EFFECTS OF CHLORMETHIAZOLE ON PSYCHOLOGICAL PERFORMANCE UNDER CONDITIONS OF CONSTANT PLASMA-CONCENTRATIONS

Chlormethiazole was administered intravenously to six healthy voluntee rs (four male, two female, aged 20-33 years) using a loading dose foll owed by a maintenance infusion lasting similar to 90 min. Doses were i ndividually calculated from previous pharmacokinetic investigations in these subjects to produce a target steady-state plasma concentration of 1.5 mu g ml(-1). Effects of chlormethiazole were determined using a short battery consisting of digit-symbol substitution, body sway and visual analogue scales, which was performed repeatedly before, during and after the active infusion. A more comprehensive battery of perform ance tests was performed once before and once during the active infusi on. The mean plasma concentration of chlormethiazole obtained was 1.33 pg ml(-1). This produced marked sedation, with subjects scoring thems elves as much more drowsy on chlormethiazole than on placebo, and glob al impairment to performance. An analysis of the dopes of scores on th e performance tests in the short battery showed no evidence of a dimin ution of the effects of chlormethiazole over the infusion period. The same was true of the majority of the visual analogue scales, but two s cales, rating eye symptoms and nose symptoms, did decline over the per iod of the infusion. Recovery was rapid, subjects returning to approxi mately baseline levels of performance within 30 min of discontinuation of the infusion. These results suggest that acute tolerance to the CN S effects of chlormethiazole does not occur over this time scale, but is found for peripheral effects such as eye and nose symptoms.