Pharmacokinetics of Kava and Kratom Alone and in Combination

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.