Table 1.
Human studies of chronic and acute administration of medium-chain triglycerides (MCT) in healthy subjects and individuals suffering from Alzheimer's disease and Mild Cognitive Impairment.
| Condition | Administered substance |
Administered amount/
concentration |
Administration protocol | Measured ketone body levels | Measured MCFA levels | Cerebral and cognitive effects | Metabolic effects |
Molecular effects/
Mechanism of Action |
References |
|---|---|---|---|---|---|---|---|---|---|
| Elderly with mild to moderate dementia | MCT (C8) (Bulletproof Brain Octane ®) | 42 g/day | Total study duration 15 months. Double blind phase: 1-month titration, 3-month therapy; Crossover arm: 1-month titration, 3-month therapy; Extension phase: 1-month titration, 6-month therapy. The first month of each phase: a week of test oil with dosing titration from 15 mL once daily to three times daily (3 x 15 mL) by week three, if clinically tolerated, or to the maximum tolerated dose. Given with meals. |
Blood: 0.19 mM βHB (baseline) 0.22 mM βHB (end of study) | Not measured |
Improvement: Cognigram® 1 (attention and psychomotor function), Mini-Mental State Examination (MMSE) Montreal Cognitive Assessment (MoCA) No change: Cognigram® 2 |
No change in blood: βHB (morning fasting level) Total cholesterol Triglyceride HDL LDL | MMSE decliners: were on AChEI (acetyl cholinesterase inhibitors) therapy (3 of 4) were homozygous or heterozygous for the APOE ε4 allele (4 of 4) | (20) |
| MCI | MCT (60% C8 + 40% C10) | 30 g/day | MCT in lactose-free skim milk, twice a day, i.e. with breakfast and dinner, over a period of 6 months. | Blood: 0.54 mM βHB | Blood: 0.13 mM C8 0.16 mM C10 |
Improved: Language (Boston Naming Test) No change: Mini-Mental State Examination (MMSE) scores Montreal Cognitive Assessment (MoCA) scores Episodic memory tests Executive function tests Attention and processing speed tests |
Increased in blood: βHB AcAc No change in blood: Total cholesterol Triglycerides Glucose Glycated hemoglobin Creatinine Thyroid stimulating hormone Vitamin B12 |
Increased: Uptake and utilization of AcAc and βHB across the whole brain Positive linear correlation: Plasma ketone body concentration with some of the cognitive assessment scores, including the Boston Naming Test | (21) |
| MCI | MCT (60% C8 + 40% C10) | 30 g/day | MCT in lactose-free skim milk, twice a day, i.e. with breakfast and dinner, over a period of 6 months. | Reported previously (21) | Reported previously (21). | Cognitive scores reported previously (21). Increased: Functional connectivity within the dorsal attention network (DAN), Ketone uptake (11C-acetoacetate PET) specifically in DAN cortical regions, Fiber density within the DAN. |
Reported previously (21). | Improved: Brain network energy status Axonal integrity Positive correlation: Functional connectivity with ketone uptake Functional connectivity with improvement in cognitive tests targeting attention | (22) |
| Elderly nursing home residents | MCT (75% C8 + 25% C10) | 6 g/day | 6 g MCTs at breakfast or dinner for 1.5 months | Not measured | Not measured | Slightly increased Mini-Mental State Examination score (P=0.06) independently of timing | Not measured | NA | (23) |
