Herb-Herb Interaction, Pharmacokinetics
Conditions
Keywords
Kava, Kratom, Pharmacokinetics, Healthy Adults, Herbal Supplement
Brief summary
This study is being conducted to evaluate how different formulations of the Feel Free® Tonic containing Kava, Kratom, or a combination of both are processed in the body in healthy adults. The goal is to compare the pharmacokinetic profiles and safety of the combined herbal formulation with Kava alone and Kratom alone to better understand how these ingredients behave when taken individually versus together.
Detailed description
This is a randomized, double blind, 3 period crossover pharmacokinetic study in healthy adults designed to compare the pharmacokinetic profiles of a combined Kava and Kratom formulation with Kava alone and Kratom alone under fasted conditions. The primary objective is to evaluate systemic exposure and key pharmacokinetic parameters following each treatment. Secondary objectives include the assessment of safety and tolerability across all study products. The investigational products are oral liquid herbal supplements containing Kava, Kratom, or a combination of both. The study will also explore subjective effects, well-being, mood, and participant perceptions of the study products. Each participant will receive all three treatments in a randomized sequence with washout periods between dosing, allowing within subject comparison of pharmacokinetic outcomes.
Interventions
DIETARY_SUPPLEMENTKava and Kratom Herbal Supplement
Half- Strength Feel Free Classic Tonic (TP1)
DIETARY_SUPPLEMENTKava Herbal Supplement
Kava Only Variant - Feel Free Tonic (TP2)
DIETARY_SUPPLEMENTKratom Herbal Supplement
Kratom Only Variant - Feel Free Tonic (TP3)
Sponsors
Botanic Tonics, LLC
Nutrasource Pharmaceutical and Nutraceutical Services, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Adults who are between 21 - 55 years of age (inclusive) at the time of signing the informed consent. 2. In otherwise good general health, as deemed by the investigator (based on review of medical history, vital signs, laboratory safety tests, and physical examination performed at screening and/or before the first dose of study product). 3. Are able to consume the study product completely within the specified timeframe. 4. Not currently using, defined as ≤ 3 uses in the past 3 months prior to Visit 2, any nicotine-containing products (patches, gums, vapes, etc.), kava products, and/or kratom products, and willing to abstain starting 14 days prior to Visit 2 and throughout the study. 5. Have a BMI range of 18.5 - 29.9 kg/m2 at screening and Visit 2. 6. Agree to follow the restrictions on concomitant treatments. 7. Agree to follow the restrictions on lifestyle. 8. Have maintained consistent dietary habits, including supplement intake, and lifestyle for the last 3 months before screening and agree to maintain them throughout the study (unless required per the restrictions) 9. Individuals with childbearing potential must agree to comply with the following requirements: * Have a negative pregnancy test at screening and on Day 1 of each treatment period prior to administration of study product. * Use a highly effective method of contraception from at least 14 days prior to the first dose through 30 days after the last dose of study product. 10. Individuals with the potential to impregnate others must agree to use a highly effective method of contraception, from at least 14 days prior to the first dose through 30 days after the last dose of study product. 11. Male-born participants must agree to abstain from sperm donation, and female-born participants must agree to abstain from ovum donation, from Screening through at least 30 days after the last dose of study product. 12. Agree to abstain from alcohol consumption for 48 hours prior to, and for the entire duration of, each treatment period. 13. Willing and able to agree to the requirements and restrictions of this study, be willing to give voluntary consent, be able to understand and read the questionnaires, and carry out all study-related procedures. 14. Must have suitable veins for repeated venipuncture. 15. Willing and able to attend video conference calls with study coordinators. 16. Agrees not to donate blood until 3 months after study completion.
