Table 2 Human studies investigating effects of exogenous ketone administration

Metabolic effects

Owen and colleagues [83]

Effect of ketones on insulin and free fatty acid release. Sodium AcAc given as i.v. infusion 1 mmol/kg over 2 hours to 12 normal adults after overnight fast

AcAc levels 4.74 mmol/l after 30 minutes. Utilization of ketones increased with rising blood concentrations to a maximum of 13 g/24 hours. Glucose remained normal

Miles and colleagues [82]

Evaluation of protein-sparing effects of i.v. infusion of NaBHB in six healthy adults

Ketone levels reached 2.33 mmol/l. No protein sparing, significant alkalosis

Hiraide and colleagues [81]

Twenty patients following severe trauma: 11 patients received i.v. 20% solution NaBHB at 25 μmol/kg/minute for 3 hours, and nine patients received sodium lactate

Ketone levels reached 1.5 mmol/l. Alanine release decreased in ketone group, suggesting a suppression of post-traumatic protein catabolism. Significant increase in sodium and pH

Dashti and colleagues [80]

64 healthy obese adults with and without diabetes fed ketogenic diet for 56 weeks

Body mass index, glucose, total and low-density lipoprotein cholesterol decreased significantly whereas high-density lipoprotein increased

Central nervous system effects

Pan and colleagues [35]

Six healthy adults infused with NaBHB at a bolus rate of 80 μmol/kg/minute, then 20 μmol/kg/minute for 75 minutes. BHB brain levels measured by MRI

BHB blood levels reached 2.12 mmol/l. BHB brain levels increased to 0.24 mmol/l. Levels lower then noted in fasted individuals suggesting differences in brain transport of ketones in fasted state

Pan and colleagues [34]

Five healthy adults. Ketones measured in brain using MRI in nonfasted state and after 2 and 3 days of fast

Plasma and brain BHB levels correlated well, with brain BHB ranging from 0.05 mmol/l in nonfasted state to 0.98 mmol/l after 3 days of fasting

Blomqvist and colleagues [79]

Six healthy and six diabetic patients received infusion of BHB at 3 to 6 mg/kg/minute for 60 minutes followed by bolus of B-[11C]HB. PET scan was performed

Utilization rate of ketones increase proportionally with plasma concentrations. Rate-limiting step for ketone body utilization is transport into the brain

Hasselbalch and colleagues [85]

Permeability of blood-brain barrier to BHB was assessed following a 3.5-day fast

Increase cerebral ketone influx during starvation determined by amount of ketone present in blood

Ritter and colleagues [78]

Twenty head-injured patients assigned to conventional or ketogenic diet for 2 weeks

Group receiving a ketogenic diet demonstrated improved glucose control with higher ketone levels. Cerebral lactate was similar

Smith and colleagues [77]

NaBHB i.v. solution known as KTX 0101 for neuroprotection post CABG. Details of study protocol not available

Phase Ia study not published

Hasselbalch and colleagues [50]

Eight healthy adults received i.v. infusion of NaBHB at 4 to 5 mg/kg/minute for 3 hours. Cerebral blood flow measured using Kety-Schmidt technique

Increased cerebral uptake of ketones was counterbalanced by reduction in glucose metabolism. Cerebral metabolic rate was unchanged, but cerebral blood flow increased

Reger and colleagues [84]

Twenty adults with Alzheimer's disease were randomized to receive a MCT diet or placebo on two occasions

On cognitive testing, MCT treatment facilitated performance for ε4-negative but not ε4-positive subjects. Also greater improvement with MCT treatment relative to placebo