Inhaled vs. oral alprazolam: subjective, behavioral and cognitive effects, and modestly increased abuse potential

Abstract

Rationale: Infrahuman and human studies suggest that a determinant of the abuse potential of a drug is rate of onset of subjective effects.

Objectives: This study sought to determine if the rate of onset of subjective effects and abuse potential of alprazolam would be increased when administered via inhalation vs. the oral route.

Methods: Placebo, inhaled alprazolam (0.5, 1, and 2 mg), and oral alprazolam (1, 2, and 4 mg) were administered under double-blind, double-dummy conditions using a crossover design in 14 healthy participants with histories of drug abuse. Participant and observer ratings and behavioral and cognitive performance measures were assessed repeatedly during 9-h sessions.

Results: Both routes of administration produced orderly dose and time-related effects, with higher doses producing greater and longer-lasting effects. Onset of subjective effects following inhaled alprazolam was very rapid (e.g., 2 vs. 49 min after 2 mg inhaled vs. oral). On measures of abuse potential (e.g., liking and good effects), inhaled alprazolam was more potent, as evidenced by a leftward shift in the dose-response curve. Despite the potency difference, at the highest doses, peak ratings of subjective effects related to abuse potential (e.g., "drug liking") were similar across the two routes. On other measures (e.g., sedation and performance), the routes were equipotent.

Conclusions: The inhaled route of administration modestly increased the abuse potential of alprazolam despite significantly increasing its rate of onset. If marketed, the reduced availability and increased cost of inhaled alprazolam may render the societal risk of increased abuse to be low.

Figures

Figure 1

Time course of effects of inhaled alprazolam (left panels) and oral alprazolam (right panels) on participant ratings of drug liking and good effects from the Drug Effect Questionnaire (top 2 rows) and performance on the Circular Lights Task and the Digit Symbol Substitution Task (bottom 2 rows). Y axes: mean participant rating of liking and good effects (0 to 4 point scale), mean score on the Circular Lights Task, and mean trials correct on the Digit Symbol Substitution Task. X axes: Left panels show the time in minutes after inhaled administration; Right panels show the time in minutes after the first set of oral capsules were administered; 0 shows the pre-administration time point. Data symbols show means (N=14). Filled symbols indicate values that are significantly different from the corresponding placebo value at the same time point (p

Figure 2

Effects of placebo (circles), inhaled alprazolam (squares) and oral alprazolam (triangles) on participant ratings of several measures specific to abuse potential. Left panels show peak ratings of drug liking, good effects, and high from the Drug Effect Questionnaire. Right panels show ratings of liking good effects, and monetary street worth from the End of Day Questionnaire. Y axes: participant rating (0 to 4 point scale) and Street Worth (in dollars). X axes: dose in mg; P designates placebo. Data points show means (N=14) brackets show plus or minus 1 SEM. Filled symbols indicate values that are significantly different from placebo; data points that do not share a common letter are significantly different from one another (p

Figure 3

Effects of placebo (circles), inhaled alprazolam (squares) and oral alprazolam (triangles) on observer ratings, participant ratings, and performance measures that do not specifically assess abuse potential. Left panels show peak effects of observer ratings of locomotor relaxation, confusion/disorientation, and slurred speech. Right panels show peak effects of participant ratings of sedation and performance on the Circular Lights and Digit Symbol Substitution Tasks. Y axes: observer ratings (0 to 4 point scale); participant rating of sedation (0 to 52 point scale); Circular Lights Task score and Digit Symbol Substitution Task trials correct; X axes: dose in mg; P designates placebo. Data points show means (N=14) brackets show plus or minus 1 SEM. Filled symbols indicate values that are significantly different from placebo; data points that do not share a common letter are significantly different from one another (p