Exclusion criteria
1. Individuals who are lactating, planning to become pregnant during the study, or pregnant as confirmed by a positive pregnancy test during study visits. 2. Have a known sensitivity, intolerability, or allergy to any of the study products, their excipients, or rescue medication. 3. Demonstrates a positive urine drug screen test for compounds listed in Table 8 4 at the Screening Visit or Visit 2, a positive urine cotinine test at the Screening Visit or Visit 2, or a positive breath alcohol test at Screening Visit or Visit 2. 4. Have abnormal respiratory rate (RR) or SpO2 measurements at Screening or Baseline at the discretion of the investigator. 5. Screening laboratory results showing liver enzyme levels \[Alanine Transaminase (ALT), Aspartate Transaminase (AST), Alkaline Phosphatase (ALP), Gamma-Glutamyl Transferase (GGT), total bilirubin\] ≥ 2 times the upper limit of normal (ULN), or any other clinically significant abnormal safety laboratory values as per the Investigator's discretion. 6. Have hemoglobin below 135 g/L for males or 125 g/L for females, or hematocrit below 0.39 l/l for males or 0.33 l/l for females at screening. 7. Demonstrates a positive screen for HIV at screening. 8. Is currently enrolled in another clinical trial or has received/used an investigational product in another research study within 28 days before Visit 2. 9. Individuals with any abnormality, obstruction, or disorder of the gastrointestinal tract that may preclude swallowing (e.g., dysphagia) or impair gastrointestinal motility, digestion, or absorption (e.g., known intestinal malabsorption, celiac disease, inflammatory bowel disease \[including Crohn's disease or ulcerative colitis\], chronic pancreatitis, or steatorrhea). In addition, any history of gastrointestinal surgery or anatomical abnormality that, in the opinion of the Investigator, may affect the oral absorption of the study product. 10. Have been diagnosed with Type I/Type II diabetes or thyroid disease 11. High BP at the Screening Visit or Visit 2 (≥140 systolic or ≥90 diastolic mmHg) 12. Have low BP (\<90 systolic or \<60 diastolic mmHg) at Baseline unless deemed clinically insignificant by the investigator and the participant is asymptomatic. 13. Have a history of heart disease, blood-clotting disorders, renal or hepatic impairment/disease, liver injury or any clinically significant liver or kidney disorder, as determined by the Investigator. 14. Have known genetic polymorphisms of CYP450 enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2B6, and/or CYP3A4. 15. Individuals with active asthma or a history of clinically significant asthma exacerbation (i.e., requiring systemic corticosteroids, emergency department intervention, or hospitalization) within the past 12 months. 16. Individuals receiving treatment for, or who have been hospitalized in the last 12 months for, psychiatric disorders (e.g., Major Depressive Disorder, Bipolar I/II, Generalized Anxiety Disorder, Schizophrenia, or other psychotic disorders), particularly when the diagnosis is established using accepted gold-standard diagnostic methods (e.g., structured clinical interviews), or with complications such as suicidal ideation or behavior. 17. Have current use of medications, including psychiatric pharmacotherapy, that are predominantly metabolized via CYP enzymes (e.g., CYP3A4, CYP2D6, CYP1A2) and/or have CNS depressant or opioid-like effects, or act on central receptors such as μ- and δ-opioid, serotonergic 5-HT2A, post-synaptic alpha-2 adrenergic, or GABA receptors, where such treatment may create clinically significant pharmacokinetic or pharmacodynamic interactions with study treatments, including antidepressants, antipsychotics, mood stabilizers, anxiolytics, or benzodiazepines. 18. Have a history of cancer with recovery occurring within 5 years prior to the Screening visit, except for localized skin cancer without metastases (e.g., completely excised basal cell carcinoma or squamous cell carcinoma of the skin) or in situ cervical cancer (e.g., adequately treated carcinoma in situ of the cervix). 19. Reports significant blood loss or blood donation totalling between 101 mL to 449 mL of blood within 30 days before baseline or a blood donation of more than 450 mL within 90 days before Visit 2. 20. Reports donating plasma (e.g., plasmapheresis) within 15 days before Visit 2. 