| Alzheimer's disease (AD) | MCT (C8 + C10), MCT (C8) | 30 g/day | One month. The dose was progressively increased to reach a plateau of 30 g/day within a week and was split between 2 meals (15 g/125 mL per meal). | Blood: 0.46 mM βHB (MCT(C8C10)) 0.57 mM βHB (MCT(C8)) | Not measured |
Increased cerebral metabolic rates (CMR): - AcAc (C8C10 and MCT(C8): whole brain, white matter, subcortical, frontal, occipital, temporal, cingulate, gray matter), - Ketones (C8C10 and MCT(C8): whole brain). No change: - CMR of glucose (C8C10 and MCT(C8): whole brain, white matter, cerebellum, subcortical, frontal, occipital, temporal, parietal, cingulate, gray matter), - global or regional gray matter volume, - cortical thickness, - intra-cranial cerebrospinal fluid volume, - default mode network connectivity. |
Increased in blood: AcAc (C8C10) βHB (C8C10), Ketones (C8C10) Insulin (C8C10 and MCT(C8)) TG (C8C10) No change in blood: AcAc (MCT(C8)) βHB (MCT(C8)) Ketones (MCT(C8)) Red cell count White cell count Hemoglobin Glucose Albumin ALT AST Creatinine Sodium, Potassium Chloride Cholesterol TG (MCT(C8)) HDL LDL | Increased: Total brain energy metabolism Ketone supply without affecting brain glucose utilization | (24) |
| AD | MCT (75% C8 + 25% C10) | 20 g/day | MCT drink (20 g of MCT in total 39.5 g of fat, suspended in hot water) for 12-weeks along with usual diet. Blood sampling and cognitive testing: every 4 weeks. Blood sampling: -> fasting for 12 h -> blood sampling 1 -> MCT intake -> +120 min blood sampling 2. |
Blood: 0.47 mM βHB | Not measured |
Improved: Digit-symbol coding (Wechsler Adult Intelligence Scale-3rd Edition) Logical memory, immediate and delayed (Wechsler Memory Scale-Revised) Stroop effect (Stroop test) No change: Trail-making test |
Increased in blood: βHB AcAc | NA | (25) |
| AD | MCT (not specified) | 40 ml. | MCT: 40 ml MCT + 152 ml heavy whipping cream, Placebo: 232 ml heavy whipping cream. Two visits: -> overnight fasting -> blood sampling 1 and ApoE genotyping -> MCT intake -> +90 min blood sampling 2 -> 30-min cognitive testing -> blood sampling 3. |
Blood: 0.52 mM βHB (+120 min; ApoE4(-)) 0.68 mM βHB (+120 min; ApoE4(+)) | Not measured |
Improved: Performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog); ApoE4(-) subjects. No change: Performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog); ApoE4(+) subjects. |
Increased in blood: βHB |
βHB elevations were moderated by ApoE genotype: ApoE4(+) - βHB continued to rise between min 90 and 120 ApoE4(-) - βHB held constant between min 90 and 120 Positive correlation: Ketone values with improvement in paragraph recall |
(26) |
| AD | MCT (C8) | 10 g/day | MCT-containing powder was mixed with water, milk, or juice prior to consumption for 90 days. Five study visits: Screening, Baseline, and post-baseline Days 45, 90, and 104 (± 3 days). |
Blood (+90 min): 0.15 mM βHB (baseline post-dose) 0.36 mM βHB (Day 45 post-dose) 0.39 mM βHB (Day 90 post-dose) | Not measured |
Improved: Performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog); ApoE4(-) subjects (Days 45 and 90). No change: Performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog); ApoE4(+) subjects. |
Increased in blood: βHB | Positive correlation in APOE4(-) subjects: Total dosage of MCT with improvement in ADAS-Cog score Blood βHB level with improvement in ADAS-Cog score | (27) |
