Impact of Flavors on Nicotine Perception and Self-Administration Via E-cigarettes

Phase 2

Completed

• Conditions: Nicotine; E-liquid Flavors
• Interventions: Drug: Nicotine 0 mg/mL; Drug: Nicotine 6 mg/mL; Drug: Nicotine 12 mg/mL; Drug: Nicotine 24 mg/mL; Other: 'Menthol' flavor; Other: 'Menthol/Mint' flavor; Other: 'Green Apple' flavor; Other: 'Watermelon' flavor; Other: 'Unflavored'

• Registration Number: NCT04038515
• Lead Sponsor: Yale University

Brief Summary

The goal of this application is to test whether menthol and fruit flavors impact e-cigarette use through dissociable mechanisms and exert their effects differentially across nicotine doses.

Detailed Description

This study examines the impact of menthol and fruit flavors on self-administration of e-cigarette solutions containing varying amounts of nicotine. This is a randomized, double-blind study with a within-subject cross-over design, using e-liquids with 5 different flavors and 4 different levels of nicotine for a total of 20 different e-liquid formulations. Each subject will participate in 4 test sessions. The order of flavor and nicotine delivery will be randomized. At each test session, they will undergo directed self-administration, in a randomized order, then an ad libitum self-administration session where they can choose among all of the e-cigarettes used during the directed session. The primary aims assess the impacts of nicotine and flavor (and their interactions) on participants' subjective ratings of the e-liquids during the 'directed' self-administration component, and self-administered puffs during the ad libitum self-administration component. In addition, the study will explore the impact of sex/gender and sensitivity to nicotine aversiveness or bitterness (as operationalized by genetic variations in the alpha-5 subunit of nicotinic acetylcholine receptor that influences the aversive effects of nicotine, or a taste receptor number 38 ( TAS2R38) important for bitterness perception) on study outcomes.

Study Timeline

• Study First Submitted: 2019-07-24
• Study First Submitted QC: 2019-07-29
• Study First Posted: 2019-07-30
• Study Start: 2022-10-27
• Primary Completion: 2024-06-03
• Study Completion: 2024-06-03
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-01
• Last Update Posted: 2024-08-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 54

Inclusion Criteria

Not provided

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Exclusion Criteria

• Any allergy or known hypersensitivity to propylene glycol, vegetable glycerin, menthol, mint, green apple or watermelon flavorants or history of allergic or hypersensitive reaction to use of an e-cigarette/vaping device;
• Has not used e-cigarettes at least 10 times in the last 6 months;
• For females, pregnant (as determined by pregnancy screening) or breast feeding;
• Seeking (or undergoing) treatment for nicotine dependence or tobacco product use (smoking or vaping) or has current plans to quit tobacco product use;
• Meet current criteria for psychiatric disorder (according to the MINI);
• Current or history of respiratory illnesses including pneumonia with COVID-19 , other medical illness, and/or psychotropic medication use that a clinician investigator deems a contraindication for study participation.
• History of environmental - bronchospastic allergies, multiple chemical sensitivities, or other airway sensitivities that require the use of an epi pen or that in the investigators view would make it risky for participation;
• Not fully vaccinated for COVID-19

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
E-liquid Order 'A'	Nicotine 6 mg/mL	Order 'A' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'B'	Nicotine 0 mg/mL	Order 'B' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'B'	Nicotine 24 mg/mL	Order 'B' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'C'	Nicotine 6 mg/mL	One nicotine level condition is a medium nicotine e-liquid (12 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'B'	Nicotine 12 mg/mL	Order 'B' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'D'	Nicotine 24 mg/mL	One nicotine level condition is a high nicotine e-liquid (24 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'A'	Nicotine 0 mg/mL	Order 'A' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'C'	Nicotine 0 mg/mL	One nicotine level condition is a medium nicotine e-liquid (12 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'D'	Nicotine 0 mg/mL	One nicotine level condition is a high nicotine e-liquid (24 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'B'	Nicotine 6 mg/mL	Order 'B' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'D'	Nicotine 6 mg/mL	One nicotine level condition is a high nicotine e-liquid (24 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'A'	Nicotine 12 mg/mL	Order 'A' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'A'	Nicotine 24 mg/mL	Order 'A' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'C'	Nicotine 12 mg/mL	One nicotine level condition is a medium nicotine e-liquid (12 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'C'	Nicotine 24 mg/mL	One nicotine level condition is a medium nicotine e-liquid (12 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'A'	'Menthol' flavor	Order 'A' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'A'	'Menthol/Mint' flavor	Order 'A' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'A'	'Watermelon' flavor	Order 'A' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'B'	'Menthol' flavor	Order 'B' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'A'	'Unflavored'	Order 'A' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'C'	'Green Apple' flavor	One nicotine level condition is a medium nicotine e-liquid (12 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'C'	'Watermelon' flavor	One nicotine level condition is a medium nicotine e-liquid (12 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'A'	'Green Apple' flavor	Order 'A' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'B'	'Green Apple' flavor	Order 'B' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'B'	'Watermelon' flavor	Order 'B' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'B'	'Unflavored'	Order 'B' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'B'	'Menthol/Mint' flavor	Order 'B' for E-liquid Self-Administration: All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'C'	'Menthol' flavor	One nicotine level condition is a medium nicotine e-liquid (12 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'C'	'Menthol/Mint' flavor	One nicotine level condition is a medium nicotine e-liquid (12 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'D'	Nicotine 12 mg/mL	One nicotine level condition is a high nicotine e-liquid (24 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'D'	'Unflavored'	One nicotine level condition is a high nicotine e-liquid (24 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'C'	'Unflavored'	One nicotine level condition is a medium nicotine e-liquid (12 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'D'	'Watermelon' flavor	One nicotine level condition is a high nicotine e-liquid (24 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'D'	'Green Apple' flavor	One nicotine level condition is a high nicotine e-liquid (24 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'D'	'Menthol' flavor	One nicotine level condition is a high nicotine e-liquid (24 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.
E-liquid Order 'D'	'Menthol/Mint' flavor	One nicotine level condition is a high nicotine e-liquid (24 mg/mL nicotine). All participants will be given all e-liquids (i.e., all 20 nicotine\*flavor combinations (4 nicotine\* 5 flavor combinations)) in this within-subject, cross-over design study. Participants will be randomized the order in which they self-administer the 20 nicotine\*flavor combinations of e-liquid (across and within the 4 visits). The specific order cannot be described here without disrupting the double-blind nature of the study design.

Primary Outcome Measures

Name	Time	Method
E-cigarette use	immediately after intervention	Number of puffs from each e-cigarette (containing different e-liquids) will be measured during the ad libitum self-administration component of each test day. E-cigarette use (ad libitum puffs) for each nicotine\*flavor condition will be tested at one test day only and the order of nicotine\*flavor conditions will be randomized across the test days (and order within test days will be randomized).
Subjective drug ratings	immediately after intervention	Subjective ratings of e-liquids delivered via e-cigarette will be assessed during the 'directed' self-administration component of each test day, using visual analogue scales (VAS). VAS scores range from 0=not at all to 100=extremely. Separate VAS scales will be collected for subjective ratings of aversive properties (higher scores reflect more aversiveness) and rewarding properties (higher scores reflect more rewarding properties) of the e-cigarettes, in each nicotine\*flavor condition. Subjective drug ratings for each nicotine\*flavor condition will be tested at one test day only and the order of nicotine\*flavor conditions will be randomized across the test days (and order within test days will be randomized).

Trial Locations

Locations (1)

Yale University School of Medicine; 🇺🇸 New Haven, Connecticut, United States