21. Major surgery in 3 months before screening or planned major surgery during the study. 22. History of alcohol or substance abuse (e.g., opioids, kratom) (including having been hospitalized for such an in-patient or out-patient intervention program). 23. Evidence of addictive tendency as indicated by an LDQ score ≥21. 24. Use of anxiolytic or sleep aids (natural health products or drugs) in the 4 weeks before Visit 2. 25. Currently consumes more than two (2) standard alcoholic beverages per day on average for 4 weeks. Note: A standard alcoholic beverage is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of liquor. 26. Excessive caffeine intake, defined as habitual consumption of \>500 mg per day. 27. Any other medical conditions, including active infections, or use of medications/supplements/therapies that, in the opinion of the investigator, may adversely affect the participant's ability to complete the study or its measures, pose a significant risk to the participant or compromise the quality of study data.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) for Kavain | Day 1 and Day 2 of each treatment period (0-24 hours post-dose) | AUC0-24 for kavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) for Dihydrokavain | Day 1 and Day 2 of each treatment period (0-24 hours post-dose) | AUC0-24 for dihydrokavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) for Mitragynine | Day 1 and Day 2 of each treatment period (0-24 hours post-dose) | AUC0-24 for mitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) for 7-Hydroxymitragynine | Day 1 and Day 2 of each treatment period (0-24 hours post-dose) | AUC0-24 for 7-Hydroxymitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72) for Kavain | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | AUC0-72 for kavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Maximum Observed Plasma Concentration (Cmax) for Kavain | Day 1 of each treatment period (0-12 hours post-dose) | Peak plasma concentration of kavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Time to Maximum Plasma Concentration (Tmax) for Kavain | Day 1 and Day 2 of each treatment period (0-24 hours post-dose) | Time to reach maximum observed plasma concentration of kavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Terminal Elimination Half-Life (T½) for Kavain | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | Terminal elimination half-life of kavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72) for Dihydrokavain | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | AUC0-72 for dihydrokavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Maximum Observed Plasma Concentration (Cmax) for Dihydrokavain | Day 1 of each treatment period (0-12 hours post-dose) | Peak plasma concentration of dihydrokavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Time to Maximum Plasma Concentration (Tmax) for Dihydrokavain | Day 1 and Day 2 of each treatment period (0-24 hours post-dose) | Time to reach maximum observed plasma concentration of dihydrokavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Terminal Elimination Half-Life (T½) for Dihydrokavain | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | Terminal elimination half-life of dihydrokavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72) for Mitragynine | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | AUC0-72 for mitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Maximum Observed Plasma Concentration (Cmax) for Mitragynine | Day 1 of each treatment period (0-12 hours post-dose) | Peak plasma concentration of mitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Time to Maximum Plasma Concentration (Tmax) for Mitragynine | Day 1 and Day 2 of each treatment period (0-24 hours post-dose) | Time to reach maximum observed plasma concentration of mitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Terminal Elimination Half-Life (T½) for Mitragynine | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | Terminal elimination half-life of mitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours (AUC0-72) for 7-Hydroxymitragynine | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | AUC0-72 for 7-Hydroxymitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Maximum Observed Plasma Concentration (Cmax) for 7-Hydroxymitragynine | Day 1 of each treatment period (0-12 hours post-dose) | Peak plasma concentration of 7-Hydroxymitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Time