Clinical Pharmacology of Electronic Cigarettes

The purpose of this study is to learn more about nicotine exposure and the safety of electronic cigarettes (EC). It will focus on the areas that are thought to most closely relate to the addictive potential of EC, namely: (1) EC as nicotine delivery devices, covering issues of nicotine intake and pharmacokinetics, temporal patterns of use and titration of nicotine; and (2) subjective effects of EC use, including relationship of use to reward, withdrawal and craving.

Study Overview

• Status: Completed
• Conditions: Nicotine Dependence
• Intervention / Treatment: Device: Tobacco Cigarette; Device: Electronic Cigarette

Detailed Description

Electronic cigarettes (EC) are nicotine delivery devices that generate a nicotine-containing aerosol which is inhaled by the user. EC are perceived by users to be useful in helping quitting smoking of conventional tobacco cigarettes (TC) as well as having a presumed lower risk of adverse health effects compared to TC, the potential for use in public places, reduced cost, and lack of the noxious clinging odors associated with TC use. Many believe that electronic cigarette (EC) function as nicotine delivery devices in the same way as tobacco cigarettes (TC), and that EC will prove to be just as addictive as TC, but this may not be the case because of fundamental differences in the design and method of use of these products. Investigators hypothesize that systemic nicotine exposure will be lower with EC compared to TC; that despite lower nicotine intake EC users will experience similar reward and no greater withdrawal symptoms or craving compared to TC; and that dual EC/ TC users will not titrate their daily intake of nicotine in the same way that TC smokers of high- vs low-yield nicotine TC do.

Investigators specifically focus on the areas that are thought to most closely relate to the addictive potential of EC, namely: (1) EC as nicotine delivery devices, covering issues of nicotine intake and pharmacokinetics, temporal patterns of use and titration of nicotine; and (2) subjective effects of EC use, including relationship of use to reward, withdrawal and craving. The investigators will also examine aspects of safety of EC use (by assessment of cardiovascular and hormonal effects of use and of biomarkers of exposure to potentially toxic constituents) and explore the identification and validation of biomarkers that may be useful in distinguishing EC from TC use. Study subjects will be dual users of TC and EC so that the investigators may compare both modalities of use in experienced users in a within-subject design.

The study will consist of two 1-week blocks (EC-only or TC-only conditions) with 4 days of outpatient ad libitum product use followed by 3 days in a clinical research ward to include a single-use pharmacokinetic study, monitoring of product use, subjective assessments, blood and urine collections to assess biomarkers, and a 24-hour period of cardiovascular monitoring. Two additional days at the end of the 2nd block will assess similar measurements during a period of nicotine-product abstention.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital (SFGH)
    • San Francisco, California, United States, 94110
      • University of California, San Francisco (UCSF)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy on the basis of medical history and limited physical examination as described below:

  • Heart rate < 105 BPM*
  • Systolic Blood Pressure < 160 and > 90*
  • Diastolic Blood Pressure < 100 and > 50*
  • Body Mass Index ≤ 38.0 *Considered out of range if both machine and manual readings are above/below these thresholds.
• Current regular "dual" user of both EC and conventional TC
• EC device is one of the most popular 1st, 2nd or 3rd generation brands (with the exception of rebuildable atomizers) as determined at time of study commencement
• Carbon monoxide ≥ 5 ppm or per discretion of Principal Investigator
• Saliva cotinine ≥50 ng/ml or urine cotinine
• Age: ≥ 21 years

Exclusion Criteria:

• Current regular use of selected psychiatric medications
• Current regular use of cardiovascular medications for cardiovascular conditions including hypertension (Example: beta and alpha-blockers)
• Current regular use of medications inducers of nicotine metabolizing enzymes CYP2A6 (Example: rifampicin, dexamethasone, phenobarbital, and other anticonvulsant drugs).
• Use of other tobacco products
• Pregnancy or breastfeeding (by history and pregnancy test)
• Concurrent use of nicotine-containing medications
• Drug/Alcohol Dependence
• Positive toxicology test at the screening visit (THC okay)
• Concurrent participation in another clinical trial
• Inability to communicate in English
• Planning to quit smoking within the next 60 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: EC Block1/TC Block 2; Participants will be randomized into one of two groups. In this group, participants will be assigned to Electronic Cigarettes only for Study Block #1, then crossover to Tobacco Cigarettes only for Study Block #2.	Device: Tobacco Cigarette; Usual brand tobacco cigarette smoked by study participant.; Other Names: TC, Cigarette; Device: Electronic Cigarette; Usual brand electronic cigarettes smoked by study participant.; Other Names: EC, E-cig, E-cigarette
Active Comparator: TC Block 1/EC Block 2; Participants will be randomized into one of two groups. In this group, participants will be assigned to Tobacco Cigarettes only for Study Block #1, then crossover to Electronic Cigarettes only for Study Block #2.	Device: Tobacco Cigarette; Usual brand tobacco cigarette smoked by study participant.; Other Names: TC, Cigarette; Device: Electronic Cigarette; Usual brand electronic cigarettes smoked by study participant.; Other Names: EC, E-cig, E-cigarette

