Pharmacokinetics and Pharmacodynamics of Synthetic Nicotine and Nicotine Analogues

Electronic cigarettes are battery-operated devices that can produce an aerosol by heating a liquid which commonly contains nicotine. In recent years, products containing synthetically produced nicotine and nicotine analogues have entered the market. However, it remains unclear whether these types of nicotine have the same effects as conventional nicotine derived from the tobacco plant. The aim of this study is to investigate the effects of these nicotine types and to gain a better understanding of their respective mechanisms of action.

Study Overview

• Status: Not yet recruiting
• Conditions: Nicotine; Vaping; Synthetic Nicotine; Nicotine Analogues
• Intervention / Treatment: Other: Vaping of synthetic S-nicotine; Other: Vaping of racemic nicotine (S-/R-nicotine); Other: Vaping of 6-methylnicotine

Detailed Description

In the first part of the study, participants will use electronic cigarettes containing synthetic nicotine or nicotine analogs at three sessions in the hospital, following a specific schedule. In the second part, each product will be used for four days outside the hospital. The study is double-blind, meaning neither the participants nor the study team will know which product is being used.

The study comprises a total of seven appointments at the hospital. During these appointments, participants will be asked questions about their electronic cigarette and tobacco use, and samples of saliva, urine, and blood will be collected.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Evangelia Liakoni, Prof.; Phone Number: +41 31 632 54 61; Email: evangelia.liakoni@insel.ch

Study Locations

• Switzerland
  • Bern, Switzerland
    • Inselspital
    • Contact: Evangelia Liakoni, Prof.; Phone Number: +41 31 632 54 61; Email: evangelia.liakoni@insel.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Men or women, age 18 or older at screening who have used EC with nicotine during at least 10 of the past 30 days
• Saliva cotinine concentration of > 30 ng/mL at screening
• Ability to communicate well with the investigator and to understand and comply with the requirements of the study
• Women of child-bearing age engaging in sexual activities which can lead to pregnancy: willingness of using a reliable/hormonal contraception method during the study (hormonal, e.g. pill, intrauterine devices, or mechanical method, e.g. condom, diaphragm)
• Signed informed consent form

Exclusion Criteria:

• Known hypersensitivity/allergy to a content of the e-liquids
• Smoking of more than 5 cigarettes per day in the past 30 days
• Pregnant or lactating women
• Intention to become pregnant during the course of the study
• BMI < 18 or > 30 kg/m2 at screening
• History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening
• Loss of ≥ 250 mL of blood within 3 months prior to screening, including blood donation
• Treatment with an investigational drug within 30 days prior to screening
• Treatment with prescribed or over-the-counter medications with known influence on CYP2A6 function within 1 week prior to screening (with the exception of contraception)
• History or clinical evidence of any disease (e.g. gastrointestinal tract-disease) and/or existence of any surgical or medical condition, which in the opinion of the investigator might interfere with the absorption, distribution, metabolism or excretion of the study drugs, or which might increase the risk of toxicity.
• Legal incapacity or limited legal capacity at screening
• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Synthetic S-Nicotine; Vaping of e-liquids contanining synthetic S-nicotine	Other: Vaping of synthetic S-nicotine; Vaping of e-liquids containing synthetic S-nicotine
Other: Racemic nicotine (S-/R-nicotine); Vaping of e-liquids contanining synthetic racemic nicotine (containing both the S- and R-nicotine enantiomers)	Other: Vaping of racemic nicotine (S-/R-nicotine); Vaping of e-liquids containing synthetic racemic nicotine (S-/R-nicotine)
Other: 6-methylnicotine; Vaping of e-liquids contanining the nicotine analogue 6-methylnicotine (6MN)	Other: Vaping of 6-methylnicotine; Vaping of e-liquids containing the nicotine analogue 6-methylnicotine (6MN)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum total nicotine concentrations (Cmax)	Comparison of the maximum total nicotine (i.e. sum of both enantiomers) in blood concentrations (Cmax) between groups	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum concentration (Cmax) of 6-methylnicotine	Maximum concentration of 6-methylnicotine in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
Maximum concentration (Cmax) of 6-methylnicotine's metabolites	Maximum concentration of 6-methylnicotine's metabolites in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
AUC (area under the concentration-time curve) nicotine enantiomers	Area under the concentration-time curve (AUC) of nicotine enantiomers in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
AUC (area under the concentration-time curve) 6-methylnicotine	Area under the concentration-time curve (AUC) of 6-methylnicotine in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
AUC (area under the concentration-time curve) 6-methylnicotine's metabolites	Area under the concentration-time curve (AUC) of 6-methylnicotine's metabolites in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
Tmax (time of Cmax) nicotine enantiomers	Tmax of nicotine enantiomers in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
Tmax (time of Cmax) 6-methylnicotine	Tmax of 6-methylnicotine in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
Tmax (time of Cmax) 6-methylnicotine's metabolites	Tmax of 6-methylnicotine's metabolites in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
T1/2 (elimination half-life) nicotine enantiomers	Elimination half-life (T1/2) of nicotine enantiomers in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
T1/2 (elimination half-life) 6-methylnicotine	Elimination half-life (T1/2) of 6-methylnicotine in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
T1/2 (elimination half-life) 6-methylnicotine's metabolites	Elimination half-life (T1/2) of 6-methylnicotine's metabolites in blood	15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff
Blood nicotine metabolite ratio (NMR)	Nicotine clearance assessed using the 3'-hydroxycotinine/cotinine ratio (i.e. nicotine metabolite ratio (NMR)	15 minutes before vaping
Saliva nicotine metabolite ratio (NMR)	Nicotine clearance assessed using the 3'-hydroxycotinine/cotinine ratio (i.e. nicotine metabolite ratio (NMR)	At baseline
Blood steroid hormone levels	Steroid hormone levels in blood	At baseline, 15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff during the first part of the study and following 4 days ad libitum use during the second part
Saliva steroid hormone levels	Steroid hormone levels in saliva	At baseline
Urine steroid hormone levels	Steroid hormone levels in urine	At baseline and following 4 days ad libitum use of each product
Heart rate	bpm	Baseline, 15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff, at study completion (2.5-6.5 weeks after screening)
Blood pressure	mmHg	Baseline, 15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff, at study completion (2.5-6.5 weeks after screening)
Modified Minnesota Nicotine Withdrawal Scale (MNWS)	Score/questionnaire asssessing withdrawal: The Modified Minnesota Nicotine Withdrawal Scale (MNWS) (excluding items related to sleep disturbance and constipation) including eight items (angry/irritable/frustrated, anxious/nervous, depressed mood/sad, desire or craving to smoke, difficulty concentrating, increased appetite/hungry, restless and impatient), rated on a 0=none to 4=severe scale.	Baseline, 10 minutes, 1 hour and 3 hours after last puff
Tiffany Questionnaire on Smoking Urges-Brief (QSU) total (global) craving score	Score/questionnaire asssessing craving: The Tiffany Questionnaire on Smoking Urges-Brief (QSU) total (global) craving score as the average of all responses (mean of ten items, rated on a 1=strongly disagree to 7=strongly agree scale).	Baseline, 10 minutes, 1 hour and 3 hours after last puff
Positive and Negative Affect Schedule (PANAS)	Score/questionnaire asssessing satisfaction: The Positive and Negative Affect Schedule (PANAS) including items assigned as Positive or Negative Affect (each score is the sum of ten items, rated on a 1=very slightly/not at all to 5=extremely scale).	Baseline, 10 minutes, 1 hour and 3 hours after last puff
Respiratory symptoms	Questions regarding shortness of breath, wheezing, cough, phlegm; posisble answers: yes/no	Baseline and 5 minutes after last puff
Direct effects	Questions regarding e.g. satisfying, calming, pleasant, vape another one right now, using visual analog scales (0-100 mm) with a single word scored from left (not at all) to right (extremely).	10 minutes post-use
Modified e-cigarette evaluation questionnaire (mCEQ)	Questionnaire asssessing subjective effects	Following 4 days ad libitum use of each product
Urinary total nicotine equivalents (TNE) concentrations	Molar sum of urinary total (parent and glucuronide) nicotine, cotinine and 3'-hydroxycotinine	Following 4 days ad libitum use of each product
Urinary volatile organic compounds (VOC) concentrations	VOC in urine	Following 4 days ad libitum use of each product

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reported adverse events	Classification and severity grading scale in accordance with the "Common Terminology Criteria for Adverse Events CTCAE Version 5.0" terminology.	Throughout study completion, an average of 2.5-6.5 weeks

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Collaborators: Swiss Tobacco Prevention Funds

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 24, 2025
• First Submitted That Met QC Criteria: January 8, 2026
• First Posted (Actual): January 16, 2026

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: vaping; synthetic nicotine; nicotine analogues
• Additional Relevant MeSH Terms: Behavior; Smoking; Vaping
• Other Study ID Numbers: BASEC-ID 2025-01893

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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