| AD | MCT (C8) | 20 g of MCT/day | 40 g/day of Axona drink (containing 20 g of C8) for 3-month | Blood: 0.32 mM βHB + AcAc | Not measured | In APOE4-negative subjects with baseline MMSE score of ≥14: Increased: Mini-Mental State Examination scores No change: Alzheimer's Disease Assessment Scale (ADAS) scores In APOE4-negative subjects with baseline MMSE score of <14 and APOE4-positive subjects: No change: Mini-Mental State Examination scores Alzheimer's Disease Assessment Scale (ADAS) scores | Not measured | NA | (28) |
| Mild cognitive impairment (MCI) | MCT | 56 g/day | 56 g of MCTs (MCT oil, Nestle™) mixed with fat-free fruit yogurt, 24 weeks | Blood: 0.39 mM βHB (after 4 weeks) 0.54 mM βHB (after 24 weeks) | Not measured |
In 1 (and only) APOE4-negative subject:
Improved: (statistical analysis was impossible due to small group size) Memory Overall cognitive assessment score In 1 (and only) APOE4-positive subject: Improved: (statistical analysis was impossible due to small group size) Memory |
Not measured | NA | (29) |
| Healthy adults | MCT (60% C8 + 40% C10) | 20 g/day | Overnight fasted subjects consumed two 250 mL carbohydrate-containing Peptamen® drinks (containing 10 g of MCT) 4 h apart | Blood: maximum ~0.28 mM at 30 min | Maximum in Blood: 0.15 mM at 30 min | NA | Not measured | Increased: Redox ratio NAD+/NADH in the brain | (30) |
| Type 1 diabetic patients in intensive care; insulin-induced hypoglycemia | MCT (67% C8 + 27% C10 + 6% other fatty acids) | 40 g | 20 g, 10 g, 10 g MCT with 25 min intervals given in 50 ml drink during stepwise hyperinsulinemic-euglycemic-hypoglycemic clamp studies | Blood: ~ 0.45 mM βHB (at 180 min) | Not measured | Improved: Hypoglycemia-induced impaired performance in tests of: - Verbal memory - Digit symbol coding - Digit span backwards - Map searching | Increased: plasma free fatty acids | NA | (31) |
| Healthy young adults | MCT (30% C8 + 70% C10) | 12 or 18 g/day | 12 g or 18 g MCT/day (as 6g gels 30 min prior to meals or cognitive testing; after overnight fasting when before breakfast) for 4 weeks | Not measured | Not measured | Improved: Trail Making A/B Digit Span Forwards/Backwards Spatial Span Backwards No changes: Attention Reaction time | Not measured | NA | (32) |
| Healthy elderly | MCT Ketogenic drink (C8 30% and C10 10% of total fatty acids) | 20 g | 50 g of low-carbohydrate Meiji817-B drink, single as emulsion after 12h fasting | Blood: 0.5 mM at 90 min | Not measured | Improved: Working memory Visual attention Task switching | Not measured | NA | (33) |
| Healthy elderly | MCT Ketogenic drink (C8 30% and C10 10% of total fatty acid) | 20 g | 50 g of low-carbohydrate Meiji817-B drink, single as emulsion after 12h fasting | Blood: ~ 0.7 mM βHB + AcAc | Not measured | Improved: (in subjects with reduced gray matter in dorsolateral prefrontal cortex) N-back task for attention NoGo task for inhibitory control | Not measured | Increased: Ketone body utilization in dorsolateral prefrontal cortex | (34) |
| Healthy adults | βHB | Infusion of 200 mmol/L sodium d-βHB | 200 mmol/L labeled sodium D-βHB infused at a bolus rate of 16.7 ml/min for 20 min, followed by 22 μmol/kg/min for 120 min | Blood: 2.2 mM βHB Brain: 0.15-0.25 mM βHB | Not measured | NA | NA | βHB is metabolized primarily in the neuronal compartment. | (35) |
