Effects of Feel Free® Classic Tonic on Stress and Pharmacokinetics in Healthy Adults

Change in PSS-10 score from baseline to Day 29 to assess the effect of the test product on self-perceived stress. Items are scored on a 5-point Likert scale ranging from 0 ('Never') to 4 ('Very Often'). Higher scores indicate higher perceived stress levels.

Change in STAI-S score from pre-dose to post-dose (pre-Trier Social Stress Test - Arithmetic [pre-TSST-A]) on Day 1 after a single dose. The scale assesses how participants feel "right-now". It measures subjective and temporary fluctuations in feelings associated with anxiety. Items (e.g., "I worry too much over something that really doesn't matter", "I am content") are rated on a 4-point scale, such as from "Almost Never" to "Almost Always". Higher score to be a higher anxiety.

Change in STAI-S score from pre-TSST-A to post-TSST-A at 0, 15, 25, and 55 minutes on Day 1. The scale assesses how participants feel "right-now". It measures subjective and temporary fluctuations in feelings associated with anxiety. Items (e.g., "I worry too much over something that really doesn't matter", "I am content") are rated on a 4-point scale, such as from "Almost Never" to "Almost Always". Higher score to be a worse outcome.

Change in STAI-S score from pre-dose to post-dose (pre-Trier Social Stress Test - Arithmetic [pre-TSST-A]) on Day 29 after a single dose. The scale assesses how participants feel "right-now". It measures subjective and temporary fluctuations in feelings associated with anxiety. Items (e.g., "I worry too much over something that really doesn't matter", "I am content") are rated on a 4-point scale, such as from "Almost Never" to "Almost Always". Higher score to be a worse outcome.

Change in STAI-S score from pre-TSST-A to post-TSST-A at 0, 15, 25, and 55 minutes on Day 29. The scale assesses how participants feel "right-now". It measures subjective and temporary fluctuations in feelings associated with anxiety. Items (e.g., "I worry too much over something that really doesn't matter", "I am content") are rated on a 4-point scale, such as from "Almost Never" to "Almost Always". Higher score to be a worse outcome.

Change in STAI-T score from pre-dose Day 1 to pre-dose Day 29. The scale assesses how respondents feel "generally". It measures relatively stable individual differences in anxiety proneness. Items (e.g., "I worry too much over something that really doesn't matter", "I am content") are rated on a 4-point scale, such as from "Almost Never" to "Almost Always". Higher score to be a higher anxiety.

Change in salivary cortisol (µg/dL) from pre-dose to post-dose (pre-Trier Social Stress Test - Arithmetic [pre-TSST-A]) on Day 1.

Change in alpha-amylase (U/mL) from pre-dose to post-dose (pre-Trier Social Stress Test - Arithmetic [pre-TSST-A]) on Day 1

Change in salivary cortisol (µg/dL) from pre-TSST-A to 10, 20, 30, and 60 minutes post-TSST-A

Change in salivary alpha-amylase (U/mL) from pre-TSST-A to 10, 20, 30, and 60 minutes post-TSST-A

Change in heart rate (bpm) from pre-TSST-A to 60 minutes post-TSST-A.

Change in salivary cortisol (µg/dL) from pre-dose to post-dose (pre-Trier Social Stress Test - Arithmetic [pre-TSST-A]) on Day 29.

Change in salivary alpha-amylase (U/mL) from pre-dose to post-dose (pre-Trier Social Stress Test - Arithmetic [pre-TSST-A]) on Day 29.

Change in salivary cortisol (µg/dL) from pre-TSST-A to 10, 20, 30, and 60 minutes post-TSST-A.

Change in salivary alpha-amylase (U/mL) from pre-TSST-A to 10, 20, 30, and 60 minutes post-TSST-A

Change in heart rate (bpm) from pre-TSST-A to 60 minutes post-TSST-A.

Change in morning awakening salivary cortisol over 30 minutes from baseline to Day 29.

Change in morning awakening alpha-amylase over 30 minutes from baseline to Day 29

Area under the plasma concentration (AUC) -time curve from 0 to 8 hours after a single dose.

