We propose to measure the effect of placebo by elimination as well as by a "balanced placebo" design, determine its interaction with active drug, and explore whether placebo exerts part of its effect at the pharmacokinetics level.

Placebos have been in use for centuries in medical practice. However, there is continued controversy regarding their effectiveness and mechanisms of action.

The results of the study are expected to further our understanding of a widely used medical intervention, i.e., placebo, and of how to maximize its potential beneficial effect. It will also help assess the appropriateness of measuring the placebo effect by elimination, which has important ethical implications in relation to the design of randomized clinical trials.

Comparison: caffeine vs placebo. Dependent variables:4 hours area under the curve (AUC) of pharmacodynamics endpoints as well as pharmacokinetics endpoints in a subgroup.

Inclusion Criteria:

• Males and nonpregnant females 18 and 40 years of age with at least high school education.

Exclusion criteria:

• Include evidence of clinically relevant deviation from normal health (such that it may affect the endpoints, make the ingestion of caffeine dangerous, or affect the pharmacokinetics/pharmacodynamics of caffeine),
• Pregnancy,
• Poor venous access,
• Hypertension (more than 140/90),
• Heart disease,
• History of panic attacks,
• Average daily caffeine consumption of more than 300 or less than 100 mg,
• Smoking,
• Alcohol abuse,
• Taking any medication other than birth control bills (including over-the-counter drugs) within one week from starting the study,
• Hypersensitivity to caffeine or related compounds,
• Hemoglobin of less than 13 gm/L, and recent (one week) acute illness