, Volume 237, Issue 1, pp 45–53 | Cite as

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 ChenEmail author
  • Shih-Ku LinEmail author
  • Ke Xu
Original Investigation



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.


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.


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.


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.


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


Funding information

This study was supported by grants from Ministry of Science and Technology, Taiwan (106-2314-B-532-005-MY3 and 106-2314-B532-008-MY2); Chang Gung Memorial Hospital, Taiwan (CMRPG2D0261, CGRPG2F0021, CRRPG2G0051, CDRPG2E0012, CPRPG2E0011, CMRPG8C1291, and CMRPG8D0481); and Taipei City Hospital (TPECH 10701-62-029 and 108-01-62-005; TPCH 107-057 and 108-57).

Compliance with ethical standards

This study was conducted at Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan after obtaining approval from its Institutional Review Board (no. TCHIRB-1030408).

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Psychiatry, Taipei City Psychiatric CenterTaipei City HospitalTaipei CityTaiwan
  2. 2.Department of Psychiatry, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  3. 3.Psychiatric Research CenterTaipei Medical University HospitalTaipeiTaiwan
  4. 4.Department of Psychiatry, Wan-Fang HospitalTaipei Medical UniversityTaipeiTaiwan
  5. 5.Institute of Epidemiology and Preventive MedicineNational Taiwan UniversityTaipeiTaiwan
  6. 6.Department of Psychiatry & Community Medicine Research CenterChang Gung Memorial HospitalKeelungTaiwan
  7. 7.Chang Gung University School of MedicineGue-Shan District Taoyuan CityTaiwan
  8. 8.Department of PsychiatryYale University School of MedicineNew HavenUSA

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