Recovery without reset: physiological-neural dissociation in anorexia nervosa – pilot study of orexin, endocannabinoid and opioid systems

Background

Recovery in anorexia nervosa (AN) is typically defined by weight restoration; however, the relationship between metabolic signals and circuits regulating motivation, reward and stress remains poorly understood. Dysregulation of orexinergic, opioid and endocannabinoid systems has been proposed as a mechanism linking AN with addiction-like features. These systems are critically involved in integrating energy balance with motivational drive and behavioral regulation. The interaction between metabolic signals (e.g., leptin) and hypothalamic circuits regulating motivation (e.g., orexin) may play a key role in the persistence of restrictive behaviors. However, longitudinal data in adolescent populations integrating these systems remain scarce, particularly in the context of treatment-related changes.

Aims

We hypothesized that metabolic recovery would be associated with normalization of neurobiological systems regulating motivation and reward.

Methods

This pilot longitudinal study included 25 female adolescents aged 11–20 years with AN, assessed at admission and discharge following inpatient treatment. A healthy control group (n = 10) was included for baseline comparison. Plasma concentrations of orexin A, leptin, β-endorphin, dynorphin, anandamide (AEA), 2-arachidonoylglycerol (2-AG), and homovanillic acid (HVA) were measured. Analyses focused on within-subject changes and associations between metabolic and neurobiological markers related to reward, anti-reward, and motivational regulation. Given the exploratory nature of the study, analyses emphasized effect direction, variability, and biological plausibility.

Results

Leptin levels increased significantly during hospitalization, indicating improvement in energy balance (p < 0.05). In contrast, orexin A showed no uniform direction of change, with both increases and decreases across individuals and marked inter-individual variability. No significant association was observed between changes in leptin and orexin (p > 0.05), indicating a dissociation between metabolic recovery and central motivational regulation.

Within the opioid system, β-endorphin showed high variability, whereas dynorphin remained relatively stable, with persistently elevated levels in a subset of patients, consistent with sustained anti-reward activation. Changes in leptin were negatively associated with anandamide (r = - 0.35, p < 0.05), while no consistent pattern was observed for 2-arachidonoylglycerol. Dopaminergic activity (HVA) did not show a uniform response. Overall, substantial inter-individual variability across all systems suggested the absence of a single neurobiological trajectory.

Conclusions

Metabolic improvement during treatment is not accompanied by normalization of neurobiological systems involved in motivation, reward, and stress regulation. The observed dissociation between leptin and orexin suggests that hypothalamic circuits regulating motivational drive may remain active despite restoration of energy balance. Within an addiction-like framework, variable reward signaling (β-endorphin), persistent anti-reward activation (dynorphin), and dysregulated motivational drive (orexin) may contribute to the maintenance of restrictive behaviors independent of metabolic need. The observed heterogeneity suggests that these mechanisms may apply to a subgroup of patients, supporting the existence of biologically distinct phenotypes of AN, including a potential addiction-like subtype, and highlighting the need for more individualized treatment approaches. These findings are exploratory and require replication in larger, well-characterized cohorts.

References

Ziemichód, W., Kajka, N., Rząd, Z., Metelska, A., Janas-Kozik, M., Biała, G., Wilczyński, K. M., Grabowska, K., & Karakuła-Juchnowicz, H. (2026). Rethinking anorexia nervosa through the lens of control, compulsion and reward: Neurobiological insights into addiction-like features via the dopaminergic, endocannabinoid, and orexinergic systems - A narrative review. Neuroscience and biobehavioral reviews, 185, 106615. https://doi.org/10.1016/j.neubiorev.2026.106615