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK-estimated Nicotine Dose	Estimated in dose received (in milligrams) during the Standardized Session.	Inpatient Day 1, Up to 4 Hours post Session
Standardized Session: Mean CMax	Maximum Plasma Nicotine Concentration (Cmax) (ng/mL)	Inpatient Day 1, Up to 4 Hours post Nicotine Administration
Standardized Session: Mean TMax	Time (min) when Max Plasma Nicotine Concentration was achieved	Inpatient Day 1, Up to 4 Hours post Session
Standardized Session: AUC 0-240	Plasma Nicotine area-under-the curve from 0 to 4 Hours (min*ng/ml)	Inpatient Day 1, Up to 4 Hours post Session

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Standardized Session: QSU Factor 1 (Vaping)	Questionnaire for Smoking Urges Brief modified for e-cigarettes to measure urge to vape.Two factor scores and a total score were derived. Factor 1 represents the desire and intention to smoke with smoking perceived as rewarding, while Factor 2 represents an anticipation of relief from negative effect with an urgent desire to smoke.Scores range from 5 to 35 with higher scores indicating a higher level of craving.	Inpatient Day 1, Up to 4 Hours post Session
Standardized Session: Positive and Negative Affect Score (Negative Affect)	The PANAS Scale or Positive and Negative Affect Schedule (PANAS) is a self-report questionnaire. PANAS, (Sandín et al., 1999; Watson, Clark & Tellegen, 1988).This instrument is composed of 20 items: 10 items measuring positive affective states and 10 items measuring negative affect states.This subscale measures a person's negative emotions. Scores range from 10- 50 with higher scores indicating stronger negative feelings.	Inpatient Day 1, Up to 4 Hours post Session
Standardized Session: Minnesota Nicotine Withdrawal Scale	Minnesota Nicotine Withdrawal Scale (MNWS) is a Self-Report Scale for measuring the severity of nicotine withdrawal symptoms.The possible range of scores for the 12-Item MNWS is between 0 and 48 with higher scores indicated greater withdrawal symptom severity.	Inpatient Day 1, Up to 4 Hours post Session
Standardized Session: QSU Factor 2 (Vaping)	Questionnaire for Smoking Urges Brief modified for e-cigarettes to measure urge to vape.Two factor scores and a total score were derived. Factor 1 represents the desire and intention to smoke with smoking perceived as rewarding, while Factor 2 represents an anticipation of relief from negative effect with an urgent desire to smoke. Scores range from 5 to 35 with higher scores indicating a higher level of craving.	Inpatient Day 1, Up to 4 Hours post Session
Standardized Session: QSU Factor 1 (Smoking)	Questionnaire for Smoking Urges Brief measures urge to smoke.Two factor scores and a total score were derived. Factor 1 represents the desire and intention to smoke with smoking perceived as rewarding, while Factor 2 represents an anticipation of relief from negative effect with an urgent desire to smoke. Scores range from 5 to 35 with higher scores indicating a higher level of craving.	Inpatient Day 1, Up to 4 Hours post Session
Standardized Session: QSU Factor 2 (Smoking)	Questionnaire for Smoking Urges Brief measures urge to smoke.Two factor scores and a total score were derived. Factor 1 represents the desire and intention to smoke with smoking perceived as rewarding, while Factor 2 represents an anticipation of relief from negative effect with an urgent desire to smoke. Scores range from 5 to 35 with higher scores indicating a higher level of craving.	Inpatient Day 1, Up to 4 Hours post Session

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Standardized Session: Half-life	Estimated Time (min) to reduce the plasma nicotine concentration by half based on observed pharmacokinetics.	Inpatient Day 1, Up to 4 Hours post Session

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH); Roswell Park Cancer Institute
• Investigators: Principal Investigator: Neal L Benowitz, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Benowitz NL, St Helen G, Nardone N, Addo N, Zhang JJ, Harvanko AM, Calfee CS, Jacob P 3rd. Twenty-Four-Hour Cardiovascular Effects of Electronic Cigarettes Compared With Cigarette Smoking in Dual Users. J Am Heart Assoc. 2020 Dec;9(23):e017317. doi: 10.1161/JAHA.120.017317. Epub 2020 Nov 19.

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2015
• Primary Completion (Actual): February 2, 2018
• Study Completion (Actual): February 2, 2018

Study Registration Dates

• First Submitted: April 30, 2015
• First Submitted That Met QC Criteria: June 9, 2015
• First Posted (Estimated): June 12, 2015

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 15, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder
• Other Study ID Numbers: 15635; R01DA039264 (U.S. NIH Grant/Contract); NCI-2018-02897 (Registry Identifier: NCI Clinical Trials Reporting Program)

Plan for Individual participant data (IPD)

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