Effects of Acute Ketone Supplementation on the Brain (KETO-BRAIN)

Effects of Acute Ketone Supplementation on the Brain [KETO-BRAIN]

The purpose of this study is to determine how a ketone ester supplement affects brain function, brain blood flow, and brain metabolism in healthy middle-aged and older adults. Ketones are naturally produced by the body during periods of fasting or carbohydrate restriction and serve as an alternative fuel source for the brain. Researchers are interested in whether increasing blood ketone levels through supplementation can alter brain activity and blood flow in ways that may support healthy brain function.

Participants will consume a ketone ester supplement and a placebo in separate study visits. Brain imaging, blood measurements, and cognitive testing will be used to evaluate the effects of each intervention. Findings from this study will help researchers better understand how ketones influence the healthy aging brain and may provide preliminary data for future studies in populations at risk for cognitive decline.

Study Overview

• Status: Recruiting
• Conditions: Brain Health
• Intervention / Treatment: Dietary supplement: Ketone Ester Drink; Dietary supplement: Placebo

Detailed Description

Alzheimer's disease and other age-related neurodegenerative conditions are associated with changes in brain energy metabolism that can occur years before symptoms develop. One of the earliest findings in these conditions is reduced utilization of glucose by certain brain regions. Ketones, including beta-hydroxybutyrate, can serve as an alternative fuel source for the brain and may help support brain metabolism when glucose utilization is impaired. Experimental evidence also suggests ketones may influence cerebral blood flow, neurotransmitter balance, and functional brain connectivity.

Despite growing interest in ketone supplementation, the acute effects of ketone esters on multiple aspects of human brain function have not been comprehensively evaluated. This study will investigate whether acute ketone ester ingestion alters cerebral blood flow, brain neurochemistry, resting-state brain connectivity, and cognitive performance in healthy adults.

This is a randomized, double-blind, placebo-controlled crossover study. Participants will complete two intervention periods, receiving a ketone ester supplement during one period and a calorie-matched placebo during the other. The order of interventions will be randomized and separated by a washout period of 3 to 7 days. Participants will consume study beverages for two days prior to each testing session and will undergo detailed testing following an overnight fast.

At each testing visit, participants will provide fingerstick blood samples to measure ketone and glucose concentrations, complete standardized cognitive testing, and undergo advanced magnetic resonance imaging (MRI). Brain imaging will include arterial spin labeling (ASL) to evaluate cerebral blood flow, proton magnetic resonance spectroscopy (1H-MRS) to assess brain metabolite and neurotransmitter concentrations, and functional MRI (fMRI) to assess resting-state brain network connectivity. Cardiac MRI measures will also be collected to explore relationships between cardiovascular and cerebrovascular responses.

The primary goal is to determine whether acute ketone supplementation changes cerebral blood flow, brain metabolite concentrations, and functional brain connectivity compared with placebo. Secondary analyses will evaluate relationships between blood ketone concentrations, imaging measures, and cognitive performance. Results from this pilot study will provide important mechanistic information regarding how ketones affect the healthy aging brain and will support the development of future clinical trials in populations at risk for cognitive impairment.

The study lasts about two weeks. There are two main test days with 3-7 days in between. Each testing session will last up to 3.5 hours at most.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Christopher Crabtree, Ph.D.; Phone Number: 614-688-5623; Email: Christopher.Crabtree@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • The Ohio State University
      • Contact: Christopher Crabtree, Ph.D.; Phone Number: 614-688-5623; Email: Chrisstopher.Crabtree@osumc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Age ≥45 years and ≤65 years
2. Able to comply with study requirements including presenting for each test session following an overnight fast and not following a ketogenic diet during the duration of the study.
3. BMI between 18.5 and 30 kg/m2

Exclusion Criteria:

