Effects of Trigonelline Monohydrate on NAD+ Metabolism, Pharmacokinetics, Safety, and Tolerability in Healthy Adults

A Randomized, Double-blind, Parallel-arm, Comparator- and Placebo-controlled Clinical Study to Evaluate the Pharmacokinetic and Pharmacodynamic Effects, Bioavailability, Safety, and Tolerability of Trigonelline Monohydrate in Healthy Adults Aged 40 to 70

This Phase 1 study is designed to evaluate the pharmacokinetic, pharmacodynamic, bioavailability, safety, and tolerability effects of trigonelline monohydrate in generally healthy adults aged 40 to 70 years. Sixty participants will be randomized in a double-blind, parallel-arm study to receive one of four doses of trigonelline monohydrate (equivalent to 150 mg, 300 mg, 450 mg, or 600 mg of trigonelline daily), an active comparator (600 mg nicotinamide mononucleotide [NMN]), or placebo for 4 weeks.

The primary objective is to assess the effect of trigonelline monohydrate supplementation on NAD+ metabolism by measuring the change from baseline in whole blood NAD+ concentrations after 4 weeks of supplementation. Secondary objectives include evaluation of trigonelline pharmacokinetics, bioavailability, plasma accumulation following repeated dosing, effects on NAD-related metabolites, and urinary excretion of trigonelline and NAD-related metabolites. Safety and tolerability will be assessed through adverse events, vital signs, anthropometric measurements, and clinical laboratory assessments. Exploratory analyses will examine inflammatory biomarkers and additional NAD-related metabolic outcomes.

Study Overview

• Status: Recruiting
• Conditions: Pharmacokinetics; Bioavailability; Healthy Adults; NAD+ Metabolism
• Intervention / Treatment: Dietary supplement: Trigonelline Monohydrate; Dietary supplement: Nicotinamide Mononucleotide (NMN); Other: Placebo

Detailed Description

Nicotinamide adenine dinucleotide (NAD+) is a vitamin B3-derived coenzyme that plays a central role in energy production, cellular metabolism, mitochondrial function, and other physiological processes. NAD+ levels decline with advancing age and this decline has been associated with metabolic dysfunction and age-related physiological changes. Trigonelline is a naturally occurring alkaloid and methylated derivative of nicotinic acid that has been identified as a potential NAD+ precursor. Preclinical and translational research suggests that trigonelline may increase NAD+ levels through the Preiss-Handler pathway. It has also been reported that trigonelline may influence mitochondrial function, muscle health, inflammation, and other metabolic processes. Human clinical data on trigonelline supplementation, however, remain limited.

This Phase 1 study will evaluate the pharmacodynamic effects, pharmacokinetics, bioavailability, safety, and tolerability of trigonelline monohydrate supplementation in generally healthy adults aged 40 to 70 years. The study will use a randomized, double-blind, parallel-arm, placebo-controlled design with an active comparator arm. A total of 60 participants will be randomized in a 1:1:1:1:1:1 ratio to receive one of four daily doses of trigonelline monohydrate (equivalent to 150 mg, 300 mg, 450 mg, or 600 mg of trigonelline daily), 600 mg nicotinamide mononucleotide (NMN; active comparator), or placebo for approximately 4 weeks.

The primary objective is to assess the effect of daily trigonelline monohydrate supplementation on NAD metabolism by evaluating the change from baseline to Week 4 in circulating whole blood NAD+ concentrations measured by liquid chromatography-mass spectrometry (LC-MS).

Secondary objectives include characterizing the bioavailability and pharmacokinetic profile of trigonelline after a single dose, assessing plasma accumulation following repeated dosing, evaluating changes in whole blood NAD-related metabolites over time, and quantifying 24-hour urinary excretion of trigonelline and NAD-related metabolites after acute and repeated dosing. Pharmacokinetic parameters include area under the plasma concentration-time curve (AUC0-24 and AUCinf), maximum plasma concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), and the AUC0-24:AUCinf ratio.

