This study will help determine if menthol administered by inhalation via electronic cigarettes (e-cigarette) changes the reinforcing effects of pure nicotine administered intravenously in cigarette smokers who smoke mentholated or non-mentholated cigarettes.

Male and female smokers will be recruited from the New Haven area through newspaper advertisements, radio advertisements, and fliers. Interested subjects will have the study described over the telephone, and they will be asked to answer a brief tobacco use history and medical screening questionnaire. If subjects pass the telephone screening, they will be invited to come to the West Haven VA clinic for a screening evaluation. This screening evaluation will be for the menthol / nicotine reinforcement study as described in detail in this project description. The dose-finding study was conducted at the John B. Pierce Laboratory. The dose finding study concluded with the establishment of the high and low dose of menthol that will be used in this protocol "Menthol's Effects on Nicotine Reinforcement in Smokers." The screening of these subjects used the same inclusion and exclusion criteria as described below.

Inclusion criteria: Female and male smokers, aged 18 to 30 years; history of smoking for the past 12 months, at least one cigarette per day; smoking status is verified with urinary cotinine levels above 10 ng/ml; not seeking treatment for nicotine dependence at the time of study entry; in good health as verified by medical history, screening examination, and screening laboratory tests; for women, not pregnant as determined by pregnancy screening, nor breast feeding, and using acceptable birth control methods.

Exclusion criteria: History of major medical illnesses that the physician investigator deems as contraindicated for the patient to be in the study; regular use of psychotropic medication (antidepressants, antipsychotics, or anxiolytics); psychiatric diagnosis and / or treatment for Axis I disorders including major depression, bipolar affective disorder, schizophrenia or panic disorder in the past month and abuse of alcohol or any other recreational or prescription drugs in the past 30 days. Any allergy to propylene glycol or menthol.

This outpatient, double-blind, placebo-controlled study consisted of an adaptation session followed by three test sessions. All participants were randomized to a test session order and received control menthol (0.0% + tobacco flavor), low menthol (0.5% + tobacco flavor), and high menthol (3.2% + tobacco flavor) by standardized inhalation from an e-cigarette just prior to each nicotine infusion (a single menthol condition for each test session). Within each test session, all 3 IV nicotine conditions were tested, one hour apart, by delivering saline, nicotine at 0.25 mg nicotine/70 kg and nicotine at 0.5 mg nicotine/70 kg, in a random order, just after last inhalation. For each participant, the randomized nicotine infusion sequence was fixed across the three test sessions, each performed at least 24 hours apart.

Inclusion Criteria:

• Female and male smokers, aged 18 to 30 years;
• History of smoking for the past 12 months, at least one cigarette per day; smoking status is verified with urinary cotinine levels above 10 ng/ml;
• Not seeking treatment for nicotine dependence at the time of study entry;
• In good health as verified by medical history, screening examination, and screening laboratory tests;
• For women, not pregnant as determined by pregnancy screening, nor breast feeding, and using acceptable birth control methods.

Exclusion Criteria:

• History of major medical illnesses that the physician investigator deems as contraindicated for the patient to be in the study
• Regular use of psychotropic medication (antidepressants, antipsychotics, or anxiolytics);
• A psychiatric diagnosis and / or treatment for Axis I disorders including major depression, bipolar affective disorder, schizophrenia or panic disorder in the past month
• Abuse of alcohol or any other recreational or prescription drugs in the past 30 days.
• Any allergy to propylene glycol or menthol.

4 hours

The Systematic Assessment for Treatment Emergent Events (SAFTEE) was utilized to monitor adverse events.

The Overall Number of Baseline Participants is not consistent with numbers provided any of the participant flow module due to analysis didn't include just number of completers but were analyzed by Day. (Adaptation, Day 1, Day 2 and Day 3)