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

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Abstract

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.

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Funding

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).

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Correspondence to Chih-Ken Chen or Shih-Ku Lin.

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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).

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The authors declare that they have no conflict of interest.

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Huang, MC., Chen, CH., Chen, LY. et al. Chronic ketamine abuse is associated with orexin-A reduction and ACTH elevation. Psychopharmacology 237, 45–53 (2020). https://doi.org/10.1007/s00213-019-05342-9

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