Exploratory objectives include assessment of plasma and peripheral blood mononuclear cell (PBMC) NAD-related metabolites, circulating inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-α], and interleukin-1 beta [IL-1β]), and dose-response relationships of trigonelline supplementation on NAD metabolism. Additional samples may be analyzed for gut microbiome composition, metabolomic profiles, short-chain fatty acids, microbial functional pathways, and methylation, oxidative stress, and redox-related metabolites.

Participants will attend a screening visit, a baseline/randomization visit (Day 1), a 24-hour pharmacokinetic and safety visit (Day 2), a Week 1 safety visit, and an end-of-study visit at Week 4. Safety and tolerability will be evaluated through monitoring of adverse events, vital signs, anthropometric measurements, and clinical laboratory assessments throughout the study.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Adam Kuttenkeuler; Phone Number: 519-341-3367; Email: akuttenkeuler@nutrasource.ca
• Study Contact Backup: Name: Stephanie Recker; Phone Number: 109 519-341-3367; Email: srecker@nutrasource.ca

Study Locations

• Canada
  • Ontario - on
    • Guelph, Ontario - on, Canada
      • Recruiting
      • Apex Trials
      • Principal Investigator: Anthony Bier, MD
      • Contact: Ann Anton; Phone Number: 120 519-341-3366; Email: aanton@apextrials.com
      • Contact: Chloe Gomes; Email: cgomes@apextrials.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults who are 40 to 70 years of age (inclusive) at the time of signing the informed consent.

• Are able to consume study product capsules whole without chewing.

• Have suitable veins for repeated venipuncture.

• Non-smokers (including nicotine vaping) and have not used any nicotine products (patches, gums, etc.) for > 3 months prior to Visit 2. Non-smoker is defined as someone who does not habitually/regularly use products containing nicotine and willing to abstain for 14 days before Visit 2 until the last procedure.

• In otherwise good general health, as deemed by the investigator (based on a review of medical history, vital signs, laboratory safety tests, and physical examination if performed at screening).

• Have a BMI between 18.5 to 29.9 kg/m2 (inclusive) and weigh no less than 50.0 kg.

• Have maintained consistent dietary habits, including medication and supplement intake, and lifestyle for the last 3 months before screening and agree to maintain them throughout the study (unless required per the restrictions).

• Agree to follow the restrictions on concomitant treatments.

• Agree to follow the restrictions on lifestyle.

• Agree to use acceptable contraceptive methods.

• Willing and able to agree to the requirements of this study, be willing to give voluntary consent, and carry out all study-related procedures.

• Willing and able to comply with the protocol, including:

  1. Agree to consume the standardized meals provided at the site during Visit 2
  2. Agree to fast overnight, i.e., no food or liquids except for water for a minimum 8 hours prior to applicable visits

Exclusion Criteria:

• Individuals of CBP who are pregnant, intending to breastfeed, or intending to conceive at the time of consent and during the study, or demonstrate a positive pregnancy test.
• Have a known sensitivity, intolerability, or allergy to any of the standardized meals/snacks, study products, their excipients, or to any known allergens that may be present due to potential cross-contamination during manufacturing or processing.
• Have positive screening tests for drugs or cotinine screening.
• Have positive alcohol breath test at screening.
• Have high BP (≥140 systolic or ≥90 diastolic mmHg).
• Have clinically significant abnormal vital signs that in the opinion of the investigator may be of a concern for the study or participant safety.
• Have clinically significant abnormal safety laboratory assessment values in the opinion of the investigator at screening.
• Have current symptoms, or symptoms within the past 7 days of baseline, of an acute infection (e.g., fever, respiratory symptoms such as persistent cough or difficulty breathing), that may influence study outcomes as assessed by the investigator.
• Have Type I or II diabetes, thyroid disease, or non-stable asthma or chronic obstructive pulmonary disease (COPD).
• Reports a clinically significant illness during the 28 days before the first dose of study product.
• Have 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).
• Have any history of gastrointestinal surgery or anatomical abnormality that, in the opinion of the investigator, may affect the oral absorption of the study product.
• Have current or a history of hematological disorders (e.g., sickle cell anemia or thalassemia), cerebrovascular disease, heart/cardiovascular disease (e.g., coronary artery disease, heart failure, stroke, peripheral vascular disease), renal disease (dialysis or renal failure), hepatic impairment/disease, neurological disorders (e.g., dementia or Parkinson's disease), immune disorders and/or immunocompromised (i.e., HIV/AIDS).
• Have a history of cancer (except localized skin cancer without metastases or in situ cervical cancer), unless recovery occurred more than 5 years before the screening visit.
• Are receiving treatments for or have been hospitalized in the last 12 months for psychiatric disorders (e.g., depression, bipolar disorder, schizophrenia, etc.) that may affect the participant's capability to carry out all procedures of the study at the investigator's discretion.
• Major surgery in 3 months prior to screening or planned major surgery during the study.
• Currently consumes, on average, more than 2 standard alcoholic beverages a day where one standard drink is defined as approximately as 330 mL (12 oz) of beer (~5% alcohol), 150 mL (5 oz) of wine (~12% alcohol), 40 mL (1.5 oz) of distilled spirits (e.g., vodka, whiskey, gin; ~40% alcohol).
• Have a history of alcohol or substance abuse in the 12 months prior to screening (including having been hospitalized for such in an in-patient or out-patient intervention program) or use that in the opinion of the investigator may be of a concern for the study.
• Reports a significant blood loss or blood donation totaling between 101 mL to 449 mL of blood within 30 days prior to baseline or a blood donation of more than 450 mL within 56 days prior to baseline.
• Reports donating plasma (e.g., plasmapheresis) within 15 days prior to baseline.
• Current enrolment or past participation in another study with any product(s) with at least one active ingredient within 30 days before first dose of study product or longer, if the previous test product is deemed by the investigator to have lasting effects that might influence the eligibility criteria or outcomes of current study.
• Living in the same household as another currently/previously enrolled participant in the present study.
• Any other medical condition/situation or use of medications/supplements/therapies that, in the opinion of the investigator, may adversely affect the participant's ability to participate in the study or its measures or pose a significant risk to the participant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trigonelline Monohydrate 170 mg; Participants receive 170 mg of trigonelline monohydrate (equivalent to 150 mg trigonelline) administered orally as 3 capsules once daily for approximately 4 weeks.	Dietary supplement: Trigonelline Monohydrate; Trigonelline monohydrate administered orally as 3 capsules once daily for approximately 4 weeks. Dose levels include 170 mg, 340 mg, 510 mg, and 680 mg trigonelline monohydrate, equivalent to 150 mg, 300 mg, 450 mg, and 600 mg trigonelline, respectively.
Experimental: Trigonelline Monohydrate 340 mg; Participants receive 340 mg of trigonelline monohydrate (equivalent to 300 mg trigonelline) administered orally as 3 capsules once daily for approximately 4 weeks.	Dietary supplement: Trigonelline Monohydrate; Trigonelline monohydrate administered orally as 3 capsules once daily for approximately 4 weeks. Dose levels include 170 mg, 340 mg, 510 mg, and 680 mg trigonelline monohydrate, equivalent to 150 mg, 300 mg, 450 mg, and 600 mg trigonelline, respectively.