Area under the plasma concentration (AUC)-time curve from 8 to 24 hours after a single dose.

Area under the plasma concentration (AUC) -time curve from 0 to 24 hours after a single dose.

Area under the plasma concentration (AUC) -time curve from 0 to infinity after a single dose.

Maximum observed plasma concentration (Cmax) after a single dose from 0 to 24 hours.

Time to reach maximum observed plasma concentration (Tmax) after a single dose from 0 to 24 hours.

Terminal elimination half-life after a single dose from 0 to 24 hours.

Terminal elimination rate constant after a single dose from 0 to 24 hours.

Area under the plasma concentration (AUC) -time curve from 0 to 8 hours after a single dose.

Area under the plasma concentration (AUC) -time curve from 8 to 24 hours after a single dose.

Area under the plasma concentration (AUC) -time curve from 0 to 24 hours after a single dose.

Area under the plasma concentration (AUC) -time curve from 0 to infinity after a single dose.

Maximum observed plasma concentration (Cmax) after a single dose from 0 to 24 hours.

Time to reach maximum observed plasma concentration (Tmax) after a single dose from 0 to 24 hours.

Terminal elimination half-life after a single dose from 0 to 24 hours.

Terminal elimination rate constant after a single dose from 0 to 24 hours.

Area under the plasma concentration (AUC) -time curve from 0 to 8 hours after a single dose.

Area under the plasma concentration (AUC) -time curve from 8 to 24 hours after a single dose.

Area under the plasma concentration (AUC) -time curve from 0 to 24 hours after a single dose.

Area under the plasma concentration (AUC) -time curve from 0 to infinity after a single dose.

Maximum observed plasma concentration (Cmax) after a single dose from 0 to 24 hours.

Time to reach maximum observed plasma concentration (Tmax) after a single dose from 0 to 24 hours.

Terminal elimination half-life after a single dose from 0 to 24 hours.

Terminal elimination rate constant after a single dose from 0 to 24 hours.

Area under the plasma concentration (AUC) - time curve from 0 to 8 hours after a single dose.

Area under the plasma concentration (AUC) - time curve from 8 to 24 hours after a single dose.

Area under the plasma concentration (AUC) - time curve from 0 to 24 hours after a single dose.

Area under the plasma concentration (AUC) - time curve from 0 to infinity after a single dose.

Maximum observed plasma concentration (Cmax) after a single dose from 0 to 24 hours.

Time to reach maximum observed plasma concentration (Tmax) after a single dose from 0 to 24 hours.

Terminal elimination half-life after a single dose from 0 to 24 hours.

Terminal elimination rate constant after a single dose from 0 to 24 hours.

Area under the plasma concentration (AUC)- time curve from 0 to 8 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 8 to 24 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to 24 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to infinity at steady state after multiple-day dosing.

Maximum observed plasma concentration (Cmax) at steady state after multiple-day dosing.

Time to reach maximum observed plasma concentration (Tmax) at steady state.

Terminal elimination half-life at steady state after multiple-day dosing.

Terminal elimination rate constant at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to 8 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 8 to 24 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to 24 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to infinity at steady state after multiple-day dosing.

Maximum observed plasma concentration (Cmax) at steady state after multiple-day dosing.

Time to reach maximum observed plasma concentration (Tmax) at steady state.

Terminal elimination half-life at steady state after multiple-day dosing.

Terminal elimination rate constant at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to 8 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 8 to 24 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to 24 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to infinity at steady state after multiple-day dosing.

Maximum observed plasma concentration (Cmax) at steady state after multiple-day dosing.

Time to reach maximum observed plasma concentration (Tmax) at steady state.

Terminal elimination half-life at steady state after multiple-day dosing.

Terminal elimination rate constant at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to 8 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 8 to 24 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to 24 hours at steady state after multiple-day dosing.

Area under the plasma concentration (AUC)- time curve from 0 to infinity at steady state after multiple-day dosing.

Maximum observed plasma concentration (Cmax) at steady state after multiple-day dosing.

Time to reach maximum observed plasma concentration (Tmax) at steady state.