1. Non-English Speaking
2. Currently taking a ketone ester supplement, ketone salt supplement, or on a ketogenic diet
3. Pregnancy, a urine pregnancy test will be given to all women before scanning to confirm nonpregnant status
4. Currently breastfeeding
5. Allergies to components in the test products, including milk protein, and not lactose intolerant
6. History of high blood pressure
7. History of alcoholism (previous 2 years)
8. History of illicit drug use
9. History of head trauma involving loss of consciousness or skull fracture
10. Diagnosed neurological disease
11. Taking psychiatric prescriptive medications (antipsychotics, antidepressants, or barbiturates) or over-the-counter (OTC) medications (other than those taken as nutritional supplements for non-therapeutic indications)
12. Current smoker
13. Currently consuming a habitual ketogenic diet, or was consuming a habitual ketogenic diet in the past three months
14. Any condition or material in the body that is a contraindication for MRI procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ketone Supplement drink; Drink contains 25 g of C8 Diester , 50g consumed total per day using split dose	Dietary supplement: Ketone Ester Drink; The ketone ester beverage contains 25 g of C8 Diester emulsified in a matrix of water, whey protein concentrate, modified gum acacia, natural and artificial flavors and cocoa powder. It contains 210 kcal, 0.5 g fat, 2 g carbohydrates, and 2 g protein. Dose consumed is 50 g, 2 times per day for 2 days. The placebo (PL) will be calorie and volume matched to the KE and be formulated with standard dietary ingredients.
Placebo Comparator: Placebo Drink; Drink contains no ketones, kcal and volume matched	Dietary supplement: Placebo; The placebo drink will be calorie and volume matched to the KE and be formulated with standard dietary ingredients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral Blood Flow	To detect a clinically meaningful difference in cerebral blood flow (CBF) between ketone ester and placebo conditions in healthy adults	Acute response following 2-day lead in
Brain Glutamate Concentration	To detect a difference in brain glutamate concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS).	Acute response following 2-day lead in
Brain GABA Concentration	To detect a difference in brain gamma-aminobutyric acid (GABA) concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS).	Acute response following 2-day lead in
Brain Lactate Concentration	To detect a difference in brain lactate concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS).	Acute response following 2-day lead in
Brain Choline Concentration	To detect a difference in brain choline concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS).	Acute response following 2-day lead in
Brain N-Acetylaspartate (NAA) Concentration	To detect a difference in brain N-acetylaspartate (NAA) concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS).	Acute response following 2-day lead in
Brain Glucose Concentration	To detect a difference in brain glucose concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS).	Acute response following 2-day lead in
Brain Beta-Hydroxybutyrate (BHB) Concentration	To detect a difference in brain beta-hydroxybutyrate (BHB) concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS).	Acute response following 2-day lead in
Functional Brain Connectivity	Change in resting-state brain network connectivity measured using blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI).	Acute response following 2-day lead in
Brain Acetoacetate Concentration	To detect a difference in brain acetoacetate concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS).	Acute response following 2-day lead in
Brain Glutamine Concentration	To detect a difference in brain glutamine concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS).	Acute response following 2-day lead in

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Ketone Concentration	Blood beta-hydroxybutyrate concentrations measured by fingerstick testing.	Acute response following 2-day lead in
Blood Glucose Concentration	Blood glucose concentrations measured by fingerstick testing.	Acute response following 2-day lead in
Cognitive Performance (RBANS Total Scale Score)	Total Scale Score on the RBANS, comparing ketone ester and placebo conditions in healthy adults.	Acute response following 2-day lead in

Collaborators and Investigators

• Sponsor: Christopher Crabtree

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: July 13, 2026
• First Submitted That Met QC Criteria: July 16, 2026
• First Posted (Actual): July 17, 2026

Study Record Updates

• Last Update Posted (Actual): July 17, 2026
• Last Update Submitted That Met QC Criteria: July 16, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: brain MRI; ketone supplement; brain MRS
• Other Study ID Numbers: STUDY20251460

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Decision on data sharing not yet finalized.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No