Rate of increase of plasma drug level influences subjective response in humans

Abstract

This study addressed the commonly held, but seldom tested, notion that faster rates of increase of drug effects are associated with more positive subjective effects. Sodium pentobarbital was administered to normal healthy volunteers in either a single oral dose or in a series of divided, cumulating doses, and subjective responses were monitored. Twelve subjects participated in three weekly sessions, during which they received capsules containing placebo, 150 mg pentobarbital in a single dose (SIN) or 180 mg pentobarbital administered in six divided doses (DIV) of 30 mg every 30 min. Doses of pentobarbital in the SIN and DIV were selected to produce similar peak plasma levels. Blood samples were obtained at regular intervals for plasma drug level determinations, and throughout the session subjects completed self-report mood questionnaires (e.g., Profile of Mood States, visual analog ratings of drug liking and drug “high”) and psychomotor performance tests (e.g., Digit Symbol Substitution Test). As expected, the SIN and DIV conditions yielded similar peak levels of pentobarbital, but the peak was attained more rapidly in the SIN condition. Despite the similarity in peak plasma levels, subjects reached greater peaks in ratings of “high” and wanted more of the drug when they were in the SIN condition. On an end-of-session liking questionnaire they also reported significantly greater liking of the drug in the SIN condition. On other measures of drug effects (e.g., sedation and psychomotor impairment) no significant differences were observed between the conditions. Thus, the rate of increase of the drug's effects specifically influenced subjects' ratings on subjective measures (e.g., “high” and liking) that may be associated with risk for abuse. The results have implications for the relative abuse liability of different formulations of psychoactive drugs.