Experimental: Trigonelline Monohydrate 510 mg; Participants receive 510 mg of trigonelline monohydrate (equivalent to 450 mg trigonelline) administered orally as 3 capsules once daily for approximately 4 weeks.	Dietary supplement: Trigonelline Monohydrate; Trigonelline monohydrate administered orally as 3 capsules once daily for approximately 4 weeks. Dose levels include 170 mg, 340 mg, 510 mg, and 680 mg trigonelline monohydrate, equivalent to 150 mg, 300 mg, 450 mg, and 600 mg trigonelline, respectively.
Experimental: Trigonelline Monohydrate 680 mg; Participants receive 680 mg of trigonelline monohydrate (equivalent to 600 mg trigonelline) administered orally as 3 capsules once daily for approximately 4 weeks.	Dietary supplement: Trigonelline Monohydrate; Trigonelline monohydrate administered orally as 3 capsules once daily for approximately 4 weeks. Dose levels include 170 mg, 340 mg, 510 mg, and 680 mg trigonelline monohydrate, equivalent to 150 mg, 300 mg, 450 mg, and 600 mg trigonelline, respectively.
Active Comparator: Nicotinamide Mononucleotide (NMN) 600 mg; Participants receive 600 mg of nicotinamide mononucleotide (NMN) administered orally as 3 capsules once daily for approximately 4 weeks.	Dietary supplement: Nicotinamide Mononucleotide (NMN); Nicotinamide mononucleotide (NMN) 600 mg/day administered orally as 3 capsules once daily for approximately 4 weeks.
Placebo Comparator: Placebo; Participants receive matching placebo capsules administered orally as 3 capsules once daily for approximately 4 weeks.	Other: Placebo; Matching placebo administered orally as 3 capsules once daily for approximately 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the effect of TP daily supplementation on NAD metabolism, as measured by NAD+ concentrations in blood compared to placebo	Circulating NAD+ levels in whole blood via liquid LC-MS	Baseline (Day 1 pre-dose [-60 min]) and Week 4 (Day 29 ±2 days, pre-dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the bioavailability and PK of single dose TP among different doses of TP and compared to a comparator and placebo	PK parameter for plasma trigonelline: AUC0-24	Over 24 hours following a single dose on Day 1 (pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose)
To determine the bioavailability and PK of single dose TP among different doses of TP and compared to a comparator and placebo	PK parameter for plasma trigonelline: Cmax	Over 24 hours following a single dose on Day 1 (pre-dose through 24 hours post-dose)
To determine the bioavailability and PK of single dose TP among different doses of TP and compared to a comparator and placebo	PK parameter for plasma trigonelline: Tmax	Over 24 hours following a single dose on Day 1 (pre-dose through 24 hours post-dose)
To determine the bioavailability and PK of single dose TP among different doses of TP and compared to a comparator and placebo	PK parameter for plasma trigonelline: T½	Over 24 hours following a single dose on Day 1 (pre-dose through 24 hours post-dose)
To determine the bioavailability and PK of single dose TP among different doses of TP and compared to a comparator and placebo	PK parameter for plasma trigonelline: AUCinf	Over 24 hours following a single dose on Day 1 (pre-dose through 24 hours post-dose)
To determine the bioavailability and PK of single dose TP among different doses of TP and compared to a comparator and placebo	PK parameter for plasma trigonelline: AUC0-24:AUCinf	Over 24 hours following a single dose on Day 1 (pre-dose through 24 hours post-dose)
To determine the potential accumulation of TP in plasma among different doses of TP and compared to a comparator and placebo after multiple-day dosing	Change in trough plasma trigonelline concentration	Baseline (Day 1 pre-dose) and Week 4 (within 24 ±60 hours of the last dose)
To evaluate the pharmacodynamic effects of the TP on NAD metabolism over time compared to a comparator and placebo	Change in whole blood NAD-related metabolites measured via LC-MS	Baseline (Day 1 pre-dose) and 4 hours post-first dose
To evaluate the pharmacodynamic effects of the TP on NAD metabolism over time compared to a comparator and placebo	Change in whole blood NAD-related metabolites measured via LC-MS	Baseline (Day 1 pre-dose) and 8 hours post-first dose
To evaluate the pharmacodynamic effects of the TP on NAD metabolism over time compared to a comparator and placebo	Change in whole blood NAD-related metabolites measured via LC-MS	Baseline (Day 1 pre-dose) and 24 hours post-first dose (Day 2)
To evaluate the pharmacodynamic effects of the TP on NAD metabolism over time compared to a comparator and placebo	Change in whole blood NAD-related metabolites measured via LC-MS	Baseline (Day 1 pre-dose) and Week 4 (Day 29 ±2 days, pre-dose)
To assess the effects of TP on 24-hour urinary excretion of trigonelline and NAD-related metabolites compared to a comparator and placebo	24-hour urinary excretion of trigonelline and NAD-related metabolites	Over 24 hours following acute dosing on Day 1 and over 24 hours following the final dose at Week 4