Terminal elimination half-life at steady state after multiple-day dosing.

Terminal elimination rate constant at steady state after multiple-day dosing.

To measure trough plasma concentrations of kratom alkaloids and kavalactones during repeated twice-daily dosing, using pre-dose blood samples collected on alternate days over the first 14 days of study product use. This evaluates concentration buildup prior to steady-state attainment.

Difference between between single-dose maximum observed plasma concentration (Cmax) on Day 1 and and steady-state Cmax at Day 29 to evaluate systemic accumulation.

Difference between single-dose area under the plasma concentration (AUC0-8) (Day 1) and steady-state AUC0-8 (Day 29) to assess accumulation over the first 8 hours.

Difference between single-dose area under the plasma concentration (AUC0-24) (Day 1 and Day 2) and steady-state AUC0-24 (Day 29 and Day 30) to assess the 24-hour exposure accumulation.

Perception of the task survey at completion of TSST-A on Days 1 and 29. This non-validated questionnaire consists of 4 questions scored from 0 to 100, that assesses the participants feeling of the TSST-A task. Higher scores indicate higher feelings of difficulty and stress.

To assess the effect of TP on subjective drug effects compared to placebo. This non-validated questionnaire consists of 4 questions scored from 0 to 100, that assesses the participants subjective experience after consuming the TP.

To assess the effect of TP on overall well-being, health, and pain compared to placebo. This non-validated questionnaire consists of 4 questions scored from 0 to 100, that assesses overall quality of life with questions specifically on physical health and pain. Higher scores indicate better overall well-being, health, and pain.

To assess the effect of TP on the severity of dependence compared to placebo. A non-validated questionnaire consisting of 3 questions assessing how dependent participants feel when taking TP. Questions are scored on a 5-point Likert scale, ranging from 0 ("Never") to 4 ("Very Often"). Higher scores indicate higher feelings of dependence.

To assess the effect of TP on mood compared to placebo. A non-validated questionnaire consisting of 13 questions assessing the participants emotional and mental/physical states they are feeling "right now." This questionnaire uses bipolar visual analogue scales in which participants how they feel "right now" on lines between two opposite feelings or physical sensations.

To assess the effect of TP on study product perceptions and attitudes compared to placebo. A non-validated questionnaire consisting of multiple items assessing participants' subjective experiences with the study product, including effects on daily functioning, energy, sleep, mood, stress/anxiety, focus, pain, muscle recovery, tolerability, and product quality. Items are scored on a 5-point Likert scale ranging from "Strongly Disagree" to "Strongly Agree." Higher scores indicate more favorable perceptions of the study product (except for the side-effects item, where higher scores indicate greater perceived side effects).

To assess participant-reported perceptions of the effects of the study product compared to placebo. A non-validated, self-administered questionnaire consisting of multiple items assessing participants' subjective experiences with the study product, including overall effect on how they feel, liking of the product, pain, muscle fatigue, mental focus/concentration, and calmness/stress. Items are scored using a 100-point visual analogue scale ranging from "Not at all" (0) to "Extremely" (100). Higher scores indicate greater perceived effects of the study product.

Number and percentage of participants experiencing treatment-emergent adverse events from first dose through follow-up.

Change in Heart Rate (beats per minute) from baseline to each study visit.

Change in Blood Pressure (mmHg) from baseline to each study visit.

Change in Respiratory Rate (breaths per minute) from baseline to each study visit.

Change in Oxygen Saturation (SpO₂ %) from baseline to each study visit.

To assess the safety of TP through the change from baseline to each study visit in hemoglobin (g/L).

To assess the safety of TP through the change from baseline to each study visit in hematocrit (%).

To assess the safety of TP through the change from baseline to each study visit in red blood cell count (×10E^12/L).

To assess the safety of TP through the change from baseline to each study visit in red cell distribution width.

To assess the safety of TP through the change from baseline to each study visit in mean corpuscular volume (fL).

To assess the safety of TP through the change from baseline to each study visit in mean corpuscular hemoglobin (pg).