to Maximum Plasma Concentration (Tmax) for 7-Hydroxymitragynine | Day 1 and Day 2 of each treatment period (0-24 hours post-dose) | Time to reach maximum observed plasma concentration of 7-Hydroxymitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Terminal Elimination Half-Life (T½) for 7-Hydroxymitragynine | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | Terminal elimination half-life of 7-Hydroxymitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Area under the plasma concentration time curve extrapolated to infinity (AUC0-∞) for Kavain | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | AUC0-∞ for kavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Ratio of area under the plasma concentration from 0 to 24 Hours (AUC0-24) to area under the plasma concentration time curve extrapolated to infinity (AUC0-∞) for Kavain | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | Ratio of exposure from 0-24 hours relative to total exposure for kavain. |
| Area under the plasma concentration time curve extrapolated to infinity (AUC0-∞) for Dihydrokavain | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | AUC0-∞ for Dihydrokavain following single-dose administration of Kava alone or combined Kava and Kratom |
| Ratio of area under the plasma concentration from 0 to 24 Hours (AUC0-24) to area under the plasma concentration time curve extrapolated to infinity (AUC0-∞) for Dihydrokavain | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | Ratio of exposure from 0-24 hours relative to total exposure for Dihydrokavain. |
| Area under the plasma concentration time curve extrapolated to infinity (AUC0-∞) for Mitragynine. | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | AUC0-∞ for mitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Ratio of area under the plasma concentration from 0 to 24 Hours (AUC0-24) to area under the plasma concentration time curve extrapolated to infinity (AUC0-∞) for Mitragynine | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | Ratio of exposure from 0-24 hours relative to total exposure for mitragynine. |
| Area under the plasma concentration time curve extrapolated to infinity (AUC0-∞) for 7-Hydroxymitragynine. | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | AUC0-∞ for 7-Hydroxymitragynine following single-dose administration of Kratom alone or combined Kava and Kratom |
| Ratio of area under the plasma concentration from 0 to 24 Hours (AUC0-24) to area under the plasma concentration time curve extrapolated to infinity (AUC0-∞) for 7-Hydroxymitragynine | Day 1 to Day 4 of each treatment period (0-72 hours post-dose) | Ratio of exposure from 0-24 hours relative to total exposure for 7-Hydroxymitragynine. |
| Area under the curve at steady state from 0 to 12 hours (AUC0-12,ss) for Kavain | Day 14 of each treatment period | AUC0-12,ss for Kavain following a multiple-day dosing of Kava alone or combined Kava and Kratom |
| Maximum Observed Plasma Concentration at steady state (Cmax,ss) for Kavain | Day 14 of each treatment period | Cmax,ss for kavain following a multiple-day dosing of Kava alone or combined Kava and Kratom |
| Time to Maximum Plasma Concentration at Steady State (Tmax,ss) for Kavain | Day 14 of each treatment period | Tmax,ss of kavain following a multiple-day dosing of Kava alone or combined Kava and Kratom |
| Terminal Elimination Half-Life at Steady State (T½,ss) for Kavain | Day 14 of each treatment period | T½,ss for kavain following a multiple-day dosing of Kava alone or combined Kava and Kratom |
| Area under the plasma concentration time curve extrapolated to infinity at steady state (AUC0-∞) for Kavain | Day 14 of each treatment period | AUC0-∞,ss for kavain following multiple-day dosing administration of Kava alone or combined Kava and Kratom |
| Ratio of area under the plasma concentration at steady state from 0 to 12 Hours (AUC0-12,ss) to area under the plasma concentration time curve extrapolated to infinity at steady state (AUC0-∞,ss) for Kavain | Day 14 of each treatment period | Ratio of exposure from 0-12 hours relative to total exposure at steady state for kavain. |
| Area under the curve at steady state from 0 to 12 hours (AUC0-12,ss) for Dihydrokavain | Day 14 of each treatment period | AUC0-12,ss for dihydrokavain following a multiple-day dosing of Kava alone or combined Kava and Kratom |
