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

• Published in: Psychopharmacology Vol. 237; no. 1; pp. 45 - 53
• Main Authors: Huang, Ming-Chyi, Chen, Chun-Hsin, Chen, Lian-Yu, Chang, Hu-Ming, Chen, Chih-Ken, Lin, Shih-Ku, Xu, Ke
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2020; Springer; Springer Nature B.V
• Subjects: Abstinence; ACTH; Addictions; Adrenal glands; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - metabolism; Adult; Anxiety; Anxiety - metabolism; Biomedical and Life Sciences; Biomedicine; Case-Control Studies; Corticosteroids; Cortisol; Craving - physiology; Depression, Mental; Depressive Disorder - metabolism; Drug abuse; Female; Hormones; Humans; Hydrocortisone - metabolism; Hypothalamo-Hypophyseal System - metabolism; Hypothalamus; Ketamine; Ketamine - adverse effects; Male; Medical colleges; Medical research; Medicine, Experimental; Mental depression; Middle Aged; Neurosciences; Orexins; Orexins - metabolism; Original Investigation; Pharmacology/Toxicology; Phenotypes; Pituitary; Pituitary-Adrenal System - metabolism; Psychiatric Status Rating Scales; Psychiatry; Reinforcement; Stress response; Substance Withdrawal Syndrome - metabolism; Substance-Related Disorders - metabolism; Substance-Related Disorders - psychology; Withdrawal; China; Taiwan; Cortisol; Adrenocorticotropic hormone (ACTH); Orexin (hypocretin); Abstinence; Ketamine dependence
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-019-05342-9

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.