for Take Drug Again | 45.9 score on a scale (VAS EMax) | Standard Error 5.2 |
Secondary
Maximum Observed Concentration
Cmax (ng/mL) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine
Time frame: 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose
Population: Placebo subjects were not included in the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, 1 g of Kratom | Maximum Observed Concentration | Speciogynine | 6.3 ng/mL | Standard Deviation 1.9 |
| Cohort 1, 1 g of Kratom | Maximum Observed Concentration | Mitragynine | 41.664 ng/mL | Standard Deviation 14.766 |
| Cohort 1, 1 g of Kratom | Maximum Observed Concentration | Paynantheine | 7.7 ng/mL | Standard Deviation 2.6 |
| Cohort 1, 1 g of Kratom | Maximum Observed Concentration | Speciociliatine | 39.1 ng/mL | Standard Deviation 11.7 |
| Cohort 1, 1 g of Kratom | Maximum Observed Concentration | 7 hydroxy-mitragynine | 6.728 ng/mL | Standard Deviation 2.182 |
| Cohort 2, 3 g of Kratom | Maximum Observed Concentration | Speciociliatine | 106.6 ng/mL | Standard Deviation 23.9 |
| Cohort 2, 3 g of Kratom | Maximum Observed Concentration | Mitragynine | 118.002 ng/mL | Standard Deviation 46.816 |
| Cohort 2, 3 g of Kratom | Maximum Observed Concentration | 7 hydroxy-mitragynine | 17.751 ng/mL | Standard Deviation 8.687 |
| Cohort 2, 3 g of Kratom | Maximum Observed Concentration | Speciogynine | 15.8 ng/mL | Standard Deviation 4.3 |
| Cohort 2, 3 g of Kratom | Maximum Observed Concentration | Paynantheine | 19.0 ng/mL | Standard Deviation 5 |
| Cohort 3, 8 g of Kratom | Maximum Observed Concentration | Paynantheine | 29.7 ng/mL | Standard Deviation 14.6 |
| Cohort 3, 8 g of Kratom | Maximum Observed Concentration | Speciogynine | 23.2 ng/mL | Standard Deviation 10.1 |
| Cohort 3, 8 g of Kratom | Maximum Observed Concentration | Speciociliatine | 168.9 ng/mL | Standard Deviation 68.1 |
| Cohort 3, 8 g of Kratom | Maximum Observed Concentration | Mitragynine | 197.496 ng/mL | Standard Deviation 88.333 |
| Cohort 3, 8 g of Kratom | Maximum Observed Concentration | 7 hydroxy-mitragynine | 33.985 ng/mL | Standard Deviation 11.184 |
| Cohort 4, 10 g of Kratom | Maximum Observed Concentration | Mitragynine | 318.112 ng/mL | Standard Deviation 163.4 |
| Cohort 4, 10 g of Kratom | Maximum Observed Concentration | Speciociliatine | 388.1 ng/mL | Standard Deviation 217.2 |
| Cohort 4, 10 g of Kratom | Maximum Observed Concentration | Paynantheine | 66.7 ng/mL | Standard Deviation 36.6 |
| Cohort 4, 10 g of Kratom | Maximum Observed Concentration | 7 hydroxy-mitragynine | 48.388 ng/mL | Standard Deviation 19.989 |
| Cohort 4, 10 g of Kratom | Maximum Observed Concentration | Speciogynine | 58.9 ng/mL | Standard Deviation 35.5 |
| Cohort 5, 12 g of Kratom | Maximum Observed Concentration | Speciociliatine | 409.7 ng/mL | Standard Deviation 193.8 |
| Cohort 5, 12 g of Kratom | Maximum Observed Concentration | Mitragynine | 378.507 ng/mL | Standard Deviation 184.981 |
| Cohort 5, 12 g of Kratom | Maximum Observed Concentration | 7 hydroxy-mitragynine | 58.400 ng/mL | Standard Deviation 22.717 |
| Cohort 5, 12 g of Kratom | Maximum Observed Concentration | Speciogynine | 55.5 ng/mL | Standard Deviation 31 |
| Cohort 5, 12 g of Kratom | Maximum Observed Concentration | Paynantheine | 65.8 ng/mL | Standard Deviation 34.2 |
Comparison: Statistical Analysis for Dose-Proportionality of Mitragynine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.659, 0.998]