| Maximum Observed Plasma Concentration at steady state (Cmax,ss) for Dihydrokavain | Day 14 of each treatment period | Cmax,ss for dyhydrokavain following a multiple-day dosing of Kava alone or combined Kava and Kratom |
| Time to Maximum Plasma Concentration at Steady State (Tmax,ss) for Dihydrokavain | Day 14 of each treatment period | Tmax,ss of dihydrokavain following a multiple-day dosing of Kava alone or combined Kava and Kratom |
| Terminal Elimination Half-Life at Steady State (T½,ss) for Dihydrokavain | Day 14 of each treatment period | T½,ss for dihydrokavain following a multiple-day dosing of Kava alone or combined Kava and Kratom |
| Area under the plasma concentration time curve extrapolated to infinity at steady state (AUC0-∞) for Dihydrokavain | Day 14 of each treatment period | AUC0-∞,ss for dihydrokavain following multiple-day dosing administration of Kava alone or combined Kava and Kratom |
| Ratio of area under the plasma concentration at steady state from 0 to 12 Hours (AUC0-12,ss) to area under the plasma concentration time curve extrapolated to infinity at steady state (AUC0-∞,ss) for Dihydrokavain | Day 14 of each treatment period | Ratio of exposure from 0-12 hours relative to total exposure at steady state for dihydrokavain. |
| Area under the curve at steady state from 0 to 12 hours (AUC0-12,ss) for Mitragynine | Day 14 of each treatment period | AUC0-12,ss for mitragynine following a multiple-day dosing of Kratom alone or combined Kava and Kratom |
| Maximum Observed Plasma Concentration at steady state (Cmax,ss) for Mitragynine | Day 14 of each treatment period | Cmax,ss for mitragynine following a multiple-day dosing of Kratom alone or combined Kava and Kratom |
| Time to Maximum Plasma Concentration at Steady State (Tmax,ss) for Mitragynine | Day 14 of each treatment period | Tmax,ss for mitragynine following a multiple-day dosing of Kratom alone or combined Kava and Kratom |
| Terminal Elimination Half-Life at Steady State (T½,ss) for Mitragynine | Day 14 of each treatment period | T½,ss for mitragynine following a multiple-day dosing of Kratom alone or combined Kava and Kratom |
| Area under the plasma concentration time curve extrapolated to infinity at steady state (AUC0-∞) for Mitragynine | Day 14 of each treatment period | AUC0-∞,ss for mitragynine following multiple-day dosing administration of Kratom alone or combined Kava and Kratom |
| Ratio of area under the plasma concentration at steady state from 0 to 12 Hours (AUC0-12,ss) to area under the plasma concentration time curve extrapolated to infinity at steady state (AUC0-∞,ss) for Mitragynine | Day 14 of each treatment period | Ratio of exposure from 0-12 hours relative to total exposure at steady state for mitragynine. |
| Area under the curve at steady state from 0 to 12 hours (AUC0-12,ss) for 7-Hydroxymitragynine | Day 14 of each treatment period | AUC0-12,ss for 7-Hydroxymitragynine following a multiple-day dosing of Kratom alone or combined Kava and Kratom |
| Maximum Observed Plasma Concentration at steady state (Cmax,ss) for 7-Hydroxymitragynine | Day 14 of each treatment period | Cmax,ss for 7-Hydroxymitragynine following a multiple-day dosing of Kratom alone or combined Kava and Kratom |
| Time to Maximum Plasma Concentration at Steady State (Tmax,ss) for 7-Hydroxymitragynine | Day 14 of each treatment period | Tmax,ss for 7-Hydroxymitragynine following a multiple-day dosing of Kratom alone or combined Kava and Kratom |
| Terminal Elimination Half-Life at Steady State (T½,ss) for 7-Hydroxymitragynine | Day 14 of each treatment period | T½,ss for 7-Hydroxymitragynine following a multiple-day dosing of Kratom alone or combined Kava and Kratom |
| Area under the plasma concentration time curve extrapolated to infinity at steady state (AUC0-∞) for 7-Hydroxymitragynine | Day 14 of each treatment period | AUC0-∞,ss for 7-Hydroxymitragynine following multiple-day dosing administration of Kratom alone or combined Kava and Kratom |
| Ratio of area under the plasma concentration at steady state from 0 to 12 Hours (AUC0-12,ss) to area under the plasma concentration time curve extrapolated to infinity at steady state (AUC0-∞,ss) for 7-Hydroxymitragynine | Day 14 of each treatment period | Ratio of exposure from 0-12 hours relative to total exposure at steady state for 7-Hydroxymitragynine. |
Countries
Canada
Contacts
STUDY_DIRECTORRamsey Atallah
Botanic Tonics
Outcome results
None listed