Preliminary examination of the orexin system on relapse-related factors in cocaine use disorder

Brain Res. 2020 Mar 15;1731:146359. doi: 10.1016/j.brainres.2019.146359. Epub 2019 Jul 30.


Rationale: Current evidence and literature reviews provide a strong justification for examining the orexin receptor (OXR) system as a therapeutic target in substance use disorders, including cocaine and other psychostimulants.

Objectives: In this preliminary, proof-of-concept examination of orexin modulation in humans with cocaine use disorder, we measured changes in domains tied to relapse: stress, sleep, cue reactivity, and inhibitory control. Additionally, mood symptoms (anxiety, depression), medication compliance, and side effects were assessed.

Methods: Twenty non-treatment seeking subjects with cocaine use disorder (CUD) received either the OX1R / OX2R antagonist suvorexant PO or placebo at 10 PM daily for two weeks (10 mg week 1, 20 mg week 2). Using psychometrics, smart-watch actigraphy, a cold-pressor stress challenge, and eye-tracking technology, the following domains were examined: sleep, stress/anxiety, cue-reactivity (attentional bias, craving), and inhibitory control. Psychometric data were collected every M/W/F (7 time points). Laboratory data were collected weekly (3 time points).

Results: Bayesian and frequentist generalized linear models were employed in parallel to examine the effects of suvorexant compared to placebo, with a Bayesian posterior probability threshold >80% as evidence of a signal for suvorexant. Notable results favoring suvorexant over placebo included fewer total anti-saccade errors, improved sleep actigraphy (sleep/awake periods), pre/post cold-pressor change in heart rate and salivary cortisol (all posterior probabilities >94%), and craving (posterior probability >87%).

Conclusions: Initial but restricted evidence is provided supporting the orexin system as a modulator of relapse-related processes in cocaine use disorder. Baseline differences in the main outcome variables were not experimentally controlled and differences in craving were observed at baseline. This, in combination with a limited sample size, constrain the nature of the project. The results may serve to inform more comprehensive future research.

Keywords: Cocaine use disorder; Cue reactivity; Inhibitory control; Orexin; Sleep; Suvorexant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Azepines / administration & dosage*
  • Cocaine-Related Disorders / physiopathology*
  • Cocaine-Related Disorders / prevention & control*
  • Executive Function / drug effects
  • Female
  • Humans
  • Inhibition, Psychological
  • Male
  • Middle Aged
  • Orexin Receptor Antagonists / administration & dosage*
  • Psychometrics
  • Recurrence
  • Secondary Prevention / methods*
  • Sleep / drug effects
  • Stress, Physiological / drug effects
  • Stress, Psychological / drug therapy
  • Triazoles / administration & dosage*


  • Azepines
  • Orexin Receptor Antagonists
  • Triazoles
  • suvorexant