This between-subjects study aims to evaluate whether e-cigarettes (ECIGS) versus oral nicotine pouches (ONPS) more readily substitute for combustible cigarettes among 200 cigarette smokers. After measuring baseline cigarette smoking rate, participants will be randomized to ECIGS or ONPS and be instructed to switch (versus smoking cigarettes) over a 6-week period. Relative reductions in biomarkers of exposure will be measured. ECIG- and ONP-associated subjective reward and the reinforcing value of ECIGS and ONPS relative to combustible cigarettes will be assessed as mechanisms.

E-cigarettes (ECIGS), and oral nicotine pouches (ONPs), expose users to few of the chemicals found in cigarette smoke and are thus promising noncombustible harm reduction tools for smokers who would not otherwise quit smoking. For their harm reduction potential to be realized, fundamental questions must be answered. One, can persistent smokers switch from combustible cigarettes to either ECIGS or ONPS? Two, what factors influence switching? Three, does one of these noncombustible alternatives expose users to lower levels of harmful chemicals than the other? The proposed research will fill these gaps in the evidence base by randomizing 200 persistent cigarette smokers to a six-week regimen of ECIGS or ONPS. Baseline smoking rate will be established during days 1-5. After biochemically confirmed overnight smoking abstinence, laboratory visits on days 6 and 7 will assess ECIG and ONP-associated subjective reward and the reinforcing value of either ECIGS or ONPS relative to combustible cigarettes. Participants will switch from cigarette smoking to ECIGS or ONPS for the following six weeks. The primary outcome measure is the longitudinal daily count of cigarettes from baseline to the end of the six-week switch period, measured via a validated collection protocol with cigarettes per day (cpd) at a 6-month follow-up as a secondary endpoint. Changes in biomarkers of potential harm, assessed at baseline and the end of the six-week switch phase, will be secondary outcome measures.

Inclusion Criteria:

1. Able to communicate fluently in English (i.e. speaking, writing, and reading)
2. Male and female smokers who are > 21 years of age and self-report smoking at least 5 cigarettes (menthol and/or non-menthol) per day for at least the last 6 months.
3. 5 or more failed quit attempts and the use of smoking cessation medication on at least one prior attempt.
4. Have a carbon monoxide (CO) greater than 10 ppm.
5. Not using any forms of nicotine regularly other than cigarettes
6. Be willing to switch to e-cigarettes or nicotine pouches for 6 weeks.
7. Plan to live in the area for the duration of the study.
8. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and HIPAA form.

Exclusion Criteria:

Smoking Behavior

1. Regular use of nicotine-containing products other than cigarettes (e.g., chewing tobacco, snuff, snus, cigars, e-cigs, etc.). Regular e-cigarette and nicotine pouch use is defined as greater than 5 days/past 30 days.

   a. Participants agreeing to abstain from using nicotine-containing products other than cigarettes for the duration of the study will be considered eligible.

2. Current enrollment or plans to enroll in a smoking cessation program over the duration of the study.

3. Current use of smoking cessation medication

4. Provide a CO breath test reading less than 10 ppm at Intake.

Alcohol and Drug

1. History of substance abuse (other than nicotine dependence) in the past 12 months.
2. Current alcohol consumption that exceeds 20 standard drinks/week.
3. Current use of recreational drugs (other than nicotine and cannabis)
4. Breath alcohol reading (BrAC) greater than .000 at Intake.

Medical

1. Women, including all individuals assigned as "female" at birth, who are pregnant, breastfeeding, or planning a pregnancy over the duration of the study period.
2. Serious or unstable disease within the past year (e.g. cancer, heart disease). Applicable conditions will be evaluated on a case-by-case basis by the Principal Investigator.

Psychiatric

1. Lifetime history of schizophrenia or psychosis.

General Exclusion

1. Past, current, anticipated, or pending enrollment in another research program over the study period that could potentially impact subject safety, study data, and/or the study design as determined by the Principal Investigator.
2. Any medical condition, illness, disorder, adverse event (AE), or concomitant medication that could compromise participant safety or significantly impact study performance as determined by the Principal Investigator. Subjects may be deemed ineligible for any of the aforementioned reasons at any point throughout the study, as well as during the initial telephone screen.
3. Significant non-compliance with protocol and/or study design as determined by the Principal Investigator. Subjects may be deemed ineligible at any point throughout the study.