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the pharmacodynamic effects of the TP on NAD metabolism over time compared to a comparator and placebo	Change in plasma NAD-related metabolite levels (e.g., NAD⁺, NADH, and related metabolites) measured via LC-MS	Baseline (Day 1 pre-dose [-60 min]) and Week 4 (Day 29 ±2 days, pre-dose)
To assess the effects of TP on systemic inflammatory biomarkers compared to a comparator and placebo	Change in circulating inflammatory biomarkers, including hs-CRP, IL-6, TNF-α, and IL-1β	Baseline (Day 1 pre-dose [-60 min]) and Week 4 (Day 29 ±2 days, pre-dose)
To assess the dose-dependent effects of TP at each dose level on systemic NAD metabolism	Dose-dependent change in whole blood NAD-related metabolite levels (e.g., NAD⁺, NADH, and related metabolites)	Baseline (Day 1 pre-dose) and Week 4 (Day 29 ±2 days, pre-dose)
To assess the effect of TP daily supplementation on NAD-related metabolite levels in circulating PBMCs compared to a comparator and placebo	Change in circulating NAD-related metabolite levels (e.g., NAD⁺, NADH, and related metabolites) in PBMCs	Baseline (Day 1 pre-dose [-60 min]) and Week 4 (Day 29 ±2 days, pre-dose)
To collect vital signs to assess safety and tolerability of TP	Assess HR (bpm) for safety and tolerability of TP	Baseline through Week 4 (Day 29 ±2 days)
To collect vital signs to assess safety and tolerability of TP	Assess BP (mmHg) for safety and tolerability of TP	Baseline through Week 4 (Day 29 ±2 days)
To take anthropometric measurements to assess the safety and tolerability of TP	To assess weight (kg) for safety and tolerability of TP	Baseline through Week 4 (Day 29 ±2 days)
To take anthropometric measurements to assess the safety and tolerability of TP	To assess BMI (kg/m2) for safety and tolerability of TP	Baseline through Week 4 (Day 29 ±2 days)
To perform laboratory blood tests to assess the safety and tolerability of TP	Blood will be collected throughout the whole study to assess hematology safety laboratory parameters consisting of hemoglobin, hematocrit, white blood cell count with differentials (neutrophils, eosinophils, basophils, lymphocytes, monocytes), red blood cell count, RBC indices [Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC)], platelet count, and mean platelet volume (MPV)	Baseline through Week 4 (Day 29 ±2 days)
To perform laboratory blood tests to assess the safety and tolerability of TP	Blood will be collected throughout the whole study to assess clinical chemistry safety laboratory parameters consisting of sodium, potassium, chloride, total protein, albumin, globulin, random/fasted glucose, random/fasted insulin, blood urea nitrogen, creatinine, estimated glomerular filtration rate, ALT, AST, ALP, GGT, and total bilirubin	Baseline through Week 4 (Day 29 ±2 days)
To perform laboratory blood tests to assess the safety and tolerability of TP	Blood will be collected throughout the whole study to assess lipids safety laboratory parameters consisting of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides	Baseline through Week 4 (Day 29 ±2 days)
To review reports of adverse events to assess the safety and tolerability of TP	Monitor/review reports of adverse events to assess the safety and tolerability of TP	From informed consent through Week 4 (Day 29 ±2 days)
To assess the tolerability of TP	Tolerability will be measured by comparing the number of dropouts due to patient-reported overall side-effect burden or functional interference in the TP groups versus placebo group	From baseline through Week 4 (Day 29 ±2 days)

Collaborators and Investigators

• Sponsor: dsm-firmenich Switzerland AG
• Collaborators: Nutrasource Pharmaceutical and Nutraceutical Services, Inc.
• Investigators: Study Chair: Gabriele Civiletto, dsm-firmenich Switzerland AG

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: September 21, 2026
• First Submitted That Met QC Criteria: October 12, 2026
• First Posted (Actual): October 19, 2026

Study Record Updates

• Last Update Posted (Actual): November 5, 2026
• Last Update Submitted That Met QC Criteria: November 3, 2026
• Last Verified: November 1, 2026

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Healthy Adults; Nicotinamide Adenine Dinucleotide; Nicotinamide Mononucleotide; Trigonelline; Trigonelline Monohydrate
• Additional Relevant MeSH Terms: Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleotides; Nucleotides; Nicotinamide Mononucleotide
• Other Study ID Numbers: D01-26-01-T0097

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No