Chronic ketamine abuse is associated with orexin-A reduction and ACTH elevation

Ming Chyi Huang, Chun Hsin Chen, Lian Yu Chen, Hu Ming Chang, Chih Ken Chen, Shih Ku Lin*, Ke Xu

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

14 Scopus citations


Background: Ketamine has emerged as a major substance of abuse worldwide. Evidence suggests a role of orexin system in reward processing, withdrawal, and stress response. It also interacts with the stress mechanisms of hypothalamic–pituitary–adrenal (HPA) axis to regulate drug-taking behavior. The study aimed to explore the relevance of orexin and stress hormones to chronic ketamine abuse. Methods: We enrolled 67 ketamine-dependent (KD) patients and 64 controls. The levels of orexin-A, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline, 1 week, and 2 weeks after ketamine discontinuation. KD patients were assessed by Beck Depression Inventory, Beck Anxiety Inventory, and Visual Analogue Scale for ketamine craving at baseline. Results: Compared with the controls, KD patients had significantly lower orexin-A (0.65 ± 0.12 vs. 0.74 ± 0.10 ng/mL, p < 0.001) and increased ACTH (32.3 ± 16.3 vs. 22.3 ± 11.0 pg/mL, p = 0.008) levels at baseline, whereas cortisol levels were similar between two groups. Levels of the three markers did not correlate with ketamine use variables, craving, depression, or anxiety symptoms. The levels did not alter after 1 or 2 weeks of ketamine discontinuation. Notably, those with higher anxiety had lower orexin-A but increased cortisol levels than did those with lower anxiety. Conclusions: This study showed that KD patients had persistent orexin-A reduction and stress hormone dysregulation in early abstinence. The anxious phenotype of KD might be associated with a lower orexin-A expression. These results point to a promising pathway to investigate the neurochemical mechanisms of ketamine addiction.

Original languageEnglish
Pages (from-to)45-53
Number of pages9
Issue number1
StatePublished - 01 01 2020

Bibliographical note

Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.


  • Abstinence
  • Adrenocorticotropic hormone (ACTH)
  • Cortisol
  • Ketamine dependence
  • Orexin (hypocretin)


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