Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, 309, Song-De Road, Xinyi District, Taipei City, 110, Taiwan.
Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing St., Taipei, 110, Taiwan.
Psychopharmacology (Berl). 2020 Jan;237(1):45-53. doi: 10.1007/s00213-019-05342-9. Epub 2019 Aug 3.
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.
氯胺酮已成为全球范围内的主要滥用物质。有证据表明，食欲素系统在奖赏处理、戒断和应激反应中起作用。它还与下丘脑-垂体-肾上腺 (HPA) 轴的应激机制相互作用，调节药物摄取行为。本研究旨在探讨食欲素和应激激素与慢性氯胺酮滥用的相关性。
我们招募了 67 名氯胺酮依赖（KD）患者和 64 名对照。在氯胺酮停药后 1 周和 2 周时，测量基线、基线时的食欲素-A、促肾上腺皮质激素（ACTH）和皮质醇水平。KD 患者在基线时通过贝克抑郁量表、贝克焦虑量表和视觉模拟量表评估氯胺酮渴求。
与对照组相比，KD 患者的食欲素-A 水平明显降低（0.65 ± 0.12 vs. 0.74 ± 0.10 ng/mL，p < 0.001），ACTH 水平升高（32.3 ± 16.3 vs. 22.3 ± 11.0 pg/mL，p = 0.008），而两组间皮质醇水平无差异。这三个标志物的水平与氯胺酮使用变量、渴求、抑郁或焦虑症状均无相关性。停药 1 或 2 周后，水平无变化。值得注意的是，焦虑程度较高的患者食欲素-A 水平较低，皮质醇水平较高。
本研究表明，KD 患者在早期戒断时存在持久的食欲素-A 减少和应激激素失调。KD 的焦虑表型可能与食欲素-A 表达降低有关。这些结果为研究氯胺酮成瘾的神经化学机制提供了一个有希望的途径。