Comparison: Statistical Analysis for Dose-Proportionality of 7-Hydroxy-Mitragynine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.713, 0.973]
Comparison: Statistical Analysis for Dose-Proportionality of Paynantheine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.637, 0.984]
Comparison: Statistical Analysis for Dose-Proportionality of Speciogynine Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.633, 0.994]
Comparison: Statistical Analysis for Dose-Proportionality of Speciociliatine Dose Adjusted Pharmacokinetic Parameters (Pharmacokinetic Population)90% CI: [0.72, 1.039]
Secondary
Time of Maximum Observed Concentration
Tmax (hours) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine
Time frame: 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose
Population: Placebo subjects were not included in the PK population.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1, 1 g of Kratom | Time of Maximum Observed Concentration | speciogynine | 4.02 hours |
| Cohort 1, 1 g of Kratom | Time of Maximum Observed Concentration | mitragynine | 4.02 hours |
| Cohort 1, 1 g of Kratom | Time of Maximum Observed Concentration | speciociliatine | 4.02 hours |
| Cohort 1, 1 g of Kratom | Time of Maximum Observed Concentration | 7 hydroxy-mitragynine | 4.02 hours |
| Cohort 1, 1 g of Kratom | Time of Maximum Observed Concentration | paynantheine | 4.02 hours |
| Cohort 2, 3 g of Kratom | Time of Maximum Observed Concentration | 7 hydroxy-mitragynine | 3.50 hours |
| Cohort 2, 3 g of Kratom | Time of Maximum Observed Concentration | paynantheine | 2.99 hours |
| Cohort 2, 3 g of Kratom | Time of Maximum Observed Concentration | speciogynine | 3.00 hours |
| Cohort 2, 3 g of Kratom | Time of Maximum Observed Concentration | mitragynine | 2.99 hours |
| Cohort 2, 3 g of Kratom | Time of Maximum Observed Concentration | speciociliatine | 5.00 hours |
| Cohort 3, 8 g of Kratom | Time of Maximum Observed Concentration | 7 hydroxy-mitragynine | 6.01 hours |
| Cohort 3, 8 g of Kratom | Time of Maximum Observed Concentration | mitragynine | 5.04 hours |
| Cohort 3, 8 g of Kratom | Time of Maximum Observed Concentration | paynantheine | 5.04 hours |
| Cohort 3, 8 g of Kratom | Time of Maximum Observed Concentration | speciogynine | 5.04 hours |
| Cohort 3, 8 g of Kratom | Time of Maximum Observed Concentration | speciociliatine | 8.07 hours |
| Cohort 4, 10 g of Kratom | Time of Maximum Observed Concentration | mitragynine | 3.50 hours |
| Cohort 4, 10 g of Kratom | Time of Maximum Observed Concentration | 7 hydroxy-mitragynine | 4.00 hours |
| Cohort 4, 10 g of Kratom | Time of Maximum Observed Concentration | speciogynine | 4.00 hours |
| Cohort 4, 10 g of Kratom | Time of Maximum Observed Concentration | paynantheine | 3.00 hours |
| Cohort 4, 10 g of Kratom | Time of Maximum Observed Concentration | speciociliatine | 5.00 hours |
| Cohort 5, 12 g of Kratom | Time of Maximum Observed Concentration | paynantheine | 3.29 hours |
| Cohort 5, 12 g of Kratom | Time of Maximum Observed Concentration | mitragynine | 2.00 hours |
| Cohort 5, 12 g of Kratom | Time of Maximum Observed Concentration | speciogynine | 2.54 hours |
| Cohort 5, 12 g of Kratom | Time of Maximum Observed Concentration | speciociliatine | 5.06 hours |
| Cohort 5, 12 g of Kratom | Time of Maximum Observed Concentration | 7 hydroxy-mitragynine | 2.75 hours |