Progressive weight loss is attenuated by THC treatment in rats with activity-based anorexia

Anorexia nervosa (AN) is a severe psychiatric disorder with limited effective pharmacological treatments. Given the role of the endocannabinoid system (ECS) in regulating energy balance and its possible involvement in AN pathophysiology, cannabinoid-based interventions may hold therapeutic potential. Using the preclinical activity-based anorexia (ABA) model, we investigated whether Δ⁹-tetrahydrocannabinol (THC) could attenuate the progression of ABA-induced weight loss. Female rats were exposed to the ABA paradigm, which combines restricted food access (2 h/day) with unrestricted access to running wheels. After 3 days, when ABA rats had lost 10-12% of their baseline body weight, they received daily injections of either THC or vehicle. Rats were removed from the paradigm after losing 23% of their body weight or on the morning of day 8, whichever occurred first. THC treatment significantly attenuated weight loss and prolonged survival in the paradigm. These beneficial effects of THC were mediated by a selective suppression of excessive dark- and light-phase wheel running with no additional effects on food intake. These findings provide the first evidence that initiating THC treatment after significant weight loss in the ABA paradigm can halt the progression of weight loss through a selective decrease in energy expenditure. Importantly, treatment was initiated after (rather than before) the emergence of ABA-induced weight loss, thus enhancing the translational relevance of the model and our findings. Together, these findings suggest that pharmacological activation of the ECS may represent a promising treatment for individuals with AN.