The purpose of the study is to examine whether an investigational medication called ketamine is able to improve treatment outcomes for tobacco use disorder when delivered in conjunction with brief motivational enhancement therapy. Participants will receive ketamine assisted motivational enhancement therapy weekly for three weeks and there will be 2 follow up visits. All visits will also consist of questionnaires and saliva samples will be taken. The overall participation will last approximately 8 weeks.

Inclusion Criteria:

1. 21 to 65 years old.
2. Able to provide informed consent.
3. Be a daily cigarette smoker with multiple unsuccessful previous quit attempts, and report a continued desire to quit smoking.
4. Agree to abstain from smoking for the ketamine session from 1 hour before ketamine administration
5. Agree to refrain from using any psychoactive drugs, including alcoholic beverages, within 24 hours of ketamine administration. Exceptions include caffeine and nicotine.
6. Subjects taking other psychotropic medications must be maintained on a stable dose for at least four weeks before study initiation.
7. Be healthy as determined by screening for medical problems via a personal interview, a medical questionnaire, a physical examination, an electrocardiogram (ECG) to verify normal QTc intervals.
8. Subjects with normal blood pressure not on antihypertensive medications or medication controlled hypertension as defined baseline visit systolic blood pressure (SBP) <140 mmHg or a diastolic blood pressure (DBP) <90 mmHg.

Exclusion Criteria:

1. Women who are pregnant (positive pregnancy test) or nursing, or are not practicing an effective means of birth control which can include oral, implant, intrauterine device, or patch contraceptive methods as well as barrier contraceptive methods, history of surgery such as hysterectomy or tubal ligation, or abstinence
2. Subjects who meet DSM-5 criteria for current or history of psychotic spectrum disorders or current depression or bipolar disorder based on clinical interview.
3. Subjects meeting DSM-5 criteria for current substance use disorder other than tobacco use disorder.
4. Subjects with hypertension as defined by a baseline visit systolic blood pressure (SBP) >140 mmHg or a diastolic blood pressure (DBP) >90 mmHg.
5. A history of allergic or other adverse reaction to ketamine (or its excipients).
6. Clinically significant physical exam findings or self-reported medical conditions for which a transient increase in blood pressure could be significantly detrimental (e.g. glaucoma, aneurysmal disease, cardiovascular disease, or end-stage renal disease).
7. Cardiovascular conditions: uncontrolled hypertension, angina, a clinically significant ECG abnormality (e.g., atrial fibrillation), TIA in the last 6 months, stroke, peripheral or pulmonary vascular disease
8. Subjects who live greater than 20 miles from the study site and cannot arrange their own transportation will be excluded from the study.
9. Subjects with clinically significant kidney or liver impairment.
10. Have any current neurological illnesses including, but not limited to, seizure disorders, frequent migraines or on prophylaxis, multiple sclerosis, movement disorders, history of significant head trauma, or CNS tumor.
11. Morbidly obese (BMI >40), or severely underweight as determined by medical examination.

Number of subjects enrolled.

up to 1 year