The effects of drugs on the size of the pupil is among the most easily detected and characteristic signs of drug action. Several animal studies conducted at the ARC have clarified the neural mechanisms through which psychoactive drugs influence pupil diameter and the light reflex. This research has been extended to clinical studies where the pupillary effects of several classes of abused drugs were compared to their performance and subjective effects. Recently it was discovered that marijuana caused dose-related effects on smooth pursuit tracking. Additional research on retinal physiology using newly developed pupillometers has yielded new information of the retinal processing of the light reflex. Since retinal neural organization mimics brain neural systems, it is proposed that the actions of drugs in the retina may model their mechanisms elsewhere in the brain. Dependent measures of these studies include pupil size, constriction and dilation velocities of the light reflex, smooth pursuit and saccadic tracking. These studies are typically a within- subject repeated measure design. Drugs are administered double-blind and placebo controlled. Progress to date: The effects of marijuana, ethanol, cocaine, opiates, amphetamine, and nicotine have been studied after various routes of administration. Pupillary effects of opiate withdrawal and detoxification with buprenorphine are measured. Pupillary measures are being evaluated as an index of opiate tone in cocaine-dependent subjects undergoing withdrawal.