, Volume 232, Issue 5, pp 871–883 | Cite as

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

  • Chad J. ReissigEmail author
  • Joseph A. Harrison
  • Lawrence P. Carter
  • Roland R. GriffithsEmail author
Original Investigation



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


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.


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.


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.


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.


Alprazolam Oral Inhalation Staccato® Abuse potential Liking Performance Drug abusers Humans 


Acknowledgments and disclosures

Conduct of this research was supported by Alexza Pharmaceuticals, Inc. and NIH grant T32DA07209. Manuscript preparation was supported in part by NIH grant R01DA03889. We thank Janna Steinberg and Jill Griffith for serving as assistant session monitors, John Yingling for technical assistance, and Linda Felch for statistical assistance. The study was conducted in compliance with US laws. Dr. Carter is an employee of Jazz Pharmaceuticals, Inc. and has received stock and stock options for shares of Jazz Pharmaceuticals plc. Dr. Reissig is an employee of the US Food and Drug Administration (FDA), however, the views presented in this article do not necessarily reflect those of the FDA and no official support or endorsement of this article by the FDA is intended or should be inferred.

Supplementary material

213_2014_3721_MOESM1_ESM.docx (34 kb)
ESM 1 (DOCX 34 kb)
213_2014_3721_MOESM2_ESM.docx (33 kb)
ESM 2 (DOCX 33 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of Pharmacology and ToxicologyUniversity of Arkansas for Medical SciencesLittle RockUSA

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