| Children with epilepsy. Age 18 months to 18 years. | MCT (not specified) | 60% of total cal. | Given as an MCT-skimmed milk drink, in small sips throughout each meal. Total period 1–4 years. | βHB in Blood: Age 2–9 years: 2.9 mM (MCT diet < 1 month) 4.3 mM (MCT diet > 1 month) Age 10–18 years: 1.2 mM (MCT diet < 1 month) 1.6 mM (MCT diet > 1 month) | Not measured | A significantly greater proportion of children with mean BHB blood levels above 2 mM achieved good to excellent seizure control than did children with mean blood level <2 mM (chi-square = 5.8, P < 0.02). |
Increase: total fatty acids in plasma (vs pre-diet levels), acetoacetate in plasma (in children <9 y.o.) Decrease: glucose in plasma; No change: cholesterol in plasma, blood pH, acetoacetate in plasma (in children >9 y.o.). |
NA | (36) |
| Healthy adults | βHB | Infusion of 200 mmol/L sodium d-βHB | 200 mmol/L labeled sodium D-βHB infused at a bolus rate of 80 mm/kg/min followed by an adjusted 20 mm/kg/min for the duration of the infusion study of approximately 75 min. |
Blood: ~ 2.12 mM βHB (relatively stable from 12 to 75 min) Occipital lobe: ~ 0.24 mM βHB (within the first 30 min) |
Not measured | Not measured |
Increase: βHB in blood βHB in occipital lobe No change: Lactate level in blood Lactate in occipital lobe |
NA | (37) |
| Children with epilepsy | MCT (81.1% C8 + 15.7% C10) | Average 45.9% of total cal. Maximum 60% of total cal. | Starvation for 1–4 days, water-restricted diet until the urine is acid, MCT slowly introduced, full diet starting day 18. MCTs are given as “Liquigen” drink (emulsion of 52% MCT + 48% water). | Not measured | Mean in Blood (45.9% cal from MCT): 0.31 mM C8 0.16 mM C10 Maximum in Blood (60% cal from MCT): 0.74 mM C8 0.55 mM C10 | Not measured | Not measured | NA | (38) |
| Healthy adults | MCT (C8) 91% pure, MCT (C10) 91% pure MCT (55% C8 + 35% C10) | A 20 mL dose of each test oil was homogenized into 250 mL of lactose-free skim milk. | Five separate metabolic study days for each participant. 8-h metabolic study day: first 20 ml dose of the homogenized test oil taken with breakfast and a second 20 ml dose taken 4 h later without an accompanying meal. |
Maximum
βHB in Blood: +0.18 mM (MCT(C10)) +0.41 mM (MCT(C8C10)) +0.6 mM (MCT(C8)) Maximum AcAc in blood: +0.1 mM (MCT(C10)) +0.2 mM (MCT(C8C10)) +0.25 mM (MCT(C8)) Maximum βHB + AcAc in blood: +0.21 mM (MCT(C10)) +0.61 mM (MCT(C8C10)) +0.85 mM (MCT(C8)) |
Maximum in blood: + 0.1 mM C8 [MCT(C8C10)]+0.29 mM C8 [MCT(C8)] +0.1 mM C10 [MCT(C8C10)] +0.25 mM C10 [MCT(C10)] | Not measured | Increased in blood: βHB AcAc | NA | (39) |
| Traumatic brain injury patients | MCT (not specified) | 23 g/1000 Kcal. | following traumatic brain injury (TBI): 1 fasting (0 Kcal; median time 37 h), 2) intermediate nutrition (7.5 Kcal/kg; median time 55 h, 3) stable nutrition 15 Kcal/kg; median time 85 h. |
βHB
+
AcAc in Blood: 0.668 mM (fasting) 0.459 mM (intermediate nutrition) 0.129 mM (stable nutrition) βHB + AcAc in Brain: 0.0347 mM (fasting) 0.0173 mM (intermediate nutrition) 0.0131 mM (stable nutrition) |
C8 in Blood: 0.0012 mM (fasting) 0.0182 mM (intermediate nutrition) 0.0163 mM (stable nutrition) C10 in Blood: 0.0079 mM (fasting) 0.0187 mM (intermediate nutrition) 0.0152 mM (stable nutrition) C8 and C10 in Brain: ranged between 0.001 and 0.002 mM and increased significantly during nutrition. |
Not measured | Brain (overall median values and 10-90 percentiles): Total ketone bodies, 0.017 mM [6.1–62.6] Glutamate, 0.003 mM [0.9–24.2] Glucose, 1.1 mM [0.5–2.7] Pyruvate, 0.104 mM [65.5–166.8] Lactate, 2.9 mM [1.8–5.4] Lactate/pyruvate ratio 29 [20–46] | NA | (40) |