To assess the safety of TP through the change from baseline to each study visit in mean corpuscular hemoglobin concentration (g/L).

To assess the safety of TP through the change from baseline to each study visit in white blood cell count (×10^9/L).

To assess the safety of TP through the change from baseline to each study visit in Neutrophil Count (×10^9/L).

To assess the safety of TP through the change from baseline to each study visit in eosinophil count (×10^9/L).

To assess the safety of TP through the change from baseline to each study visit in basophil count (x 10^9/L).

To assess the safety of TP through the change from baseline to each study visit in lymphocyte count (×10^9/L).

To assess the safety of TP through the change from baseline to each study visit in hemoglobin (×10^9/L).

To assess the safety of TP through the change from baseline to each study visit in platelet count (×10^9/µL).

To assess the safety of TP through the change from baseline to each study visit in mean platelet volume (fL).

To assess the safety of TP through the change from baseline to each study visit in blood smear findings.

To assess the safety of TP through the change from baseline to each study visit in blood urea nitrogen (mmol/L).

To assess the safety of TP through the change from baseline to each study visit in creatinine (umol/L).

To assess the safety of TP through the change from baseline to each study visit in estimated glomerular filtration rate (ml/min/1.7m^2).

To assess the safety of TP through the change from baseline to each study visit in albumin (g/L).

To assess the safety of TP through the change from baseline to each study visit in random glucose (mmol/L).

To assess the safety of TP through the change from baseline to each study visit in fasting glucose (mmol/L).

To assess the safety of TP through the change from baseline to each study visit in total protein (g/L).

To assess the safety of TP through the change from baseline to each study visit in Sodium (mmol/L).

To assess the safety of TP through the change from baseline to each study visit in Potassium (mmol/L).

To assess the safety of TP through the change from baseline to each study visit in Chloride (mmol/L).

To assess the safety of TP through the change from baseline to each study visit in Aspartate Transaminase (AST) in U/L.

To assess the safety of TP through the change from baseline to each study visit in Alanine Transaminase (ALT) in U/L.

To assess the safety of TP through the change from baseline to each study visit in Gamma-Glutamyl Transferase (GGT) in U/L.

To assess the safety of TP through the change from baseline to each study visit in Total Bilirubin in µmol/L.

To assess the safety of TP through the change from baseline to each study visit in Direct Bilirubin in µmol/L.

To assess the safety of TP through the change from baseline to each study visit in Total Bile Acids in µmol/L.

To assess the safety of TP through the change from baseline to each study visit in Alkaline Phosphatase (ALP) in U/L.

To assess the safety of TP through the change from baseline to each study visit in Prothrombin Time (PT) in seconds.

To assess the safety of TP through the change from baseline to each study visit in International Normalized Ratio (INR).

To assess the safety of TP through the change from baseline to each study visit in Thyroid-Stimulating Hormone (TSH) in mIU/L.

To assess the safety of TP through the change from baseline to each study visit in Triiodothyronine (T3) in nmol/L.

To assess the safety of TP through the change from baseline to each study visit in Thyroxine (T4) in ug/dL.

To assess the safety of TP through the change from baseline to each study visit in Total Cholesterol in mmol/L.

To assess the safety of TP through the change from baseline to each study visit in high-density lipoprotein (HDL) cholesterol in mmol/L.

To assess the safety of TP through the change from baseline to each study visit in low-density lipoprotein (LDL) cholesterol in mmol/L.

To assess the safety of TP through the change from baseline to each study visit in HDL:LDL Ratio.

To assess the safety of TP through the change from baseline to each study visit in Triglycerides in mmol/L.

To test the safety of TP by assessing the change in SOWS. This validated questionnaire is used to assess participants intensity of potential opioid withdrawal symptoms. Items are scored on a 5-point Likert scale ranging from 0 ('Not at all') to 4 ('Extremely'). Higher scores indicate higher potential withdrawal symptoms.

To test the safety of TP by assessing the change in COWS. This validated questionnaire is used to assess common signs and symptoms of opiate withdrawal. Items are scored from 0 to 48. Higher scores indicate higher withdrawal symptoms.