The Role of Endocannabinoids in Insulin Production and Action

Background: \- The endocannabinoid system is involved in different body functions and processes. It helps regulate appetite and mood, and sends signals to the nervous system. It may also be involved in how the body produces insulin during digestion. Researchers want to test two drugs that work on the endocannabinoid system: nabilone and CP-945,598. These drugs may be able to affect insulin levels in the blood. This information may suggest possible new treatments for people with diabetes. Objectives: \- To study how the endocannabinoid system is involved in insulin production and action. Eligibility: \- Healthy men between 21 and 55 years of age. Design: * Participants will be screened with a physical exam and medical history. They will provide blood and urine samples. They will also have imaging studies to test their brain responses, especially to food-related cues. Some participants will also have a study visit to test their insulin resistance levels. * Participants will have four separate study visits 6 weeks apart. They will keep a food diary before each visit. At each visit, they will have one of the following combinations of drugs: * Double placebo * Placebo and nabilone * Placebo and low dose of CP-945,598 * Placebo and high dose of CP-945,598. * Participants will have follow-up visits 1 week after each study visit. Blood samples will be taken.

* INCLUSION CRITERIA: 1. Healthy men only (We want to study men because the magnitude of acute insulin response for men and women is different. In addition, as women may become pregnant in the course of the study, and since this is a physiology study only, and not one related to treatments, we want to remove any confounders and lessen any chance of drop-out.) 2. Age 21-55 (Age restriction is used to remove age as a confounding factor because Beta cells function tends to deteriorate and first phase secretion becomes less defined with age. 3. Screening laboratory evaluations with no clinically significant abnormal results (minor deviations from normal lab results will be at the discretion of the principal investigator): 1. fasting comprehensive metabolic panel 2. complete blood count with differential and platelet 3. thyroid function test (TSH, free T4) 4. urinalysis 5. urine drug screen 4. BMI less than 30 (Men with BMI greater than or equal to 30 are excluded because obesity has been associated with altered beta cell function. 5. Have NOT participated in another clinical trial involving any pharmacologic agents within the past 30 days 6. Able to complete an inform consent 7. Agree to not participate in other clinical trials within the study period (at the discretion of the study investigator) EXCLUSION CRITERIA: 1. Women 2. FPG greater than or equal to 100 mg/dl or 2-hr OGTT greater than or equal to 140 mg/dL 3. Evidence of illicit drug use 4. History of substance abuse including marijuana within the past 6 months 5. History of smoking any tobacco products within six months prior to screening 6. Alcohol intake greater than 30 grams (drink more than 2 beers per day OR equivalent amount of alcohol) 7. History of Human Immunodeficiency Virus (HIV) infection 8. History of active or chronic Hepatitis B and/or C infection 9. History of malignancy 10. History of coronary disease 11. History of seizures or other neurologic diseases 12. History of psychiatric illnesses including major depressive disorder, schizophrenia, bipolar disorder 13. Any lifetime history of suicide attempt 14. History of suicidal behavior in the last year 15. Any suicidal behavior during any follow-up visits 16. History of any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in the last year 17. Any suicidal ideation of type 4 or 5 on the C-SSRS during any follow-up visits. 18. Patient Health Questionnaire-9 (PHQ-9) score greater than or equal to 10 during screening visit or any follow-up study visits 19. Generalized Anxiety Disorder-7 (GAD-7) score greater than or equal to 10 during screening visit or any follow-up visits 20. History of liver or renal diseases 21. History of gastrointestinal or endocrine disorders 22. History of glucocorticoid use (over one month) or other immunosuppressive agents (any) 23. Any condition or non-removable device contraindicated for MRI (pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips, metallic prostheses, permanent eyeliner, implanted delivery pump, or shrapnel fragments, or history of working as a welders or metal worker) 24. Any medical history that, in the opinion of the investigator(s), will make participation of the subject in the study unsafe