Ketamine Sustains and Enhances the Protective Effects of a Ketogenic Diet Against Relapses in an Anorexia Mouse Model
Yiru Dong, Jundi Wang, Olivia Ge, Yuki Lin, Chiye Aoki
Hippocampus October 7, 2025 DOI: 10.1002/hipo.70039 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study (Activity-Based Anorexia model) Peer reviewed |
|---|---|
| Population | Activity-Based Anorexia (ABA) animal model |
| Interventions | Ketogenic diet Ketamine |
| Dose | sub-anesthetic ketamine |
| Duration | Two ABA inductions with 10 recovery days between; protection sustained >10 days |
| Topics | Esketamine Ketamine |
| Key findings | Ketogenic diet reduced relapse-like vulnerability in the Activity-Based Anorexia model, but only while maintained; adding sub-anesthetic ketamine sustained and boosted this protection for more than 10 days even after both were withdrawn, supporting clinical reports that short-term KGD plus KET may help prevent anorexia nervosa relapse. Electron microscopy suggested KGD increases GABAergic synapse lengths. |
Abstract
Anorexia nervosa (AN) has high mortality and relapse rates, yet no accepted pharmacotherapies. Reports based on six individuals suggest that ketogenic diet (KGD) combined with sub‐anesthetic ketamine (KET) is an effective treatment. The animal model, Activity‐Based Anorexia (ABA), captures AN's maladaptive behaviors of voluntary food restriction, excessive exercise, severe weight loss, heightened anxiety and relapse vulnerability. Using ABA, we tested whether (1) KGD, alone, can protect against relapses after a severe anorexia‐like experience; (2) KGD must be maintained to prevent relapses; (3) sub‐anesthetic KET combined with KGD is more ameliorative than KGD alone. We also (4) explored KGD's mechanism for protecting against relapses by electron microscopic (EM) analysis of synapses in the hippocampus. To simulate AN relapses, we imposed ABA induction twice (ABA1, ABA2), with 10 recovery days in between. Animals were fed a standard diet (SD, pellet plus wet food) during ABA1 and KGD during ABA2 (SD ➔ KGD). ABA vulnerability, measured by food restriction‐evoked hyperactivity and weight loss, was severe during ABA1 but significantly less during ABA2, compared to those fed SD throughout ABA1 and ABA2 (SD ➔ SD). KGD withdrawal after ABA1 (KGD ➔ SD) caused vulnerability during ABA2 to become as severe as for the SD ➔ SD, indicating that KGD must be maintained to be protective. We tested whether KET plus KGD during ABA1 can protect against ABA2 relapse in the absence of KGD or KET (KGD + KET ➔ SD). During ABA2, KGD + KET ➔ SD exhibited low maladaptive behaviors, similarly to those maintained on KGD throughout ABA1 and ABA2 (KGD ➔KGD), with greater weight during recovery. Thus, KET sustains and boosts KGD's benefits for > 10 days, supporting clinical findings that short‐term KGD + KET may be an effective treatment for preventing AN relapses. EM revealed that KGD increases GABAergic synapse lengths and may reduce ABA vulnerability by increasing excitatory synaptic drive of GABAergic interneurons and increasing E‐to‐E synapses' role in body weight regulation.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 4
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- Subanesthetic Ketamine Ameliorates Activity-Based Anorexia of Adult Mice. Synapse 2025
- Bridging rapid and sustained antidepressant effects of ketamine Trends in molecular medicine March 1, 2023
- Individual differences in the positive outcome from adolescent ketamine treatment in a female mouse model of anorexia nervosa involve drebrin A at excitatory synapses of the medial prefrontal cortex Synapse September 19, 2022