Discover how targeting brain metabolism with a ketogenic diet could transform the approach to this challenging eating disorder.
Review: Therapeutic ketogenic diet as treatment for anorexia nervosa. Image Credit: Patnaree Asavacharanitich
A recent study published in the journal Frontiers in Nutrition presented a neurobiological model supporting a therapeutic ketogenic diet (TKD) for anorexia nervosa (AN). This model integrates behavioral traits, brain neural energy metabolism, and neurotransmitter function, providing a comprehensive framework for understanding how TKD might address the underlying neurobiological mechanisms of AN.
AN is a severe, chronic psychiatric illness characterized by severe emaciation, food avoidance, and a perception of being overweight. AN has a high disease burden, treatment cost, and frequent relapse. Besides, treatment effectiveness is limited, and the mortality rate is 12 times higher in females aged 15–24 compared to death from all causes.
Further, upon weight recovery in people with AN (wrAN), fears of body dissatisfaction, body image distortion, and weight gain are elevated, which may persist for years. The neural mechanisms underlying self-starvation are unclear. Therefore, understanding the core behaviors in AN and wrAN can help develop effective therapies. The present study proposed a neurobiological model supporting TKD for AN, which not only targets the metabolic alterations associated with the disorder but also addresses the psychological factors contributing to its persistence and severity.
The proposed model suggests that stress and anxiety, combined with perfectionistic traits, interfere with normal brain glucose utilization in individuals predisposed to AN. This disrupted glucose metabolism triggers a shift to ketone bodies as an alternative energy source, which, in turn, reinforces the cycle of self-starvation and anxiety relief.
Anorexia nervosa neurobiology
Studies have reported alterations in brain structure, neurotransmitter systems, and specific brain circuits in AN. Previously, the authors found that weight loss and food avoidance in AN altered circuits processing reward valence and motivation salience. People with AN overestimate their body size despite being underweight and lean.
Environmental factors like social media messages may trigger such thoughts, conditioning a fear response. Unpleasant feelings contribute to negative affect and may drive AN behavior. For instance, worrying has been associated with fasting and fear of weight or fat gain in people with AN and wrAN. In wrAN, negative affect is associated with the perception of inefficiency.
Difficulties with emotion regulation and negative affect linger into recovery and could be risk factors for relapse. Further, stress can influence glucose metabolism, and it is speculated that stress-related disorders could be linked with altered glucose metabolism. Besides, research in cancer patients has revealed negative correlations between negative affect and glucose metabolism in subcortical and cortical brain regions.
The neurobiological model proposed by the researchers integrates these findings to suggest that AN could be viewed as a disorder where metabolic and psychological factors interact in a self-perpetuating cycle. The shift to a ketogenic state in response to stress-induced glucose metabolism disruptions might temporarily alleviate anxiety, thus reinforcing the cycle of starvation.
Anorexia nervosa as a metabolic disorder
Metabolic abnormalities have been reported in AN, with genetic studies implicating metabolic traits as risk factors for AN. Stress increases glucose allocation to the brain, albeit its utilization (in the brain) is not elevated. This increased glucose need may deplete energy resources, and reduced utilization may result in overeating.
People with AN have perfectionistic traits and high trait and state anxiety, which may interfere with brain glucose utilization before, during, and after weight loss. The researchers hypothesize that in individuals predisposed to AN, reduced glucose utilization, despite high demand, contributes to the development and maintenance of the disorder. As such, people with this disposition lose weight and enter a ketosis state, wherein ketones are used as an alternative source of energy. Therefore, the researchers believe that providing ketone bodies to such individuals will eliminate self-starvation and support weight maintenance.
Therapeutic ketogenic diet and a neurobiological model
TKD is similar to fasting in several aspects. During fasting, an energy deficit occurs as glucose and insulin levels decline, leading to an increased white fat metabolism and the generation of fatty acids to supplement energy requirements. Besides, most energy in a TKD is supplied as fat, which is converted into fatty acids. Fatty acids are converted into acetyl-coenzyme A (acetyl-CoA).
Acetyl-CoA is shunted to ketogenesis when fatty acid levels surpass the metabolic capacity of the tricarboxylic acid cycle. Exogenous ketones and TKD are associated with changes in glucose metabolism in the brain. Higher blood ketone levels lead to lower glucose uptake in the brain. One study reported that infusing beta-hydroxybutyrate (BHB), a ketone body, decreased brain glucose uptake and improved blood flow.
As such, TKD could be an effective treatment for AN to eliminate self-starvation and normalize energy homeostasis. The researchers conceptualized a neurobiological model for TKD as a therapeutic intervention for AN. Accordingly, under typical conditions, the brain uses glucose to generate energy; however, in AN, elevated anxiety and perfectionism result in stress, reducing glucose utilization despite heightened demand.
Body dissatisfaction and the urge for thinness in vulnerable individuals lead to starvation. Imbalances between intake and energy demands result in ketone production and the use of BHB, acetoacetate (ACA), and acetone as the energy source in the brain. Ketosis elevates the synthesis of gamma-aminobutyric acid (GABA) from glutamate and glutamine, which might reduce anxiety and help regulate emotion.
Ketosis also improves brain energy supply, stabilizes neuronal function, and further drives a positive feedback mechanism to promote starvation-mediated ketosis. An energy-rich ketogenic diet for weight gain in AN or weight maintenance in wrAN replaces starvation-driven ketosis with nutritional ketosis.
This neurobiological model also proposes that the increased synthesis of gamma-aminobutyric acid (GABA) from glutamate and glutamine during ketosis could help regulate emotion and reduce anxiety, further supporting the rationale for TKD as a therapeutic approach.
Pilot study
A case study revealed that TKD, followed by ketamine infusion, recovered a patient with AN. Building upon this, the researchers performed an open-label trial to replicate the findings. Five wrAN adults with persistent thoughts and behaviors of eating disorders were started on a TKD for weight maintenance. They received ketamine infusions after 4–8 weeks of stable ketosis.
All subjects followed the TKD for at least eight weeks. Participants exhibited significant improvements in the eating disorder examination questionnaire (EDEQ), EDEQ weight and shape concerns, clinical impairment assessment, eating disorders recovery questionnaire (EDRQ), social and emotional connection, and EDRQ acceptance of self and body.
Body weight was stable throughout the trial. These measures showed substantial improvements even before introducing ketamine infusions, suggesting TKD alone was effective. Four subjects have remained recovered for one year at least. One participant who ceased TKD after eight weeks had a relapse four months later.
It is important to note that these findings are preliminary and based on a small sample size. While the initial results are promising, further research in larger, more diverse populations is needed to confirm the efficacy and safety of TKD as a treatment for AN.
Concluding remarks
In sum, AN, a severe psychiatric disorder, still lacks approved biological interventions. The neurobiological model and preliminary clinical data suggest that targeting brain metabolism might provide a novel therapeutic avenue for AN. A follow-up study is underway in a larger wrAN sample to assess reductions in AN-specific behaviors, thoughts, and feelings. Future studies should also investigate TKD in underweight people with AN.
The researchers caution that while TKD shows potential, more extensive trials are necessary to establish its role in the standard treatment of AN. The integration of metabolic and psychological factors in the proposed model highlights the complexity of AN and the need for multifaceted approaches to its treatment.