INTRODUCTION: We present the results of a two-experiment study designed to evaluate the neurocognitive and psychological effects of six-degree head-down bedrest and pharmacologic interventions (3,5,3′-triiodothyronine; T3) implemented to enhance the muscle and bone atrophy associated with simulated microgravity. Subsequently, the effects of countermeasures (alendronate and testosterone) administered to retard or reverse these T3 plus bedrest enhanced atrophic changes, were evaluated. Each participant was tested weekly for 5 weeks during Bedrest or non-bedrest (Up) conditions with the Neurobehavioral Evaluation System 2 (NES2), the Symptom Check List 90 Revised (SCL-90-R), and the Coping Responses Inventory (CRI). Resultant data were subjected to repeated measures, between groups analysis of variance testing for all 82 neurocognitive and psychological test measures. RESULTS: In Experiment 1, participants in the Placebo-Bedrest condition performed better on several neurocognitive measures compared to participants in the T3-Up condition. However, participants in the Placebo-Bedrest condition also reported more confusion. In Experiment 2 (countermeasure trials), superior coordination was observed for participants in the Testosterone-T3 condition over those in the Alendronate-T3 condition, but just the opposite for reaction time. Also, testosterone and to a lesser degree, alendronate, were associated with less self-reported emotional distress than T3 plus bedrest alone. CONCLUSION: Triiodothyronine, alendronate, and testosterone each influence participant response to simulated microgravity. Between group differences for significant findings were substantial and averaged 1.62 standard deviations. Although the observed neurocognitive effects likely pose no immediate danger for research participants, the significantly greater level of self-reported psychological symptoms by T3-Placebo and Placebo-Bedrest treated participants is of clinical importance.