The investigators' project has two overarching goals. 1) The investigators will use newly developed positron emission tomography (PET) technology to investigate the dopaminergic neurochemistry of drugs of abuse including marijuana, traditional cigarettes, and cocaine, and 2) The investigators will extend PET technology to an additional neurotransmitter system - namely, the opioid-ergic system, using the same drugs of abuse.

Aim 1. To examine the magnitude, location and timing of drug-induced dopamine release.

1. Tobacco smokers (n=20) will be imaged with [11C]raclopride PET, after overnight abstinence from tobacco. Subjects will smoke their preferred brand of cigarette during the PET scan.
2. Marijuana smokers (n=20) will be imaged with [11C]raclopride PET, after overnight abstinence from marijuana. Subjects will smoke a marijuana cigarette during the PET scan.
3. Cocaine users (n=20) will be imaged with [11C]raclopride PET, after overnight abstinence from cocaine. Subjects will be administered cocaine during the PET scan.

Aim 2. To examine the magnitude, location and timing of drug-induced beta-endorphin release. *The Investigators will attempt to use the same subjects from Aim 1 for Aim 2.

1. Tobacco smokers (n=20) will be imaged with [11C]carfentanil PET, after overnight abstinence from tobacco. Subjects will smoke their preferred brand of cigarette during the PET scan.
2. Marijuana smokers (n=20) will be imaged with [11C]carfentanil PET, after overnight abstinence from marijuana. Subjects will smoke a marijuana cigarette during the PET scan.
3. Cocaine users (n=20) will be imaged with [11C]carfentanil PET, after overnight abstinence from cocaine. Subjects will be administered cocaine during the PET scan.

Inclusion Criteria:

• General Inclusion Criteria:

  1. Men and women, aged 18-55 years
  2. Able to read and write English and give voluntary written informed consent
  3. Not treatment seeking or using treatment medications

Tobacco Smokers

1. Have a Fagerström Test for Nicotine Dependence (FTND) rating of at least 3.
2. Have been using at least 7 cigarettes per day for at least 1 year
3. Carbon monoxide levels > 10 ppm during intake evaluation
4. Urine cotinine levels of > 150 ng/mL during intake evaluation
5. Are not current users of marijuana or other illicit drugs

Marijuana Smokers

1. Meet DSM-V criteria for cannabis use disorder based on the structured clinical interview diagnostic (SCID) or regular cannabis use of >5 times/week
2. Test positive for THC
3. Have been smoking cannabis on a regular basis for > 1 year

Cocaine Users

1. DSM-V criteria for Cocaine Abuse or Dependence
2. Recent street cocaine use in excess of amounts to be administered in the current study
3. Intravenous and/or smoked (crack/ freebase) use
4. Positive urine toxicology screen for cocaine

Exclusion Criteria:

• 1. Current significant medical condition such as neurological, cardiovascular, endocrine, renal, liver, or thyroid pathology.

  2. History of or current neurological or significant psychiatric disorder such as schizophrenia or bipolar disorder (DSM-IV Axis 1).

  3. History of significant head trauma. 4. Women who are pregnant or nursing, or fail to use one of the following methods of birth control unless she or partner is surgically sterile or she is postmenopausal (hormone contraceptives [oral, implant, injection, patch, or ring], contraceptive sponge, double barrier [diaphragm or condom plus spermicide], or IUD).

  5. Regular or current significant use of any prescription, herbal or illegal psychotropic medications (e.g., antidepressants, antipsychotics, anxiolytics, ecstasy) in the past 6 mo, with no current illegal drug use confirmed by urine toxicology (except for cocaine and marijuana when relevant).

  6. Significant substance misuse (including alcohol, and excluding cannabis and marijuana when relevant) that in the PI's determination interferes with the study results or safety of the subject.

  7. Have MRI-incompatible implants and other contraindications for MRI, such as a pacemaker, artificial joints, non-removable body piercings, claustrophobia, etc.

  8. Subjects with history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over FDA limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year.

  9. Subjects with current, past or anticipated exposure to radiation in the work place within one year of proposed research PET scans.

  10. Subjects with history of IV drug use which would prevent venous access for PET tracer injection.

5 years