A double-blind study of the sedative effects of the thalidomide enantiomers in humans

This study investigated the sedative effects of the enantiomers of thalidomide in humans. Since the enantiomers undergo chiral inversion in vivo this entailed application of suitable statistical methodology to distinguish the effects of each enantiomer in the presence of the other one. Six healthy male volunteers received single oral doses of (+)-(R)-thalidomide, (-)-(S)-thalidomide or racemic thalidomide in a double-blind study, and the results of this study were compared with those of a similar study where three subjects received (+)-(R)-thalidomide, (-)-(S)-thalidomide or placebo in a double-blind fashion. Blood samples for analysis of (+)-(R)-thalidomide and (-)-(S)-thalidomide were obtained. Prior to sampling it was noted whether the subject was awake or asleep, and his feelings of tiredness and heaviness were estimated using Borg scales. After blood sampling continuous reaction time was measured by a 10-min series of auditory signals. The concentration-effect relationships were analyzed by logistic regression techniques and Cox regression for the reaction time data. The (+)-(R)-thalidomide concentrations, but not the (-)-(S)-thalidomide concentrations, exhibited significant positive influences on all sedative effects studied (sleep, tiredness, and reaction times). In some of the analyses of reaction times the (-)-(S)-thalidomide concentrations had a significant effect in the opposite direction. The time course and intensity of sedative effect is thus influenced by which enantiomer is administered and by the kinetics of in vivo chiral inversion.