| Non-obese adults | MCT (61% C8 + 32% C10) | Formulated diet with 40% MCT or long-chain fat, 150% of estimated energy requirements | The subjects consumed the experimental diet (40% MCT or long-chain fat, 150% of estimated energy requirements) for 6 days. | Not measured | Not measured | NA | Increased: Triglycerides | MCT cause a significant increase in the hepatic synthesis of these fatty acids from MCFA through de novo synthesis and/or chain elongation and desaturation. | (41) |
| Healthy adults | MCT (65,8% C8 + 33,5 C10) | 70 g/day | 70 g of daily fat intake was replaced with MCT (or sunflower oil) for 2 weeks | Not measured | Not measured | NA | Increased: Total cholesterol LDL cholesterol Triglycerides Glucose | NA | (42) |
| Primary hypertriglyceridemic patients | MCT (72% C8 + 24% C10) | Ad libitum MCT:long-chain fat in different proportions | Subjects were given 500 ml bottles of oil (MCT and corn oil in different proportions) and asked to add it to their regular food. The amount of oil not consumed was measured each week. | Not measured | Not measured | NA | No change: HDL-cholesterol Triglycerides Increased: Total cholesterol | NA | (43) |
| Moderately overweight Chinese subjects with type 2 diabetes mellitus | MCT (not specified) | 18 g/day | MCT was administered as part of daily food intake for 90 days | Not measured | Not measured | NA |
Increased: Serum C-peptide Decreased: Waist circumference Body weight Insulin resistance Caloric intake No change: Glucose Insulin Triglycerides Total cholesterol HDL cholesterol LDL cholesterol Apolipoprotein A Apolipoprotein B |
NA | (44) |
| Children with epilepsy | MCT (not specified) | MCT diet (60% MCT) Modified MCT diet (30% MCT) | 24 h metabolic study was conducted in children 3 weeks after the diet was established. | MCT diet: Total plasma ketone bodies up to 2 mM Modified MCT diet: Total plasma ketone bodies up to 1 mM | Not measured | NA |
Both MCT diets: No changes: Total cholesterol HDL cholesterol LDL cholesterol Pyruvate Lactate Decreased: Alanine |
NA | (45) |
| MCI | MCT (60% C8 + 40% C10) | 30 g/day | MCT in lactose-free skim milk, twice a day, i.e. with breakfast and dinner, over a period of 6 months. | Blood: 0.8 mM βHB (after 6 months) | Blood: 5.5 mg/dl C8 (after 6 months) 5.0 mg/dl C10 (after 6 months) | Reported previously (21) |
Increased: Interleukin 8 βHB C8 C10 No change: Body mass index HbA1c (glycated hemoglobin) Glucose Insulin HDL, LDL, Total cholesterol Triglycerides C-reactive protein Granulocyte-macrophage colony-stimulating factor (GMCSF) Interferon gamma Interleukin 10 Interleukin 6 Interleukin 17 Interferon gamma-inducible protein 10 (IP10) Monocyte chemoattractant protein 1 (MCP1) Tumor necrosis factor-alpha (TNFα) Tumor necrosis factor-α receptor 1 (TNFR1) |
NA | (46) |
AcAc, acetoacetate; AD, Alzheimer's disease; ALT, alanine aminotransferase; APOE4, apolipoprotein 4; AST, aspartate transaminase; C10, capric acid; C8, caprylic acid; HDL, high density lipoprotein; LCFA, long-chain fatty acids; LDL, low density lipoprotein; MCFA, medium-chain fatty acids; MCI, Mild cognitive impairment; MCT, medium-chain triglycerides; MMSE, Mini-Mental State Examination; NA, not applicable; βHB, β-hydroxybutyrate.