The purpose of this study is to examine the effect of doses of cannabidiol (CBD) during exposure to stress and nicotine withdrawal in nicotine users. The main objectives of the study include examining the effect CBD has on stress, tobacco dependence, tobacco withdrawal, and sex differences between these types of stress. Participants will be administered CBD and exposed to stress. Biological and subjective measures will be collected. Participants may be asked to stop use for 24 hours. Researchers will also investigate withdrawal effects between participants who have not smoked nicotine in 24 hours and those who have continued to smoke before each session.

This study will use a double-blind, placebo-controlled, within-subjects crossover design to examine the effect of acute doses of CBD during exposure to acute stress and nicotine withdrawal using a relevant set of biological and subjective measures that are known to be sensitive to acute stress and to nicotine withdrawal. There will be one in-person medical screening session, 3 pre-laboratory phone sessions, and 3 in-person experimental laboratory sessions separated by at least 72 hrs. Total duration for a study completer is estimated to be 2-3 weeks. Three doses of CBD (0mg, 200mg, and 400mg) will be administered, one at each of three separate laboratory sessions that will last approximately 5 hours each and be separated by at least 72 hours. Two effective induction challenges will be implemented: one is behavioral (an established and well validated acute psychological stress induction) and one is a nicotine withdrawal challenge (24 hours abstinence from all nicotine products). Nicotine users reporting daily cigarette use (N=90) will be recruited. Nicotine users will be randomly assigned to continue nicotine use ad libitum or to abstain for 24 hours before each of three laboratory sessions. Randomization will be stratified based on participant sex and current use of other tobacco products (e.g. e-cigarettes, smokeless tobacco, pouches, cigars/cigarillos). Participants who use other nicotine-related products (e.g., e-cigarettes) will be accepted in the study if they also smoke cigarettes. Use of other nicotine products will be assessed and tracked to account for their effects on the collected measures.

Inclusion Criteria:

1. Healthy non-treatment seeking adults aged 21-70 (inclusive).
2. Use of > 5 cigarettes per day for > 2 years. (Use of other tobacco/nicotine products in addition to cigarettes will be acceptable).
3. Biological confirmation of cigarette use: have an expired carbon monoxide (CO) level > 8 ppm.
4. Alcohol Use: < 2 drinks/day on average (< 14 drinks/week).
5. Sleep schedule: No graveyard or third shift work (i.e., participants must report a normal nighttime sleep schedule).
6. For women of children bearing potential and men with female partners of child-bearing potential, must be willing to use an effective form of contraception during the study and for at least 30 days after the last study drug administration.

Exclusion Criteria:

1. Report current intention to reduce or quit cannabis or tobacco use within the next 30 days
2. Meet Diagnostic and Statistical Manual (DSM-5) criteria for a substance use disorder other than alcohol, cannabis, or nicotine
3. Test positive for illicit drugs other than cannabis
4. Positive breath alcohol test (>.01 g/210L) at study admission
5. Have a current physical or mental illness or takes a medication judged by the study team to negatively impact participant safety or scientific integrity
6. Have a resting heart rate >100, systolic blood pressure >160mmHg or <100mmHg, or diastolic blood pressure >100mmHg or <50mmHg at screening.
7. Have cold intolerance or a medical condition that might be exacerbated by exposure to cold (e.g. Reynaud's, peripheral neuropathy, trigeminal neuralgia, poorly controlled/uncontrolled hypothyroidism).
8. Are currently pregnant, planning to become pregnant in the next three months, or are currently breastfeeding
9. Have a history of clinically significant cardiac arrhythmias or vasospastic disease (e.g., Prinzmetal's angina, Raynaud's).
10. Have a history of and/or current liver disease, or elevated serum liver transaminase (AST or ALT) above 3 x Upper Limit of Normal (ULN), or elevated bilirubin above 2 x ULN at screening.
11. Are currently enrolled in another clinical trial or have received any drug as part of a research study within 30 days of study participation.